Conformational changes of the amyloid beta-peptide (1-40) adsorbed on solid surfaces

NARCIS (Netherlands)

Giacomelli, CE; Norde, W

2005-01-01

The conformational change of the 39-43 residues of the amyloid beta-peptide (A beta) toward a beta-sheet enriched state promotes self-aggregation of the peptide molecules and constitutes the major peptide component of the amyloid plaques in Alzheimer patients. The crucial question behind the

Conformational changes of the amyloid beta-peptide (1-40) adsorbed on solid surfaces

NARCIS (Netherlands)

Giacomelli, C.E.; Norde, W.

2005-01-01

The conformational change of the 39-43 residues of the amyloid beta -peptide (A beta) toward a beta -sheet enriched state promotes self-aggregation of the peptide molecules and constitutes the major peptide component of the amyloid plaques in Alzheimer patients. The crucial question behind the

Beta-amyloid and cholinergic neurons

Czech Academy of Sciences Publication Activity Database

Doležal, Vladimír; Kašparová, Jana

2003-01-01

Roč. 28, 3-4 (2003), s. 499-506 ISSN 0364-3190 R&D Projects: GA ČR GA305/01/0283; GA AV ČR IAA5011206 Institutional research plan: CEZ:AV0Z5011922 Keywords : cholinergic neurons * AlzheimerŽs disease * beta-amyloid Subject RIV: FH - Neurology Impact factor: 1.511, year: 2003

Beta-secretase-cleaved amyloid precursor protein in Alzheimer brain: a morphologic study

DEFF Research Database (Denmark)

Sennvik, Kristina; Bogdanovic, N; Volkmann, Inga

2004-01-01

beta-amyloid (Abeta) is the main constituent of senile plaques seen in Alzheimer's disease. Abeta is derived from the amyloid precursor protein (APP) via proteolytic cleavage by proteases beta- and gamma-secretase. In this study, we examined content and localization of beta-secretase-cleaved APP...... the beta-sAPP immunostaining to be stronger and more extensive in gray matter in Alzheimer disease (AD) cases than controls. The axonal beta-sAPP staining was patchy and unevenly distributed for the AD cases, indicating impaired axonal transport. beta-sAPP was also found surrounding senile plaques...

Kinetically controlled thermal response of beta2-microglobulin amyloid fibrils.

Science.gov (United States)

Sasahara, Kenji; Naiki, Hironobu; Goto, Yuji

2005-09-23

Calorimetric measurements were carried out using a differential scanning calorimeter in the temperature range from 10 to 120 degrees C for characterizing the thermal response of beta2-microglobulin amyloid fibrils. The thermograms of amyloid fibril solution showed a remarkably large decrease in heat capacity that was essentially released upon the thermal unfolding of the fibrils, in which the magnitude of negative heat capacity change was not explicable in terms of the current accessible surface area model of protein structural thermodynamics. The heat capacity-temperature curve of amyloid fibrils prior to the fibril unfolding exhibited an unusual dependence on the fibril concentration and the heating rate. Particularly, the heat needed to induce the thermal response was found to be linearly dependent on the heating rate, indicating that its thermal response is under a kinetic control and precluding the interpretation in terms of equilibrium thermodynamics. Furthermore, amyloid fibrils of amyloid beta peptides also exhibited a heating rate-dependent exothermic process before the fibril unfolding, indicating that the kinetically controlled thermal response may be a common phenomenon to amyloid fibrils. We suggest that the heating rate-dependent negative change in heat capacity is coupled to the association of amyloid fibrils with characteristic hydration pattern.

Stereoselective determination of amino acids in beta-amyloid peptides and senile plaques.

Science.gov (United States)

Thorsén, G; Bergquist, J; Westlind-Danielsson, A; Josefsson, B

2001-06-01

A novel method for the determination of the enantiomeric composition of peptides is presented. In this paper, the focus has been on beta-amyloid peptides from deceased Alzheimer's disease patients. The peptides are hydrolyzed using mineral acid. The free amino acids are derivatized with the chiral reagent (+)- or (-)-1-(9-anthryl)-2-propyl chloroformate and subsequently separated using micellar electrokinetic chromatography (MEKC) and detected using laser-induced fluorescence (LIF) detection. The high separation efficiency of the MEKC-LIF system, yielding approximately 1 million theoretical plates/m for most amino acids, facilitates the simultaneous chiral determination of nine amino acids. The samples that have been analyzed were standard 1-40 beta-amyloid peptides, in vitro precipitated beta-amyloid fibrils, and human senile plaque samples.

The role of mutated amyloid beta 1-42 stimulating dendritic cells in a PDAPP transgenic mouse

Directory of Open Access Journals (Sweden)

LI Jia-lin

2012-06-01

Full Text Available Background Amyloid plaque is one of the pathological hallmarks of Alzheimer's disease (AD. Anti-beta-amyloid (Aβ immunotherapy is effective in removing brain Aβ, but has shown to be associated with detrimental effects. To avoid severe adverse effects such as meningoencephalitis induced by amyloid beta vaccine with adjuvant, and take advantage of amyloid beta antibody's therapeutic effect on Alzheimer's disease sufficiently, our group has developed a new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating dendritic cells (DC. Our previous work has confirmed that DC vaccine can induce adequate anti-amyloid beta antibody in PDAPP Tg mice safely and efficiently. The DC vaccine can improve impaired learning and memory in the Alzheimer's animal model, and did not cause microvasculitis, microhemorrhage or meningoencephalitis in the animal model. However, the exact mechanism of immunotherapy which reduces Aβ deposition remains unknown. In this report, we studied the mechanism of the vaccine, thinking that this may have implications for better understanding of the pathogenesis of Alzheimer's disease. Methods A new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating DC which were obtained from C57/B6 mouse bone marrow was developed. Amyloid beta with Freund's adjuvant was inoculated at the same time to act as positive control. After the treatment was done, the samples of brains were collected, fixed, cut. Immunohistochemical staining was performed to observe the expression of the nuclear hormone liver X receptor (LXR, membrane-bound protein tyrosine phosphatase (CD45, the ATP-binding cassette family of active transporters (ABCA1, receptor for advanced glycation end products (RAGE, β-site APP-cleaving enzyme (BACE and Aβ in mouse brain tissue. Semi-quantitative analysis was used to defect CA1, CA2, CA3, DG, Rad in hippocampus region and positive neuron in cortex region. Results Aβ was significantly reduced in the

PEGylated nanoparticles bind to and alter amyloid-beta peptide conformation

DEFF Research Database (Denmark)

Brambilla, Davide; Verpillot, Romain; Le Droumaguet, Benjamin

2012-01-01

We have demonstrated that the polyethylene glycol (PEG) corona of long-circulating polymeric nanoparticles (NPs) favors interaction with the amyloid-beta (Aß(1-42)) peptide both in solution and in serum. The influence of PEGylation of poly(alkyl cyanoacrylate) and poly(lactic acid) NPs on the int......We have demonstrated that the polyethylene glycol (PEG) corona of long-circulating polymeric nanoparticles (NPs) favors interaction with the amyloid-beta (Aß(1-42)) peptide both in solution and in serum. The influence of PEGylation of poly(alkyl cyanoacrylate) and poly(lactic acid) NPs...

Evidence for novel beta-sheet structures in Iowa mutant beta-amyloid fibrils.

Science.gov (United States)

Tycko, Robert; Sciarretta, Kimberly L; Orgel, Joseph P R O; Meredith, Stephen C

2009-07-07

Asp23-to-Asn mutation within the coding sequence of beta-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-Abeta40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-Abeta40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10(-3) min(-1) and 1.07 x 10(-4) min(-1) for D23N-Abeta40 and the wild-type peptide WT-Abeta40, respectively) and without a lag phase. Electron microscopy shows that D23N-Abeta40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-beta pattern, with a sharp reflection at 4.7 A and a broad reflection at 9.4 A, which is notably smaller than the value for WT-Abeta40 fibrils (10.4 A). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-Abeta40 fibrils containing the in-register, parallel beta-sheet structure commonly found in WT-Abeta40 fibrils and most other amyloid fibrils. Antiparallel beta-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through (13)C-(13)C and (15)N-(13)C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-Abeta40 fibrils and the unusual vasculotropic clinical picture in these patients.

Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

DEFF Research Database (Denmark)

Weiner, H L; Lemere, C A; Maron, R

2000-01-01

Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated ......Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease...... cerebral Abeta deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD....

Low background and high contrast PET imaging of amyloid-{beta} with [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in Alzheimer's disease patients

Energy Technology Data Exchange (ETDEWEB)

Forsberg, Anton; Andersson, Jan; Varnaes, Katarina; Halldin, Christer [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Jureus, Anders; Swahn, Britt-Marie; Sandell, Johan; Julin, Per; Svensson, Samuel [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Cselenyi, Zsolt; Schou, Magnus; Johnstroem, Peter; Farde, Lars [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Karolinska Hospital, AstraZeneca Translational Sciences Centre, PET CoE, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Eriksdotter, Maria; Freund-Levi, Yvonne [Karolinska Institutet, Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Karolinska University Hospital, Department of Geriatric Medicine, Stockholm (Sweden); Jeppsson, Fredrik [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Karolinska Institutet, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Stockholm (Sweden)

2013-04-15

The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-{beta} in Alzheimer's disease (AD). In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-{beta} PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in three healthy control subjects and seven AD patients. AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-{beta}. [{sup 3}H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [{sup 11}C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [{sup 11}C]AZD2995 was greater in areas with lower amyloid-{beta} load, e.g. the hippocampus. Both AZD2995 and AZD2184 detect amyloid-{beta} with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [{sup 11}C]AZD2184 seems to be an amyloid-{beta} radioligand with higher uptake and better group separation when compared to [{sup 11}C]AZD2995. However, the very low nonspecific binding of [{sup 11}C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-{beta}. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy. (orig.)

Minocycline does not affect amyloid beta phagocytosis by human microglial cells

NARCIS (Netherlands)

Familian, Atoosa; Eikelenboom, Piet; Veerhuis, Robert

2007-01-01

Activated microglia accumulate in amyloid beta (Abeta) plaques containing amyloid associated factors SAP and C1q in Alzheimer's disease (AD) brain. Microglia are involved in AD pathogenesis by promoting Abeta plaque formation and production of pro-inflammatory cytokines. On the other hand,

Microglia kill amyloid-beta1-42 damaged neurons by a CD14-dependent process

NARCIS (Netherlands)

Bate, Clive; Veerhuis, Robert; Eikelenboom, Piet; Williams, Alun

2004-01-01

Activated microglia are closely associated with neuronal damage in Alzheimer's disease. In the present study, neurons exposed to low concentrations of amyloid-beta1-42, a toxic fragment of the amyloid-beta protein, were killed by microglia in a process that required cell-cell contact. Pre-treating

alpha7 Nicotinic acetylcholine receptor knockout selectively enhances ethanol-, but not beta-amyloid-induced neurotoxicity.

Science.gov (United States)

de Fiebre, Nancyellen C; de Fiebre, Christopher M

2005-01-03

The alpha7 subtype of nicotinic acetylcholine receptor (nAChR) has been implicated as a potential site of action for two neurotoxins, ethanol and the Alzheimer's disease related peptide, beta-amyloid. Here, we utilized primary neuronal cultures of cerebral cortex from alpha7 nAChR null mutant mice to examine the role of this receptor in modulating the neurotoxic properties of subchronic, "binge" ethanol and beta-amyloid. Knockout of the alpha7 nAChR gene selectively enhanced ethanol-induced neurotoxicity in a gene dosage-related fashion. Susceptibility of cultures to beta-amyloid induced toxicity, however, was unaffected by alpha7 nAChR gene null mutation. Further, beta-amyloid did not inhibit the binding of the highly alpha7-selective radioligand, [(125)I]alpha-bungarotoxin. On the other hand, in studies in Xenopus oocytes ethanol efficaciously inhibited alpha7 nAChR function. These data suggest that alpha7 nAChRs modulate the neurotoxic effects of binge ethanol, but not the neurotoxicity produced by beta-amyloid. It is hypothesized that inhibition of alpha7 nAChRs by ethanol provides partial protection against the neurotoxic properties of subchronic ethanol.

Levels of amyloid-beta-42 and CSF pressure are directly related in patients with Alzheimer's disease.

Science.gov (United States)

Schirinzi, Tommaso; Di Lazzaro, Giulia; Sancesario, Giulia Maria; Colona, Vito Luigi; Scaricamazza, Eugenia; Mercuri, Nicola Biagio; Martorana, Alessandro; Sancesario, Giuseppe

2017-12-01

Experimental data suggest that the cerebrospinal fluid (CSF) dynamic is involved in the clearance of beta-amyloid, a key event in the pathogenesis of Alzheimer's disease (AD). At this regard no evidence still exists in vivo. In this study we explored the relationships between CSF pressure and AD pathology, as measured with CSF core biomarkers. We enrolled 16 patients with probable AD and 21 controls, collecting demographics, clinical data, CSF opening pressure and CSF levels of beta-amyloid-42 fragment (Aβ42), total-tau (t-tau), phosphorylated-tau-181 (p-tau), albumin and albumin ratio. Differences between the groups were calculated with non-parametric tests, while correlations among all parameters were separately calculated with Spearman's test in each group. The groups significantly differed in biomarkers' concentration with lower Aβ42, and higher t-tau and p-tau in AD patients. Moreover, CSF pressure was significantly lower in AD group (11.0 ± 2.8 vs. 13.3 ± 3.0 mmHg, p < 0.05) and directly correlated with Aβ42 levels (R = 0.512; p < 0.05), but not with other biomarkers or parameters. No significant correlations emerged for biomarkers in control group. AD patients exhibit low CSF pressure whose values are directly and selectively related to CSF Aβ42 levels. This interesting correlation may confirm in vivo the association between CSF dynamic and beta-amyloid metabolism occurring in AD.

Absence of beta-amyloid in cortical cataracts of donors with and without Alzheimer's disease.

Science.gov (United States)

Michael, Ralph; Rosandić, Jurja; Montenegro, Gustavo A; Lobato, Elvira; Tresserra, Francisco; Barraquer, Rafael I; Vrensen, Gijs F J M

2013-01-01

Eye lenses from human donors with and without Alzheimer's disease (AD) were studied to evaluate the presence of amyloid in cortical cataract. We obtained 39 lenses from 21 postmortem donors with AD and 15 lenses from age-matched controls provided by the Banco de Ojos para Tratamientos de la Ceguera (Barcelona, Spain). For 17 donors, AD was clinically diagnosed by general physicians and for 4 donors the AD diagnosis was neuropathologically confirmed. Of the 21 donors with AD, 6 had pronounced bilateral cortical lens opacities and 15 only minor or no cortical opacities. As controls, 7 donors with pronounced cortical opacities and 8 donors with almost transparent lenses were selected. All lenses were photographed in a dark field stereomicroscope. Histological sections were analyzed using a standard and a more sensitive Congo red protocol, thioflavin staining and beta-amyloid immunohistochemistry. Brain tissue from two donors, one with cerebral amyloid angiopathy and another with advanced AD-related changes and one cornea with lattice dystrophy were used as positive controls for the staining techniques. Thioflavin, standard and modified Congo red staining were positive in the control brain tissues and in the dystrophic cornea. Beta-amyloid immunohistochemistry was positive in the brain tissues but not in the cornea sample. Lenses from control and AD donors were, without exception, negative after Congo red, thioflavin, and beta-amyloid immunohistochemical staining. The results of the positive control tissues correspond well with known observations in AD, amyloid angiopathy and corneas with lattice dystrophy. The absence of staining in AD and control lenses with the techniques employed lead us to conclude that there is no beta-amyloid in lenses from donors with AD or in control cortical cataracts. The inconsistency with previous studies of Goldstein et al. (2003) and Moncaster et al. (2010), both of which demonstrated positive Congo red, thioflavin, and beta-amyloid

Human amyloid beta protein gene locus: HaeIII RFLP

Energy Technology Data Exchange (ETDEWEB)

Taylor, J E; Gonzalez-DeWhitt, P A; Fuller, F; Cordell, B; Frossard, P M [California Biotechnology Inc., Mountain View (USA); Tinklenberg, J R; Davies, H D; Eng, L F; Yesavage, J A [Stanford Univ. School of Medicine, Palo Alto, CA (USA)

1988-07-25

A 2.2 kb EcoRI-EcoRI fragment from the 5{prime} end of the human amyloid beta protein cDNA was isolated from a human fibroblast cDNA library and subcloned into pGEM3. HaeIII (GGCC) detects 6 invariant bands at 0.5 kb, 1.0 kb, 1.1 kb, 1.3 kb, 1.4 kb and 1.6 kb and a two-allele polymorphism with bands at either 1.9 kb or 2.1 kb. Its frequency was studied in 50 North Americans. Human amyloid beta protein gene mapped to the long arm of chromosome 21 (21q11.2-21q21) by Southern blot analysis of human-rodent somatic cell hybrids. Co-dominant segregation was observed in two families (15 individuals).

Influence of hydrophobic Teflon particles on the structure of amyloid beta-peptide

NARCIS (Netherlands)

Giacomelli, C.E.; Norde, W.

2003-01-01

The amyloid beta-protein (Abeta) constitutes the major peptide component of the amyloid plaque deposits of Alzheimer's disease in humans. The Abeta changes from a nonpathogenic to a pathogenic conformation resulting in self-aggregation and deposition of the peptide. It has been established that

Quantification of amyloid-beta 40 in cerebrospinal fluid

NARCIS (Netherlands)

Verwey, N.A.; Veerhuis, R.; Twaalfhoven, H.A.M.; Wouters, D.; Hoozemans, J.J.M.; Bollen, Y.J.M.; Killestein, J.; Bibl, M.; Wiltfang, J.; Hack, C.E.; Scheltens, P.; Blankenstein, M.A.

2009-01-01

Background: Truncated forms and full-length forms of the amyloid-beta 40 (Aβ40) are key molecules in the pathogenesis of dementia, and are detectable in CSF. Reliable methods to detect these biomarkers in CSF are of great importance for understanding the disease mechanisms and for diagnostic

Beta-amyloid, cholinergní neurony a Alzheimerova choroba

Czech Academy of Sciences Publication Activity Database

Kašparová, Jana; Doležal, Vladimír

2002-01-01

Roč. 51, č. 2 (2002), s. 82-94 ISSN 0009-0557 R&D Projects: GA MZd NF5183; GA ČR GA305/01/0283 Institutional research plan: CEZ:AV0Z5011922 Keywords : Alzheimer 's disease * beta-amyloid * cholinergic neurons Subject RIV: FR - Pharmacology ; Medidal Chemistry

Neuroinflammation and Complexes of 17 beta-Hydroxysteroid Dehydrogenase type 10-Amyloid beta in Alzheimer's Disease

Czech Academy of Sciences Publication Activity Database

Krištofíková, Z.; Řípová, D.; Bartoš, A.; Bocková, Markéta; Hegnerová, Kateřina; Říčný, J.; Čechová, L.; Vrajová, M.; Homola, Jiří

2013-01-01

Roč. 10, č. 2 (2013), s. 165-173 ISSN 1567-2050 R&D Projects: GA MZd(CZ) NT11225 Institutional support: RVO:67985882 Keywords : Amyloid beta * mitochondrial enzyme * Alzheimer 's disease Subject RIV: JB - Sensors, Measurment, Regulation Impact factor: 3.796, year: 2013

Effects of Memantine and Oleocanthal on Alzheimer's Disease

Science.gov (United States)

Houston, Mariyam; Bonacum, Jason; Zhang, Guoping

2014-03-01

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by accumulation of neuritic plaques composed of amyloid- β (A β) proteins and neurofibrillary tangles composed of tau proteins. Although there is no known cure for AD, the symptoms can be treated with a drug called memantine. Memantine acts an NMDAR antagonist by inhibiting the action of the NMDA receptor. Recently, Oleocanthal, a phenolic molecule that is found in extra virgin olive oil, has been linked to reduced risk of AD. Though the mechanism by which Oleocanthal plays in reducing the risk of AD is not completely understood, recent studies have shown that Oleocanthal somehow inhibits the formation of the neurofibrillary tangles and reduces the formation of A β senile plaques. Our first-principles calculation, based on Gaussian03 program, shows that in the M2 segment, memantine binds to serine, but ketamine binds to glycine. This may explain their different effects, despite the fact that they are both NMDAR antagonists. Using the same method, we also investigate how Oleocanthal binds to the peptides by comparing the relative energies of each of the structures. Our results may help better understand the mechanism by which Oleocanthal decreases the chances of developing AD. U.S. DOE, DE-FG02-06ER46304; ISU SURE program; University of the CSRC; DEPT of Chemistry and Physics.

Organotypic vibrosections from whole brain adult Alzheimer mice (overexpressing amyloid-precursor-protein with the Swedish-Dutch-Iowa mutations as a model to study clearance of beta-amyloid plaques

Directory of Open Access Journals (Sweden)

Christian eHumpel

2015-04-01

Full Text Available Alzheimer´s disease is a severe neurodegenerative disorder of the brain, pathologically characterized by extracellular beta-amyloid plaques, intraneuronal Tau inclusions, inflammation, reactive glial cells, vascular pathology and neuronal cell death. The degradation and clearance of beta-amyloid plaques is an interesting therapeutic approach, and the proteases neprilysin (NEP, insulysin and matrix metalloproteinases (MMP are of particular interest. The aim of this project was to establish and characterize a simple in vitro model to study the degrading effects of these proteases. Organoytpic brain vibrosections (120 µm thick were sectioned from adult (9 month old wildtype and transgenic mice (expressing amyloid precursor protein (APP harboring the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations; APP_SDI and cultured for 2 weeks. Plaques were stained by immunohistochemistry for beta-amyloid and Thioflavin S. Our data show that plaques were evident in 2 week old cultures from 9 month old transgenic mice. These plaques were surrounded by reactive GFAP+ astroglia and Iba1+ microglia. Incubation of fresh slices for 2 weeks with 1-0.1-0.01 µg/ml of NEP, insulysin, MMP-2 or MMP-9 showed that NEP, insulysin and MMP-9 markedly degradeded beta-amyloid plaques but only at the highest concentration. Our data provide for the first time a potent and powerful living brain vibrosection model containing a high number of plaques, which allows to rapidly and simply study the degradation and clearance of beta-amyloid plaques in vitro.

Molecular simulations of beta-amyloid protein near hydrated lipids (PECASE).

Energy Technology Data Exchange (ETDEWEB)

Thompson, Aidan Patrick; Han, Kunwoo (Texas A& M University, College Station, TX); Ford, David M. (Texas A& M University, College Station, TX)

2005-12-01

We performed molecular dynamics simulations of beta-amyloid (A{beta}) protein and A{beta} fragment(31-42) in bulk water and near hydrated lipids to study the mechanism of neurotoxicity associated with the aggregation of the protein. We constructed full atomistic models using Cerius2 and ran simulations using LAMMPS. MD simulations with different conformations and positions of the protein fragment were performed. Thermodynamic properties were compared with previous literature and the results were analyzed. Longer simulations and data analyses based on the free energy profiles along the distance between the protein and the interface are ongoing.

Calcium ionophore A23187 specifically decreases the secretion of beta-secretase cleaved amyloid precursor protein during apoptosis in primary rat cortical cultures

DEFF Research Database (Denmark)

Sennvik, K; Benedikz, Eirikur; Fastbom, J

2001-01-01

Alzheimer's disease (AD) is characterized by the degeneration and loss of neurons, intracellular neurofibrillary tangles and the accumulation of extracellular senile plaques consisting mainly of beta-amyloid (A beta). A beta is generated from the amyloid precursor protein (APP) by sequential beta...

Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation

NARCIS (Netherlands)

Leuner, K.; Schutt, T.; Kurz, C.; Eckert, S.H.; Schiller, C.; Occhipinti, A.; Mai, S.; Jendrach, M.; Eckert, G.P.; Kruse, S.E.; Palmiter, R.D.; Brandt, U.; Drose, S.; Wittig, I.; Willem, M.; Haass, C.; Reichert, A.S.; Muller, W.E.

2012-01-01

AIMS: Intracellular amyloid beta (Abeta) oligomers and extracellular Abeta plaques are key players in the progression of sporadic Alzheimer's disease (AD). Still, the molecular signals triggering Abeta production are largely unclear. We asked whether mitochondrion-derived reactive oxygen species

Spatial distribution of diffuse, primitive, and classic amyloid-beta deposits and blood vessels in the upper laminae of the frontal cortex in Alzheimer disease.

Science.gov (United States)

Armstrong, R A; Cairns, N J; Lantos, P L

1998-12-01

The spatial distribution of the diffuse, primitive, and classic amyloid-beta deposits was studied in the upper laminae of the superior frontal gyrus in cases of sporadic Alzheimer disease (AD). Amyloid-beta-stained tissue was counterstained with collagen IV to determine whether the spatial distribution of the amyloid-beta deposits along the cortex was related to blood vessels. In all patients, amyloid-beta deposits and blood vessels were aggregated into distinct clusters and in many patients, the clusters were distributed with a regular periodicity along the cortex. The clusters of diffuse and primitive deposits did not coincide with the clusters of blood vessels in most patients. However, the clusters of classic amyloid-beta deposits coincided with those of the large diameter (>10 microm) blood vessels in all patients and with clusters of small-diameter (upper cortical laminae.

Mapping of the gene encoding the. beta. -amyloid precursor protein and its relationship to the Down syndrome region of chromosome 21

Energy Technology Data Exchange (ETDEWEB)

Patterson, D.; Gardiner, K.; Kao, F.T.; Tanzi, R.; Watkins, P.; Gusella, J.F. (Eleanor Roosevelt Institute for Cancer Research, Denver, CO (USA))

1988-11-01

The gene encoding the {beta}-amyloid precursor protein has been assigned to human chromosome 21, as has a gene responsible for at least some cases of familial Alzheimer disease. Linkage studies strongly suggest that the {beta}-amyloid precursor protein and the product corresponding to familial Alzheimer disease are from two genes, or at least that several million base pairs of DNA separate the markers. The precise location of the {beta}-amyloid precursor protein gene on chromosome 21 has not yet been determined. Here the authors show, by using a somatic-cell/hybrid-cell mapping panel, in situ hybridization, and transverse-alternating-field electrophoresis, that the {beta}-amyloid precursor protein gene is located on chromosome 21 very near the 21q21/21q/22 border and probably within the region of chromosome 21 that, when trisomic, results in Down syndrome.

Development and characterization of a TAPIR-like mouse monoclonal antibody to amyloid-beta.

Science.gov (United States)

Wang, Jun; Hara, Hideo; Makifuchi, Takao; Tabira, Takeshi

2008-06-01

Tissue amyloid plaque immuno-reactive (TAPIR) antibody was better related to the effect of immunotherapy in Alzheimer's disease (AD) than ELISA antibody. Here we used a hybridoma technique to develop a TAPIR-like anti-human amyloid-beta (Abeta) mouse monoclonal antibody. The obtained monoclonal antibody, 3.4A10, was an IgG2b isotype and recognized N-terminal portion of Abeta1-42 without binding denatured or native amyloid-beta protein precursor. It had higher affinity to Abeta1-42 than to Abeta1-40 by Biacore affinity analysis and stained preferably the peripheral part of senile plaques and recognized the plaque core less than 4G8. It inhibited the Abeta1-42 fibril formation as well as degraded pre-aggregated Abeta1-42 peptide in a thioflavin T fluorescence spectrophotometry assay. The in vivo studies showed that 3.4A10 treatment decreased amyloid burden compared to the control group and significantly reduced Abeta42 levels rather than Abeta40 levels in brain lysates as well as the Abeta*56 oligomer (12mer) in TBS fraction of the brain lysates. 3.4A10 entered brain and decorated some plaques, which is surrounded by more Iba1-positive microglia. 3.4A10 therapy did not induce lymphocytic infiltration and obvious increase in microhemorrhage. We conclude that 3.4A10 is a TAPIR-like anti-human amyloid monoclonal antibody, and has a potential of therapeutic application for AD.

Adherence to the Mediterranean Diet Is not Related to Beta-Amyloid Deposition: Data from the Women's Healthy Ageing Project.

Science.gov (United States)

Hill, E; Szoeke, C; Dennerstein, L; Campbell, S; Clifton, P

2018-01-01

Research has indicated the neuroprotective potential of the Mediterranean diet. Adherence to the Mediterranean diet has shown preventative potential for Alzheimer's disease incidence and prevalence, yet few studies have investigated the impact of Mediterranean diet adherence on the hallmark protein; beta-amyloid. To investigate the association between Mediterranean diet adherence and beta-amyloid deposition in a cohort of healthy older Australian women. This study was a cross-sectional investigation of participants from the longitudinal, epidemiologically sourced Women's Healthy Ageing Project which is a follow-up of the Melbourne Women's Midlife Health Project. Assessments were conducted at the Centre for Medical Research, Royal Melbourne Hospital in Melbourne, Australia. F-18 Florbetaben positron emission tomography scanning was conducted at the Austin Centre for PET in Victoria, Australia. One hundred and eleven Women's Healthy Ageing Project participants were included in the study. Mediterranean diet adherence scores for all participants were calculated from the administration of a validated food frequency questionnaire constructed by the Cancer Council of Victoria. Beta-amyloid deposition was measured using positron emission tomography standardised uptake value ratios. Gamma regression analysis displayed no association between Mediterranean diet adherence and beta-amyloid deposition. This result was consistent across APOE-ε4 +/- cohorts and with the inclusion of covariates such as age, education, body mass index and cognition. This study found no association between adherence to the Mediterranean diet and beta-amyloid deposition in a cohort of healthy Australian women.

The Aggregation Potential of the 1-15-and 1-16-Fragments of the Amyloid beta Peptide and Their Influence on the Aggregation of A beta 40

NARCIS (Netherlands)

Shabestari, M.; Plug, T.; Motazacker, M. M.; Meeuwenoord, N. J.; Filippov, D. V.; Meijers, J. C. M.; Huber, M.

2013-01-01

The aggregation of amyloid beta (A beta) peptide is important in Alzheimer's disease. Shorter A beta fragments may reduce A beta's cytotoxicity and are used in diagnostics. The aggregation of A beta 16 is controversial; Liu et al. (J. Neurosci. Res. 75:162-171, 2004) and Liao et al. (FEBS Lett.

DNA polymerase-beta is expressed early in neurons of Alzheimer's disease brain and is loaded into DNA replication forks in neurons challenged with beta-amyloid

NARCIS (Netherlands)

Copani, Agata; Hoozemans, Jeroen J. M.; Caraci, Filippo; Calafiore, Marco; van Haastert, Elise S.; Veerhuis, Robert; Rozemuller, Annemieke J. M.; Aronica, Eleonora; Sortino, Maria Angela; Nicoletti, Ferdinando

2006-01-01

Cultured neurons exposed to synthetic beta-amyloid (Abeta) fragments reenter the cell cycle and initiate a pathway of DNA replication that involves the repair enzyme DNA polymerase-beta (DNA pol-beta) before undergoing apoptotic death. In this study, by performing coimmunoprecipitation experiments

[Noopept improves the spatial memory and stimulates prefibrillar beta-amyloid(25-35) antibody production in mice].

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Bobkova, N V; Gruden', M A; Samokhin, A N; Medvinskaia, N I; Morozova-Roch, L; Uudasheva, T A; Ostrovskaia, R U; Seredinin, S B

2005-01-01

The effects of the novel proline-containing nootropic and neuroprotective dipeptide noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were studied on NMRI mice upon olfactory bulbectomy, which had been previously shown to imitate the main morphological and biochemical signs of Alzheimer's disease (AD). The spatial memory was assessed using the Morris (water maze) test; the immunological status was characterized by ELISA with antibodies to prefibrillar beta-amyloid(25-35), S100b protein, and protofilaments of equine lysozyme, which are the molecular factors involved in the pathogenesis of AD. The control (sham-operated) animals during the Morris test preferred a sector where the safety platform was placed during the learning session. Bulbectomized animals treated with saline failed to recognize this sector, while bulbectomized animals treated with noopept (0.01 mg/kg for 21 days) restored this predominance, thus demonstrating the improvement of the spatial memory. These animals also demonstrated an increase in the level of antibodies to beta-amyloid(25-35)--the effect, which was more pronounced in the sham-operated than in bulbectomized mice. The latter demonstrated a profound decrease of immunological reactivity in a large number of tests. Noopept, stimulating the production of antibodies to beta-amyloid(25-35), can attenuate the well-known neurotoxic effects of beta-amyloid. The obtained data on the mnemotropic and immunostimulant effects noopept are indicative of good prospects for the clinical usage of this drug in the therapy of patients with neurodegenerative diseases.

Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.

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Payel Das

Full Text Available Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17-42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.

Calcium-dependent and -independent binding of the pentraxin serum amyloid P component to glycosaminoglycans and amyloid proteins

DEFF Research Database (Denmark)

Danielsen, B; Sørensen, I J; Nybo, Mads

1997-01-01

precursor protein beta2M was observed. This binding was also enhanced at slightly acid pH, most pronounced at pH 5.0. The results of this study indicate that SAP can exhibit both Ca2(+)-dependent and -independent binding to ligands involved in amyloid fibril formation and that the binding is enhanced under...... and beta2M) by ELISA. An increase in the dose-dependent binding of SAP to heparan sulfate, AA-protein and beta2M was observed as the pH decreased from 8.0 to 5.0. Furthermore, a lower, but significant Ca2(+)-independent binding of SAP to heparan sulfate, dermatan sulfate, AA protein and the amyloid...

Insulin inhibits amyloid beta-induced cell death in cultured human brain pericytes

NARCIS (Netherlands)

Rensink, Annemieke A M; Otte-Höller, Irene; de Boer, Roelie; Bosch, Remko R; ten Donkelaar, Hans J; de Waal, Robert M W; Verbeek, Marcel M; Kremer, Berry

Amyloid-beta (Abeta) deposition in the cerebral arterial and capillary walls is one of the characteristics of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type. In vitro, Abeta1-40, carrying the "Dutch" mutation (DAbeta1-40), induced reproducible degeneration of

Brain-predicted age in Down syndrome is associated with beta amyloid deposition and cognitive decline.

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Cole, James H; Annus, Tiina; Wilson, Liam R; Remtulla, Ridhaa; Hong, Young T; Fryer, Tim D; Acosta-Cabronero, Julio; Cardenas-Blanco, Arturo; Smith, Robert; Menon, David K; Zaman, Shahid H; Nestor, Peter J; Holland, Anthony J

2017-08-01

Individuals with Down syndrome (DS) are more likely to experience earlier onset of multiple facets of physiological aging. This includes brain atrophy, beta amyloid deposition, cognitive decline, and Alzheimer's disease-factors indicative of brain aging. Here, we employed a machine learning approach, using structural neuroimaging data to predict age (i.e., brain-predicted age) in people with DS (N = 46) and typically developing controls (N = 30). Chronological age was then subtracted from brain-predicted age to generate a brain-predicted age difference (brain-PAD) score. DS participants also underwent [ 11 C]-PiB positron emission tomography (PET) scans to index the levels of cerebral beta amyloid deposition, and cognitive assessment. Mean brain-PAD in DS participants' was +2.49 years, significantly greater than controls (p brain-PAD was associated with the presence and the magnitude of PiB-binding and levels of cognitive performance. Our study indicates that DS is associated with premature structural brain aging, and that age-related alterations in brain structure are associated with individual differences in the rate of beta amyloid deposition and cognitive impairment. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Multiscale Molecular Dynamics Simulations of Beta-Amyloid Interactions with Neurons

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Qiu, Liming; Vaughn, Mark; Cheng, Kelvin

2012-10-01

Early events of human beta-amyloid protein interactions with cholesterol-containing membranes are critical to understanding the pathogenesis of Alzheimer's disease (AD) and to exploring new therapeutic interventions of AD. Atomistic molecular dynamics (AMD) simulations have been extensively used to study the protein-lipid interaction at high atomic resolutions. However, traditional MD simulations are not efficient in sampling the phase space of complex lipid/protein systems with rugged free energy landscapes. Meanwhile, coarse-grained MD (CGD) simulations are efficient in the phase space sampling but suffered from low spatial resolutions and from the fact that the energy landscapes are not identical to those of the AMD. Here, a multiscale approach was employed to simulate the protein-lipid interactions of beta-amyloid upon its release from proteolysis residing in the neuronal membranes. We utilized a forward (AMD to CGD) and reverse (CGD-AMD) strategy to explore new transmembrane and surface protein configuration and evaluate the stabilization mechanisms by measuring the residue-specific protein-lipid or protein conformations. The detailed molecular interactions revealed in this multiscale MD approach will provide new insights into understanding the early molecular events leading to the pathogenesis of AD.

Clinical Benefits of Memantine Treatment for Alzheimer's Disease in the Okayama Memantine Study II (OMS II).

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Matsuzono, Kosuke; Yamashita, Toru; Ohta, Yasuyuki; Hishikawa, Nozomi; Koike, Makoto; Sato, Kota; Kono, Syoichiro; Deguchi, Kentaro; Nakano, Yumiko; Abe, Koji

2015-01-01

The clinical benefits of memantine, depending on the baseline cognitive and affective conditions in real world dementia clinics, have not been completely examined. We performed the "Okayama Memantine Study II (OMS II)" to retrospectively evaluate the clinical effects of memantine monotherapy (n = 38) in Alzheimer's disease (AD) patients using seven batteries to assess dementia at the baseline, at 3, 6, and 12 months. Additionally, we divided 163 AD patients treated with memantine into two subgroups depending on the baseline cognitive score of the Mini-Mental State Examination (MMSE): the MMSE OMS II showed that memantine monotherapy improved BPSD until 12 months. The higher baseline cognitive subgroup (MMSE ≥15) and the worse baseline BPSD subgroup were expected to show better effects with memantine.

Memantine for dementia?

Science.gov (United States)

2003-10-01

Memantine (Ebixa--Lundbeck Ltd), an oral medicine, is available in the UK for treating "patients with moderately severe to severe Alzheimer's disease". It differs from other licensed dementia medicines in that it is an N-methyl-D-aspartate (NMDA) receptor antagonist. The company has claimed that, with memantine therapy, "improvements in activities of daily living help patients to maintain a degree of independence and be easier to care for, potentially avoiding the need for nursing home care". We assess the efficacy of memantine for dementia and discuss its place in the management of patients with Alzheimer's disease.

Interaction between amyloid beta peptide and an aggregation blocker peptide mimicking islet amyloid polypeptide.

Directory of Open Access Journals (Sweden)

Nasrollah Rezaei-Ghaleh

Full Text Available Assembly of amyloid-beta peptide (Aβ into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in Alzheimer's disease (AD and interfering with Aβ aggregation is an important strategy in the development of novel therapeutic approaches. Prior studies have shown that the double N-methylated analogue of islet amyloid polypeptide (IAPP IAPP-GI, which is a conformationally constrained IAPP analogue mimicking a non-amyloidogenic IAPP conformation, is capable of blocking cytotoxic self-assembly of Aβ. Here we investigate the interaction of IAPP-GI with Aβ40 and Aβ42 using NMR spectroscopy. The most pronounced NMR chemical shift changes were observed for residues 13-20, while residues 7-9, 15-16 as well as the C-terminal half of Aβ--that is both regions of the Aβ sequence that are converted into β-strands in amyloid fibrils--were less accessible to solvent in the presence of IAPP-GI. At the same time, interaction of IAPP-GI with Aβ resulted in a concentration-dependent co-aggregation of Aβ and IAPP-GI that was enhanced for the more aggregation prone Aβ42 peptide. On the basis of the reduced toxicity of the Aβ peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects Aβ into nontoxic "off-pathway" aggregates.

The proton-pump inhibitor lansoprazole enhances amyloid beta production.

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Badiola, Nahuai; Alcalde, Victor; Pujol, Albert; Münter, Lisa-Marie; Multhaup, Gerd; Lleó, Alberto; Coma, Mireia; Soler-López, Montserrat; Aloy, Patrick

2013-01-01

A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. We found that lansoprazole enhances Aβ37, Aβ40 and Aβ42 production and lowers Aβ38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Aβ40 levels in brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.

Management of moderate to severe Alzheimer’s disease: Focus on memantine

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Evangelyn Dominguez

2011-12-01

Full Text Available Alzheimer’s disease (AD is the most common form of dementia, and one of the principal causes leading to death around the world. It is a progressive neurodegenerative disorder that still remains without definite cure. Memantine, a licensed AD drug, is an open-channel and partial trapping blocker that functions as a potent NMDA receptor antagonist, even at low concentrations. Aside from being uncompetitive, it also allows near-normal physiological NMDA receptor activity throughout the brain even with high glutamate concentrations, making it more reliable and tolerable than other AD-targeted drugs. It has also been found to be effective, safe, and well-tolerated in animal models as well as patients with moderate-to-severe AD. Aside from NMDA receptor antagonism, numerous studies have reported that memantine can also affect dopamine receptors, block excessive calcium influx and production of reactive oxygen species (ROS induced by Aβ oligomers, and inhibit the internal ribosome entry site (IRES, thus preventing the expression of the amyloid precursor and tau proteins which are considered as early indicators of Alzheimer's.

Anti-amyloid treatments in Alzheimer's disease.

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Sapra, Mamta; Kim, Kye Y

2009-06-01

Alzheimer's disease is one of the most challenging threats to the healthcare system in society. One of the main characteristic of Alzheimer's disease (AD) pathology is formation of amyloid plaques from accumulation of amyloid beta peptide. The therapeutic agents that are currently available for AD including acetylcholinesterase inhibitors (AchEIs) and the N-methyl-D-aspartate (NMDA) antagonist are focused on improving the symptoms and do not revert the progression of the disease. This limitation coupled with the burgeoning increase in the prevalence of AD and resultant impact on healthcare economics calls for more substantial treatments for AD. According to the leading amyloid hypothesis, cleavage of amyloid precursor protein to release amyloid beta peptide is the critical event in pathogenesis of Alzheimer's disease. Recently treatment strategies have been focused on modifying the formation, clearance and accumulation of neurotoxic amyloid beta peptide. This article reviews different therapeutic approaches that have been investigated to target amyloid beta ranging from secretase modulators, antiaggregation agents to amyloid immunotherapy. Authors review the different novel drugs which are in clinical trials.

Lithium chloride increases the production of amyloid-beta peptide independently from its inhibition of glycogen synthase kinase 3.

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Feyt, Christine; Kienlen-Campard, Pascal; Leroy, Karelle; N'Kuli, Francisca; Courtoy, Pierre J; Brion, Jean-Pierre; Octave, Jean-Noël

2005-09-30

Glycogen synthase kinase 3 (GSK3) is able to phosphorylate tau at many sites that are found to be phosphorylated in paired helical filaments in Alzheimer disease. Lithium chloride (LiCl) efficiently inhibits GSK3 and was recently reported to also decrease the production of amyloid-beta peptide (Abeta) from its precursor, the amyloid precursor protein. Therefore, lithium has been proposed as a combined therapeutic agent, inhibiting both the hyperphosphorylation of tau and the production of Abeta. Here, we demonstrate that the inhibition of GSK3 by LiCl induced the nuclear translocation of beta-catenin in Chinese hamster ovary cells and rat cultured neurons, in which a decrease in tau phosphorylation was observed. In both cellular models, a nontoxic concentration of LiCl increased the production of Abeta by increasing the beta-cleavage of amyloid precursor protein, generating more substrate for an unmodified gamma-secretase activity. SB415286, another GSK3 inhibitor, induced the nuclear translocation of beta-catenin and slightly decreased Abeta production. It is concluded that the LiCl-mediated increase in Abeta production is not related to GSK3 inhibition.

Memantine for prophylaxis of chronic tension-type headache--a double-blind, randomized, crossover clinical trial

DEFF Research Database (Denmark)

Lindelof, K; Bendtsen, L; Lindelof, K

2009-01-01

Treatment for chronic tension-type headache (CTTH) is unsatisfactory. Our aim was to investigate the efficacy of the N-methyl D-aspartate (NMDA) antagonist memantine in the prophylactic treatment of CTTH. We included 40 patients in a randomized, double-blind, placebo-controlled, crossover trial....... Memantine 20-40 mg/day or placebo was each given for 10 weeks separated by a 2-week wash-out period; 29 patients completed the study. The primary efficacy variable, area-under-the-headache curve (duration x intensity), did not differ between memantine (1352 +/- 927) and placebo (1449 +/- 976; P = 0.......10). Headache intensity in both sexes was significantly lower on a 0-10 verbal rating scale with memantine (3.8) than with placebo (4.1; P = 0.03). In women, area-under-the-headache curve was significantly lower with memantine (1343 +/- 919) than with placebo (1555 +/- 1019; P = 0.01). The most common side...

Loss of function of ATXN1 increases amyloid beta-protein levels by potentiating beta-secretase processing of beta-amyloid precursor protein.

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Zhang, Can; Browne, Andrew; Child, Daniel; Divito, Jason R; Stevenson, Jesse A; Tanzi, Rudolph E

2010-03-19

Alzheimer disease (AD) is a devastating neurodegenerative disease with complex and strong genetic inheritance. Four genes have been established to either cause familial early onset AD (APP, PSEN1, and PSEN2) or to increase susceptibility for late onset AD (APOE). To date approximately 80% of the late onset AD genetic variance remains elusive. Recently our genome-wide association screen identified four novel late onset AD candidate genes. Ataxin 1 (ATXN1) is one of these four AD candidate genes and has been indicated to be the disease gene for spinocerebellar ataxia type 1, which is also a neurodegenerative disease. Mounting evidence suggests that the excessive accumulation of Abeta, the proteolytic product of beta-amyloid precursor protein (APP), is the primary AD pathological event. In this study, we ask whether ATXN1 may lead to AD pathogenesis by affecting Abeta and APP processing utilizing RNA interference in a human neuronal cell model and mouse primary cortical neurons. We show that knock-down of ATXN1 significantly increases the levels of both Abeta40 and Abeta42. This effect could be rescued with concurrent overexpression of ATXN1. Moreover, overexpression of ATXN1 decreased Abeta levels. Regarding the underlying molecular mechanism, we show that the effect of ATXN1 expression on Abeta levels is modulated via beta-secretase cleavage of APP. Taken together, ATXN1 functions as a genetic risk modifier that contributes to AD pathogenesis through a loss-of-function mechanism by regulating beta-secretase cleavage of APP and Abeta levels.

Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration

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Schaefer, Patrick M.; von Einem, Bjoern; Walther, Paul; Calzia, Enrico; von Arnim, Christine A. F.

2016-01-01

One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), increasing APP and Aβ levels or Aβ alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Aβ levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Aβ-mediated mitochondrial toxicity. Analyzing Aβ localization revealed that intracellular levels of Aβ and an increased spatial association of APP/Aβ with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Aβ accumulation in Alzheimer´s disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases. PMID:28005987

The role of beta amyloid in Alzheimer's disease: still a cause of everything or the only one who got caught?

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Verdile, Giuseppe; Fuller, Stephanie; Atwood, Craig S; Laws, Simon M; Gandy, Samuel E; Martins, Ralph N

2004-10-01

The beta amyloid (A beta) protein is a key molecule in the pathogenesis of Alzheimer's disease (AD). The tendency of the A beta peptide to aggregate, its reported neurotoxicity, and genetic linkage studies, have led to a hypothesis of AD pathogenesis that many AD researchers term the amyloid cascade hypothesis. In this hypothesis, an increased production of A beta results in neurodegeneration and ultimately dementia through a cascade of events. In the past 15 years, debate amongst AD researchers has arisen as to whether A beta is a cause or an effect of the pathogenic process. Recent in vitro and in vivo research has consolidated the theory that A beta is the primary cause, initiating secondary events, culminating in the neuropathological hallmarks associated with AD. This research has led to the development of therapeutic agents, currently in human clinical trials, which target A beta.

How ionic strength affects the conformational behavior of human and rat beta amyloids--a computational study.

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Zdeněk Kříž

Full Text Available Progressive cerebral deposition of amyloid beta occurs in Alzheimers disease and during the aging of certain mammals (human, monkey, dog, bear, cow, cat but not others (rat, mouse. It is possibly due to different amino acid sequences at positions 5, 10 and 13. To address this issue, we performed series of 100 ns long trajectories (each trajectory was run twice with different initial velocity distribution on amyloid beta (1-42 with the human and rat amino acid sequence in three different environments: water with only counter ions, water with NaCl at a concentration of 0.15 M as a model of intracellular Na(+ concentration at steady state, and water with NaCl at a concentration of 0.30 M as a model of intracellular Na(+ concentration under stimulated conditions. We analyzed secondary structure stability, internal hydrogen bonds, and residual fluctuation. It was observed that the change in ionic strength affects the stability of internal hydrogen bonds. Increasing the ionic strength increases atomic fluctuation in the hydrophobic core of the human amyloid, and decreases the atomic fluctuation in the case of rat amyloid. The secondary structure analyses show a stable α-helix part between residues 10 and 20. However, C-terminus of investigated amyloids is much more flexible showing no stable secondary structure elements. Increasing ionic strength of the solvent leads to decreasing stability of the secondary structural elements. The difference in conformational behavior of the three amino acids at position 5, 10 and 13 for human and rat amyloids significantly changes the conformational behavior of the whole peptide.

Cholesterol enhances amyloid {beta} deposition in mouse retina by modulating the activities of A{beta}-regulating enzymes in retinal pigment epithelial cells

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Wang, Jiying [Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan); Ohno-Matsui, Kyoko, E-mail: k.ohno.oph@tmd.ac.jp [Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan); Morita, Ikuo [Section of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan)

2012-08-10

Highlights: Black-Right-Pointing-Pointer Cholesterol-treated RPE produces more A{beta} than non-treated RPE. Black-Right-Pointing-Pointer Neprilysin expression and activity decreased in cholesterol-treated RPE. Black-Right-Pointing-Pointer {alpha}-Secretase expression and activity decreased in cholesterol-treated RPE. Black-Right-Pointing-Pointer Cholesterol-enriched diet induced subRPE deposits in aged mice. Black-Right-Pointing-Pointer A{beta} were present in cholesterol-enriched-diet-induced subRPE deposits in aged mice. -- Abstract: Subretinally-deposited amyloid {beta} (A{beta}) is a main contributor of developing age-related macular degeneration (AMD). However, the mechanism causing A{beta} deposition in AMD eyes is unknown. Hypercholesterolemia is a significant risk for developing AMD. Thus, we investigated the effects of cholesterol on A{beta} production in retinal pigment epithelial (RPE) cells in vitro and in the mouse retina in vivo. RPE cells isolated from senescent (12-month-old) C57BL/6 mice were treated with 10 {mu}g/ml cholesterol for 48 h. A{beta} amounts in culture supernatants were measured by ELISA. Activity and expression of enzymes and proteins that regulate A{beta} production were examined by activity assay and real time PCR. The retina of mice fed cholesterol-enriched diet was examined by transmission electron microscopy. Cholesterol significantly increased A{beta} production in cultured RPE cells. Activities of A{beta} degradation enzyme; neprilysin (NEP) and anti-amyloidogenic secretase; {alpha}-secretase were significantly decreased in cell lysates of cholesterol-treated RPE cells compared to non-treated cells, but there was no change in the activities of {beta}- or {gamma}-secretase. mRNA levels of NEP and {alpha}-secretase (ADAM10 and ADAM17) were significantly lower in cholesterol-treated RPE cells than non-treated cells. Senescent (12-month-old) mice fed cholesterol-enriched chow developed subRPE deposits containing A{beta}, whereas

Memantine in frontotemporal lobar degeneration: A multicenter, randomised, double-blind, placebo-controlled trial

Science.gov (United States)

Boxer, Adam L.; Knopman, David S.; Kaufer, Daniel I.; Grossman, Murray; Onyike, Chiadi; Graf-Radford, Neill; Mendez, Mario; Kerwin, Diana; Lerner, Alan; Wu, Chuang-Kuo; Koestler, Mary; Shapira, Jill; Sullivan, Kathryn; Klepac, Kristen; Lipowski, Kristine; Ullah, Jerin; Fields, Scott; Kramer, Joel H.; Merrilees, Jennifer; Neuhaus, John; Mesulam, M. Marsel; Miller, Bruce L.

2013-01-01

Background Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26 week open label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI). Methods We performed a randomized, parallel group, double blind, placebo controlled trial of 20 mg memantine taken orally daily for 26 weeks in FTD. Participants met Neary criteria for behavioral variant (bvFTD) or semantic dementia (SD) and had characteristic brain atrophy. Use of cholinesterase inhibitors was prohibited. The objective of the study was to determine whether memantine is an effective treatment for FTD. Individuals were randomized to memantine or matched placebo tablets in blocks of two and four. Primary endpoints were the change in total NPI score and Clinical Global Impression of Change (CGIC) scores after 26 weeks. Secondary outcomes included a neuropsychological battery, and other cognitive, global and activity of daily living measures. Clinicaltrials.gov identifier: NCT00545974 Findings 100 subjects were screened, 81 were randomized, 5 (6%) discontinued and 76 completed all visits. Enrollment numbers were lower than planned due to many subjects’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. 39 memantine and 42 placebo subjects entered the primary intent to treat analysis. There was no effect of memantine treatment on either the NPI (mean difference [MD] 2.2, 95%CI: −3.9, 8.3, p = 0.47) or CGIC (MD 0, 95%CI: −0.4, 0.4, p = 0.90) after 26 weeks of treatment. Memantine was generally well tolerated, however there were more frequent cognitive adverse events in the memantine group. Interpretation There was no benefit of memantine treatment in bvFTD or SD. These data do not support memantine use in FTD. Funding Forest Research Institute PMID:23290598

Radioiodinated benzimidazole derivatives as single photon emission computed tomography probes for imaging of {beta}-amyloid plaques in Alzheimer's disease

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Cui Mengchao [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875 (China); Ono, Masahiro, E-mail: ono@pharm.kyoto-u.ac.j [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Kimura, Hiroyuki; Kawashima, Hidekazu [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Liu Boli [Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875 (China); Saji, Hideo, E-mail: hsaji@pharm.kyoto-u.ac.j [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)

2011-04-15

Five iodinated 2-phenyl-1H-benzo[d]imidazole derivatives were synthesized and evaluated as potential probes for {beta}-amyloid (A{beta}) plaques. One of the compounds, 4-(6-iodo-1H-benzo[d]imidazol-2-yl)-N,N-dimethylaniline (12), showed excellent affinity for A{beta}{sub 1-42} aggregates (K{sub i}=9.8 nM). Autoradiography with sections of postmortem Alzheimer's disease (AD) brain revealed that a radioiodinated probe [{sup 125}I]12, labeled A{beta} plaques selectively with low nonspecific binding. Biodistribution experiments with normal mice injected intravenously with [{sup 125}I]12 showed high uptake [4.14 percent injected dose per gram (% ID/g) at 2 min] into and rapid clearance (0.15% ID/g at 60 min) from the brain, which may bring about a good signal-to-noise ratio and therefore achieve highly sensitive detection of A{beta} plaques. In addition, [{sup 125}I]12 labeled amyloid plaques in vivo in an AD transgenic model. The preliminary results strongly suggest that [{sup 125}I]12 bears characteristics suitable for detecting amyloid plaques in vivo. When labeled with {sup 123}I, it may be a useful SPECT imaging agent for A{beta} plaques in the brain of living AD patients.

A hydrogel biosensor for high selective and sensitive detection of amyloid-beta oligomers

Directory of Open Access Journals (Sweden)

Sun LP

2018-02-01

Full Text Available Liping Sun,1 Yong Zhong,1 Jie Gui,1 Xianwu Wang,1 Xiaorong Zhuang,2 Jian Weng1 1Key Laboratory of Biomedical Engineering of Fujian Province, Research Center of Biomedical Engineering of Xiamen, Department of Biomaterials, College of Materials, Xiamen University, 2Department of Neurology, The Affiliated Zhongshan Hospital of Xiamen University, Xiamen, People’s Republic of China Background: Alzheimer’s disease (AD is a neurodegenerative disorder characterized by progressive cognitive and memory impairment. It is the most common neurological disease that causes dementia. Soluble amyloid-beta oligomers (AβO in blood or cerebrospinal fluid (CSF are the pathogenic biomarker correlated with AD. Methods: A simple electrochemical biosensor using graphene oxide/gold nanoparticles (GNPs hydrogel electrode was developed in this study. Thiolated cellular prion protein (PrPC peptide probe was immobilized on GNPs of the hydrogel electrode to construct an AβO biosensor. Electrochemical impedance spectroscopy was utilized for AβO analysis. Results: The specific binding between AβO and PrPC probes on the hydrogel electrode resulted in an increase in the electron-transfer resistance. The biosensor showed high specificity and sensitivity for AβO detection. It could selectively differentiate AβO from amyloid-beta (Aβ monomers or fibrils. Meanwhile, it was highly sensitive to detect as low as 0.1 pM AβO in artificial CSF or blood plasma. The linear range for AβO detection is from 0.1 pM to 10 nM. Conclusion: This biosensor could be used as a cost-effective tool for early diagnosis of AD due to its high electrochemical performance and bionic structure. Keywords: Alzheimer’s disease, amyloid-beta oligomer, graphene, gold nanoparticles, biosensor

CD147 is a regulatory subunit of the gamma-secretase complex inAlzheimer's disease amyloid beta-peptide production

Energy Technology Data Exchange (ETDEWEB)

Zhou, Shuxia; Zhou, Hua; Walian, Peter J.; Jap, Bing K.

2005-04-06

{gamma}-secretase is a membrane protein complex that cleaves the {beta}-amyloid precursor protein (APP) within the transmembrane region, following prior processing by {beta}-secretase, producing amyloid {beta}-peptides (A{beta}{sub 40} and A{beta}{sub 42}). Errant production of A{beta}-peptides that substantially increases A{beta}{sub 42} production has been associated with the formation of amyloid plaques in Alzheimer's disease patients. Biophysical and genetic studies indicate that presenilin-1 (Psn-1), which contains the proteolytic active site, and three other membrane proteins, nicastrin (Nct), APH-1, and PEN-2 are required to form the core of the active {gamma}-secretase complex. Here, we report the purification of the native {gamma}-secretase complexes from HeLa cell membranes and the identification of an additional {gamma}-secretase complex subunit, CD147, a transmembrane glycoprotein with two immunoglobulin-like domains. The presence of this subunit as an integral part of the complex itself was confirmed through co-immunoprecipitation studies of the purified protein from HeLa cells and solubilized complexes from other cell lines such as neural cell HCN-1A and HEK293. Depletion of CD147 by RNA interference was found to increase the production of A{beta} peptides without changing the expression level of the other {gamma}-secretase components or APP substrates while CD147 overexpression had no statistically significant effect on amyloid {beta}-peptide production, other {gamma}-secretase components or APP substrates, indicating that the presence of the CD147 subunit within the {gamma}-secretase complex directly down-modulates the production of A{beta}-peptides. {gamma}-secretase was first recognized through its role in the production of the A{beta} peptides that are pathogenic in Alzheimer's disease (AD) (1). {gamma}-secretase is a membrane protein complex with unusual aspartyl protease activity that cleaves a variety of type I membrane proteins

Cationization increases brain distribution of an amyloid-beta protofibril selective F(ab')2 fragment

OpenAIRE

Syvänen, Stina; Edén, Desireé; Sehlin, Dag

2017-01-01

Antibodies and fragments thereof are, because of high selectivity for their targets, considered as potential therapeutics and biomarkers for several neurological disorders. However, due to their large molecular size, antibodies/fragments do not easily penetrate into the brain. The aim of the present study was to improve the brain distribution via adsorptive-mediated transcytosis of an amyloid-beta (A beta) protofibril selective F(ab')2 fragment (F(ab')2-h158). F(ab')2-h158 was cationized to d...

Gray matter network disruptions and amyloid beta in cognitively normal adults.

Science.gov (United States)

Tijms, Betty M; Kate, Mara Ten; Wink, Alle Meije; Visser, Pieter Jelle; Ecay, Mirian; Clerigue, Montserrat; Estanga, Ainara; Garcia Sebastian, Maite; Izagirre, Andrea; Villanua, Jorge; Martinez Lage, Pablo; van der Flier, Wiesje M; Scheltens, Philip; Sanz Arigita, Ernesto; Barkhof, Frederik

2016-01-01

Gray matter networks are disrupted in Alzheimer's disease (AD). It is unclear when these disruptions start during the development of AD. Amyloid beta 1-42 (Aβ42) is among the earliest changes in AD. We studied, in cognitively healthy adults, the relationship between Aβ42 levels in cerebrospinal fluid (CSF) and single-subject cortical gray matter network measures. Single-subject gray matter networks were extracted from structural magnetic resonance imaging scans in a sample of cognitively healthy adults (N = 185; age range 39-79, mini-mental state examination >25, N = 12 showed abnormal Aβ42 level and for 90 anatomical areas. Associations between continuous Aβ42 CSF levels and single-subject cortical gray matter network measures were tested. Smoothing splines were used to determine whether a linear or nonlinear relationship gave a better fit to the data. Lower Aβ42 CSF levels were linearly associated at whole brain level with lower connectivity density, and nonlinearly with lower clustering values and higher path length values, which is indicative of a less-efficient network organization. These relationships were specific to medial temporal areas, precuneus, and the middle frontal gyrus (all p levels can be related to gray matter networks disruptions. Copyright © 2016 Elsevier Inc. All rights reserved.

Cartilage acidic protein 1, a new member of the beta-propeller protein family with amyloid propensity.

Science.gov (United States)

Anjos, Liliana; Morgado, Isabel; Guerreiro, Marta; Cardoso, João C R; Melo, Eduardo P; Power, Deborah M

2017-02-01

Cartilage acidic protein1 (CRTAC1) is an extracellular matrix protein of chondrogenic tissue in humans and its presence in bacteria indicate it is of ancient origin. Structural modeling of piscine CRTAC1 reveals it belongs to the large family of beta-propeller proteins that in mammals have been associated with diseases, including amyloid diseases such as Alzheimer's. In order to characterize the structure/function evolution of this new member of the beta-propeller family we exploited the unique characteristics of piscine duplicate genes Crtac1a and Crtac1b and compared their structural and biochemical modifications with human recombinant CRTAC1. We demonstrate that CRTAC1 has a beta-propeller structure that has been conserved during evolution and easily forms high molecular weight thermo-stable aggregates. We reveal for the first time the propensity of CRTAC1 to form amyloid-like structures, and hypothesize that the aggregating property of CRTAC1 may be related to its disease-association. We further contribute to the general understating of CRTAC1's and beta-propeller family evolution and function. Proteins 2017; 85:242-255. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Amyloid-beta binds catalase with high affinity and inhibits hydrogen peroxide breakdown.

OpenAIRE

Milton, N G

1999-01-01

Amyloid-beta (Abeta) specifically bound purified catalase with high affinity and inhibited catalase breakdown of H(2)O(2). The Abeta-induced catalase inhibition involved formation of the inactive catalase Compound II and was reversible. CatalaseAbeta interactions provide rapid functional assays for the cytotoxic domain of Abeta and suggest a mechanism for some of the observed actions of Abeta plus catalase in vitro.

Bloodstream Amyloid-beta (1-40) Peptide, Cognition, and Outcomes in Heart Failure.

Science.gov (United States)

Bayes-Genis, Antoni; Barallat, Jaume; de Antonio, Marta; Domingo, Mar; Zamora, Elisabet; Vila, Joan; Subirana, Isaac; Gastelurrutia, Paloma; Pastor, M Cruz; Januzzi, James L; Lupón, Josep

2017-11-01

In the brain, amyloid-beta generation participates in the pathophysiology of cognitive disorders; in the bloodstream, the role of amyloid-beta is uncertain but may be linked to sterile inflammation and senescence. We explored the relationship between blood levels of amyloid-beta 1-40 peptide (Aβ40), cognition, and mortality (all-cause, cardiovascular, and heart failure [HF]-related) in ambulatory patients with HF. Bloodstream Aβ40 was measured in 939 consecutive patients with HF. Cognition was evaluated with the Pfeiffer questionnaire (adjusted for educational level) at baseline and during follow-up. Multivariate Cox regression analyses and measurements of performance (discrimination, calibration, and reclassification) were used, with competing risk for specific causes of death. Over 5.1 ± 2.9 years, 471 patients died (all-cause): 250 from cardiovascular causes and 131 HF-related. The median Aβ40 concentration was 519.1 pg/mL [Q1-Q3: 361.8-749.9 pg/mL]. The Aβ40 concentration correlated with age, body mass index, renal dysfunction, and New York Heart Association functional class (all P < .001). There were no differences in Aβ40 in patients with and without cognitive impairment at baseline (P = .97) or during follow-up (P = .20). In multivariable analysis, including relevant clinical predictors and N-terminal pro-B-type natriuretic peptide, Aβ40 remained significantly associated with all-cause death (HR, 1.22; 95%CI, 1.10-1.35; P < .001) and cardiovascular death (HR, 1.18; 95%CI, 1.03-1.36; P = .02), but not with HF-related death (HR, 1.13; 95%CI, 0.93-1.37; P = .22). Circulating Aβ40 improved calibration and patient reclassification. Blood levels of Aβ40 are not associated with cognitive decline in HF. Circulating Aβ40 was predictive of mortality and may indicate systemic aging. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Molecular architecture of human prion protein amyloid: a parallel, in-register beta-structure.

Science.gov (United States)

Cobb, Nathan J; Sönnichsen, Frank D; McHaourab, Hassane; Surewicz, Witold K

2007-11-27

Transmissible spongiform encephalopathies (TSEs) represent a group of fatal neurodegenerative diseases that are associated with conformational conversion of the normally monomeric and alpha-helical prion protein, PrP(C), to the beta-sheet-rich PrP(Sc). This latter conformer is believed to constitute the main component of the infectious TSE agent. In contrast to high-resolution data for the PrP(C) monomer, structures of the pathogenic PrP(Sc) or synthetic PrP(Sc)-like aggregates remain elusive. Here we have used site-directed spin labeling and EPR spectroscopy to probe the molecular architecture of the recombinant PrP amyloid, a misfolded form recently reported to induce transmissible disease in mice overexpressing an N-terminally truncated form of PrP(C). Our data show that, in contrast to earlier, largely theoretical models, the con formational conversion of PrP(C) involves major refolding of the C-terminal alpha-helical region. The core of the amyloid maps to C-terminal residues from approximately 160-220, and these residues form single-molecule layers that stack on top of one another with parallel, in-register alignment of beta-strands. This structural insight has important implications for understanding the molecular basis of prion propagation, as well as hereditary prion diseases, most of which are associated with point mutations in the region found to undergo a refolding to beta-structure.

Generation of the beta-amyloid peptide and the amyloid precursor protein C-terminal fragment gamma are potentiated by FE65L1.

Science.gov (United States)

Chang, Yang; Tesco, Giuseppina; Jeong, William J; Lindsley, Loren; Eckman, Elizabeth A; Eckman, Christopher B; Tanzi, Rudolph E; Guénette, Suzanne Y

2003-12-19

Members of the FE65 family of adaptor proteins, FE65, FE65L1, and FE65L2, bind the C-terminal region of the amyloid precursor protein (APP). Overexpression of FE65 and FE65L1 was previously reported to increase the levels of alpha-secretase-derived APP (APPs alpha). Increased beta-amyloid (A beta) generation was also observed in cells showing the FE65-dependent increase in APPs alpha. To understand the mechanism for the observed increase in both A beta and APPs alpha given that alpha-secretase cleavage of a single APP molecule precludes A beta generation, we examined the effects of FE65L1 overexpression on APP C-terminal fragments (APP CTFs). Our data show that FE65L1 potentiates gamma-secretase processing of APP CTFs, including the amyloidogenic CTF C99, accounting for the ability of FE65L1 to increase generation of APP C-terminal domain and A beta 40. The FE65L1 modulation of these processing events requires binding of FE65L1 to APP and APP CTFs and is not because of a direct effect on gamma-secretase activity, because Notch intracellular domain generation is not altered by FE65L1. Furthermore, enhanced APP CTF processing can be detected in early endosome vesicles but not in endoplasmic reticulum or Golgi membranes, suggesting that the effects of FE65L1 occur at or near the plasma membrane. Finally, although FE65L1 increases APP C-terminal domain production, it does not mediate the APP-dependent transcriptional activation observed with FE65.

Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

Directory of Open Access Journals (Sweden)

C. Cheignon

2018-04-01

Full Text Available Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer’s disease (AD, an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS when bound to the amyloid-β (Aβ. The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …. This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level. Keywords: Oxidative stress, Amyloid beta peptide, Metal-ions, Reactive oxygen species, Oxidative damages

Disease-modifying drugs in Alzheimer's disease

Directory of Open Access Journals (Sweden)

Ghezzi L

2013-12-01

Full Text Available Laura Ghezzi, Elio Scarpini, Daniela Galimberti Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy Abstract: Alzheimer's disease (AD is an age-dependent neurodegenerative disorder and the most common cause of dementia. The early stages of AD are characterized by short-term memory loss. Once the disease progresses, patients experience difficulties in sense of direction, oral communication, calculation, ability to learn, and cognitive thinking. The median duration of the disease is 10 years. The pathology is characterized by deposition of amyloid beta peptide (so-called senile plaques and tau protein in the form of neurofibrillary tangles. Currently, two classes of drugs are licensed by the European Medicines Agency for the treatment of AD, ie, acetylcholinesterase inhibitors for mild to moderate AD, and memantine, an N-methyl-D-aspartate receptor antagonist, for moderate and severe AD. Treatment with acetylcholinesterase inhibitors or memantine aims at slowing progression and controlling symptoms, whereas drugs under development are intended to modify the pathologic steps leading to AD. Herein, we review the clinical features, pharmacologic properties, and cost-effectiveness of the available acetylcholinesterase inhibitors and memantine, and focus on disease-modifying drugs aiming to interfere with the amyloid beta peptide, including vaccination, passive immunization, and tau deposition. Keywords: Alzheimer's disease, acetylcholinesterase inhibitors, memantine, disease-modifying drugs, diagnosis, treatment

Effect of copper (II) ion against elongation behavior of amyloid {beta} fibrils on liposome membranes

Energy Technology Data Exchange (ETDEWEB)

Shimanouchi, T.; Onishi, R.; Kitaura, N.; Umakoshi, H.; Kuboi, R. [Division of Chemical Engineering, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama-cho, Toyonaka, Osaka (Japan)

2012-01-15

The fibril growth behavior of amyloid {beta} protein (A{beta}) on cell membranes is relating to the progression of Alzheimer's disease. This growth behavior of A{beta} fibrils is sensitively affected by the metal ions, neurotransmitters, or bioreactive substrate. The inhibitory effect of those materials was quantitatively estimated from the viewpoints of ''crystal growth''. In a bulk aqueous solution, copper (II) ion showed the strong inhibitory effect on the growth of A{beta} fibrils. Meanwhile, the addition of a closed-phospholipid bilayer membrane (liposome) could reduce the above inhibitory effect of copper (II) ion. (copyright 2012 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice.

Science.gov (United States)

Pan, Xiaoli; Gong, Neng; Zhao, Jing; Yu, Zhe; Gu, Fenghua; Chen, Jia; Sun, Xiaojing; Zhao, Lei; Yu, Meijing; Xu, Zhiru; Dong, Wenxin; Qin, Yan; Fei, Guoqiang; Zhong, Chunjiu; Xu, Tian-Le

2010-05-01

Reduction of glucose metabolism in brain is one of the main features of Alzheimer's disease. Thiamine (vitamin B1)-dependent processes are critical in glucose metabolism and have been found to be impaired in brains from patients with Alzheimer's disease. However, thiamine treatment exerts little beneficial effect in these patients. Here, we tested the effect of benfotiamine, a thiamine derivative with better bioavailability than thiamine, on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 transgenic mouse. We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. Unexpectedly, these effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine were effective in increasing the levels of free thiamine in the brain. Most notably, benfotiamine, but not fursultiamine, significantly elevated the phosphorylation level of glycogen synthase kinase-3alpha and -3beta, and reduced their enzymatic activities in the amyloid precursor protein/presenilin-1 transgenic brain. Therefore, in the animal Alzheimer's disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely to include the suppression of glycogen synthase kinase-3 activities. These results suggest that, unlike many other thiamine-related drugs, benfotiamine may be beneficial for clinical Alzheimer's disease treatment.

Quantifying the pattern of beta/A4 amyloid protein distribution in Alzheimer's disease by image analysis.

Science.gov (United States)

Bruce, C V; Clinton, J; Gentleman, S M; Roberts, G W; Royston, M C

1992-04-01

We have undertaken a study of the distribution of the beta/A4 amyloid deposited in the cerebral cortex in Alzheimer's disease. Previous studies which have examined the differential distribution of amyloid in the cortex in order to determine the laminar pattern of cortical pathology have not proved to be conclusive. We have developed an alternative method for the solution of this problem. It involves the immunostaining of sections followed by computer-enhanced image analysis. A mathematical model is then used to describe both the amount and the pattern of amyloid across the cortex. This method is both accurate and reliable and also removes many of the problems concerning inter and intra-rater variability in measurement. This method will provide the basis for further quantitative studies on the differential distribution of amyloid in Alzheimer's disease and other cases of dementia where cerebral amyloidosis occurs.

Effect of four medicinal plants on amyloid-beta induced neurotoxicity in SH-SY5Y Cells

CSIR Research Space (South Africa)

Adewusi, EA

2013-01-01

Full Text Available Amyloid-beta peptide (Aß) is implicated in the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative disorder. This study was designed to determine the effect of four medicinal plants used to treat neurodegenerative diseases on Aß...

Plasma Membrane Protein Profiling in Beta-Amyloid-Treated Microglia Cell Line.

Science.gov (United States)

Correani, Virginia; Di Francesco, Laura; Mignogna, Giuseppina; Fabrizi, Cinzia; Leone, Stefano; Giorgi, Alessandra; Passeri, Alessia; Casata, Roberto; Fumagalli, Lorenzo; Maras, Bruno; Schininà, M Eugenia

2017-09-01

In the responsiveness of microglia to toxic stimuli, plasma membrane proteins play a key role. In this study we treated with a synthetic beta amyloid peptide murine microglial cells metabolically differently labelled with stable isotope amino acids (SILAC). The plasma membrane was selectively enriched by a multi-stage aqueous two-phase partition system. We were able to identify by 1D-LC-MS/MS analyses 1577 proteins, most of them are plasma membrane proteins according to the Gene Ontology annotation. An unchanged level of amyloid receptors in this data set suggests that microglia preserve their responsiveness capability to the environment even after 24-h challenge with amyloid peptides. On the other hand, 14 proteins were observed to change their plasma membrane abundance to a statistically significant extent. Among these, we proposed as reliable biomarkers of the inflammatory microglia phenotype in AD damaged tissues MAP/microtubule affinity-regulating kinase 3 (MARK3), Interferon-induced transmembrane protein 3 (IFITM3), Annexins A5 and A7 (ANXA5, ANXA7) and Neuropilin-1 (NRP1), all proteins known to be involved in the inflammation processes and in microtubule network assembly rate. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chaperones ameliorate beta cell dysfunction associated with human islet amyloid polypeptide overexpression.

Directory of Open Access Journals (Sweden)

Lisa Cadavez

Full Text Available In type 2 diabetes, beta-cell dysfunction is thought to be due to several causes, one being the formation of toxic protein aggregates called islet amyloid, formed by accumulations of misfolded human islet amyloid polypeptide (hIAPP. The process of hIAPP misfolding and aggregation is one of the factors that may activate the unfolded protein response (UPR, perturbing endoplasmic reticulum (ER homeostasis. Molecular chaperones have been described to be important in regulating ER response to ER stress. In the present work, we evaluate the role of chaperones in a stressed cellular model of hIAPP overexpression. A rat pancreatic beta-cell line expressing hIAPP exposed to thapsigargin or treated with high glucose and palmitic acid, both of which are known ER stress inducers, showed an increase in ER stress genes when compared to INS1E cells expressing rat IAPP or INS1E control cells. Treatment with molecular chaperone glucose-regulated protein 78 kDa (GRP78, also known as BiP or protein disulfite isomerase (PDI, and chemical chaperones taurine-conjugated ursodeoxycholic acid (TUDCA or 4-phenylbutyrate (PBA, alleviated ER stress and increased insulin secretion in hIAPP-expressing cells. Our results suggest that the overexpression of hIAPP induces a stronger response of ER stress markers. Moreover, endogenous and chemical chaperones are able to ameliorate induced ER stress and increase insulin secretion, suggesting that improving chaperone capacity can play an important role in improving beta-cell function in type 2 diabetes.

Amyloid-beta induced CA1 pyramidal cell loss in young adult rats is alleviated by systemic treatment with FGL, a neural cell adhesion molecule-derived mimetic peptide.

Directory of Open Access Journals (Sweden)

Nicola J Corbett

Full Text Available Increased levels of neurotoxic amyloid-beta in the brain are a prominent feature of Alzheimer's disease. FG-Loop (FGL, a neural cell adhesion molecule-derived peptide that corresponds to its second fibronectin type III module, has been shown to provide neuroprotection against a range of cellular insults. In the present study impairments in social recognition memory were seen 24 days after a 5 mg/15 µl amyloid-beta(25-35 injection into the right lateral ventricle of the young adult rat brain. This impairment was prevented if the animal was given a systemic treatment of FGL. Unbiased stereology was used to investigate the ability of FGL to alleviate the deleterious effects on CA1 pyramidal cells of the amyloid-beta(25-35 injection. NeuN, a neuronal marker (for nuclear staining was used to identify pyramidal cells, and immunocytochemistry was also used to identify inactive glycogen synthase kinase 3beta (GSK3β and to determine the effects of amyloid-beta(25-35 and FGL on the activation state of GSK3β, since active GSK3β has been shown to cause a range of AD pathologies. The cognitive deficits were not due to hippocampal atrophy as volume estimations of the entire hippocampus and its regions showed no significant loss, but amyloid-beta caused a 40% loss of pyramidal cells in the dorsal CA1 which was alleviated partially by FGL. However, FGL treatment without amyloid-beta was also found to cause a 40% decrease in CA1 pyramidal cells. The action of FGL may be due to inactivation of GSK3β, as an increased proportion of CA1 pyramidal neurons contained inactive GSK3β after FGL treatment. These data suggest that FGL, although potentially disruptive in non-pathological conditions, can be neuroprotective in disease-like conditions.

Amyloid beta peptide immunotherapy in Alzheimer disease.

Science.gov (United States)

Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

2014-12-01

Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chronic exposure of NG108-15 cells to amyloid beta peptide (A beta(1-42)) abolishes calcium influx via N-type calcium channels

Czech Academy of Sciences Publication Activity Database

Kašparová, Jana; Lisá, Věra; Tuček, Stanislav; Doležal, Vladimír

2001-01-01

Roč. 26, 8-9 (2001), s. 1079-1084 ISSN 0364-3190 R&D Projects: GA MZd NF5183 Institutional research plan: CEZ:AV0Z5011922 Keywords : amyloid beta peptide * Alzheimer's disease * calcium Subject RIV: FH - Neurology Impact factor: 1.638, year: 2001

Towards a Pharmacophore for Amyloid

Energy Technology Data Exchange (ETDEWEB)

Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David (UCLA)

2011-09-16

Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of {beta}-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-{beta}, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, the natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-{beta}. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the {beta}-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a

Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

LENUS (Irish Health Repository)

Hampel, Harald

2010-06-01

Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

LENUS (Irish Health Repository)

Hampel, Harald

2012-02-01

Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation

Czech Academy of Sciences Publication Activity Database

Koistinaho, M.; Kettunen, M. I.; Goldsteins, G.; Keinänen, R.; Salminen, A.; Ort, Michael; Bureš, Jan; Liu, D.; Kauppinen, R. A.; Higgins, L. S.; Koistinaho, J.

2002-01-01

Roč. 99, č. 3 (2002), s. 1610-1615 ISSN 0027-8424 R&D Projects: GA ČR GA309/00/1656 Institutional research plan: CEZ:AV0Z5011922 Keywords : Beta-amyloid * Alzheimer disease * brain ischemia Subject RIV: FH - Neurology Impact factor: 10.701, year: 2002

A hydrogel biosensor for high selective and sensitive detection of amyloid-beta oligomers.

Science.gov (United States)

Sun, Liping; Zhong, Yong; Gui, Jie; Wang, Xianwu; Zhuang, Xiaorong; Weng, Jian

2018-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive and memory impairment. It is the most common neurological disease that causes dementia. Soluble amyloid-beta oligomers (AβO) in blood or cerebrospinal fluid (CSF) are the pathogenic biomarker correlated with AD. A simple electrochemical biosensor using graphene oxide/gold nanoparticles (GNPs) hydrogel electrode was developed in this study. Thiolated cellular prion protein (PrP C ) peptide probe was immobilized on GNPs of the hydrogel electrode to construct an AβO biosensor. Electrochemical impedance spectroscopy was utilized for AβO analysis. The specific binding between AβO and PrP C probes on the hydrogel electrode resulted in an increase in the electron-transfer resistance. The biosensor showed high specificity and sensitivity for AβO detection. It could selectively differentiate AβO from amyloid-beta (Aβ) monomers or fibrils. Meanwhile, it was highly sensitive to detect as low as 0.1 pM AβO in artificial CSF or blood plasma. The linear range for AβO detection is from 0.1 pM to 10 nM. This biosensor could be used as a cost-effective tool for early diagnosis of AD due to its high electrochemical performance and bionic structure.

Alzheimer's disease amyloid-beta links lens and brain pathology in Down syndrome.

Directory of Open Access Journals (Sweden)

Juliet A Moncaster

2010-05-01

Full Text Available Down syndrome (DS, trisomy 21 is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21 encoding the Alzheimer's disease (AD amyloid precursor protein (APP. Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-beta peptides (Abeta, early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased Abeta accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked Abeta pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear Abeta accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic Abeta aggregates (approximately 5 to 50 nm identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of Abeta in DS lenses. Incubation of synthetic Abeta with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased Abeta

Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability

OpenAIRE

Allaman, Igor; Gavillet, Mathilde; Bélanger, Mireille; Laroche, Thierry; Viertl, David; Lashuel, Hilal A.; Magistretti, Pierre J.

2010-01-01

Amyloid-beta (Abeta) peptides play a key role in the pathogenesis of Alzheimer's disease and exert various toxic effects on neurons; however, relatively little is known about their influence on glial cells. Astrocytes play a pivotal role in brain homeostasis, contributing to the regulation of local energy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of Abeta peptides on glucose metabolism ...

Characterization of amyloid beta peptides from brain extracts of transgenic mice overexpressing the London mutant of human amyloid precursor protein.

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Pype, Stefan; Moechars, Dieder; Dillen, Lieve; Mercken, Marc

2003-02-01

Alzheimer's disease (AD) is marked by the presence of neurofibrillary tangles and amyloid plaques in the brain of patients. To study plaque formation, we report on further quantitative and qualitative analysis of human and mouse amyloid beta peptides (Abeta) from brain extracts of transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP). Using enzyme-linked immunosorbant assays (ELISAs) specific for either human or rodent Abeta, we found that the peptides from both species aggregated to form plaques. The ratios of deposited Abeta1-42/1-40 were in the order of 2-3 for human and 8-9 for mouse peptides, indicating preferential deposition of Abeta42. We also determined the identity and relative levels of other Abeta variants present in protein extracts from soluble and insoluble brain fractions. This was done by combined immunoprecipitation and mass spectrometry (IP/MS). The most prominent peptides truncated either at the carboxyl- or the amino-terminus were Abeta1-38 and Abeta11-42, respectively, and the latter was strongly enriched in the extracts of deposited peptides. Taken together, our data indicate that plaques of APP-London transgenic mice consist of aggregates of multiple human and mouse Abeta variants, and the human variants that we identified were previously detected in brain extracts of AD patients.

A kinetic model for beta-amyloid adsorption at the air/solution interface and its implication to the beta-amyloid aggregation process.

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Jiang, Dianlu; Dinh, Kim Lien; Ruthenburg, Travis C; Zhang, Yi; Su, Lei; Land, Donald P; Zhou, Feimeng

2009-03-12

At the air/buffer solution interface the kinetics of adsorption of amyloid beta peptide, Abeta(1-42), whose bulk concentration (submicromolar) is more than 2 orders of magnitude lower than that typically used in other in vitro aggregation studies, has been studied using a Langmuir-Blodgett trough. The pressure-time curves exhibit a lag phase, wherein the surface pressure essentially remains at zero, and a rising phase, corresponding to the Abeta adsorption at the interface. The duration of the lag phase was found to be highly dependent on both the Abeta bulk concentration and the solution temperature. A large activation energy (62.2 +/- 4.1 KJ/mol) was determined and the apparent adsorption rate constant was found to be linearly dependent on the Abeta bulk concentration. Attenuated total reflection-IR spectra of the adsorbed Abeta transferred to a solid substrate and circular dichroism measurements of Abeta in the solution layer near the interface reveal that the natively unstructured Abeta in the bulk undergo a conformation change (folding) to mainly the alpha-helical structure. The results suggest that, prior to the adsorption step, an equilibrium between Abeta conformations is established within the subsurface. The kinetic equation derived from this model confirms that the overall Abeta adsorption is kinetically controlled and the apparent rate constant is proportional to the Abeta bulk concentration. This model also indicates that interfaces such as cell membranes and lipid bilayers may facilitate Abeta aggregation/ fibrillation by providing a thin hydrophobic layer adjacent to the interface for the initial A/beta conformation change (misfolding) and accumulation. Such a preconcentration effect offers a plausible explanation of the fact that Abeta fibrillation occurs in vivo at nanomolar concentrations. Another important biological implication from our work is that Abeta misfolding may occur before its adsorption onto a cell membrane. This general kinetic model

Comparing the use of Memantine with Dextromethorphan and Placebo to Reduce Pain before Orthopedic Surgery

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Mehrdad Taheri

2017-12-01

Full Text Available Introduction: To compare the use of Memantine with Dextromethorphan and placebo to reduce pain after orthopedic surgery.Materials and Methods: The present study was a double-blind clinical trial including180 patients undergoing elective orthopedic surgery of the lower limbs. Patients were divided randomly into three groups of 60 patients each. The first group (Group M received 30 mg Memantine orally, the second group (Group D received 45 mg of Dextromethorphan and the third group (Group P received only placebo, two and a half hours before the operation. The intensity of pain (VAS score, sedation score, and nausea and vomiting were recorded postoperatively.Results: In this study, 60 patients were enrolled in each group. The total VAS (Visual Analogue Scale score was significantly lower among patients receiving Memantine and the satisfaction was significantly higher compared to the Dextromethorphan and placebo groups (P-value <0.001.Conclusion: The present study results indicate that Memantine has a relatively better outcome compared to Dextromethorphan or placebo in reducing the post surgical pain among patients undergoing orthopedic surgeries. It also reduced the need for post surgical opioid use and improved the patients’ satisfaction.  

Update on the use of memantine in Alzheimer’s disease

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Robert J van Marum

2009-03-01

Full Text Available Robert J van MarumGeriatric Department, University Medical Center Utrecht, Utrecht, The NetherlandsAbstract: Memantine is a low to moderate affinity N-methyl-D-aspartate receptor (NMDAR antagonist. The effects of memantine in Alzheimer’s disease (AD have been studied in 7 randomized controlled trials in many post-hoc analyses. Three out of four RCTs in patients with moderate to severe AD (Mini Mental State Examination [MMSE] 14 showed a statistically significant but clinically small positive effect of memantine on cognition, global functioning, activities of daily living (ADL and neuropsychiatric symptoms. No effects on these outcome measures could be found in the three RCTs studying patients with mild to moderate AD (MMSE 14–24. Two of these studies evaluated the effect of addition of memantine to donepezil. Only the study in patients with mild to moderate AD showed a positive effect of addition of memantine on cognition, ADL, global functioning and neuropsychiatric functioning. Cost-effectiveness of memantine therapy remains controversial. Post-hoc analyses and observational studies suggest some effects on agitation/aggression, delusions or hallucinations. Side effects of memantine are usually mild and seem to be comparable with placebo. In this review, an oversight of pharmacodynamics and pharmacokinetics of memantine is presented. Also, published data concerning efficacy and safety in patients with AD are presented.Keywords: dementia, Alzheimer’s disease, drug therapy, memantine

HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

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András, Ibolya E.; Toborek, Michal

2014-01-01

Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood–brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. - Highlights: • HIV-1 induces nuclear accumulation of amyloid beta (Aβ) in brain endothelial cells. • EEA-1 and TGF-Β/Smad act in concert to regulate nuclear entry of Aβ. • Dynamin appropriates the EEA-1 and TGF-Β/Smad signaling. • Dynamin serves as a master regulator of HIV-1-induced nuclear accumulation of Aβ

HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

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András, Ibolya E., E-mail: iandras@med.miami; Toborek, Michal, E-mail: mtoborek@med.miami.edu

2014-04-15

Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood–brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. - Highlights: • HIV-1 induces nuclear accumulation of amyloid beta (Aβ) in brain endothelial cells. • EEA-1 and TGF-Β/Smad act in concert to regulate nuclear entry of Aβ. • Dynamin appropriates the EEA-1 and TGF-Β/Smad signaling. • Dynamin serves as a master regulator of HIV-1-induced nuclear accumulation of Aβ.

A systematic review of amyloid-beta peptides as putative mediators of the association between affective disorders and Alzheimer's disease

DEFF Research Database (Denmark)

Abbasowa, Leda; Heegaard, N. H. H.

2014-01-01

Background: Affective disorders are associated with an increased occurrence of cognitive deficits and have been linked to cognitive impairment and Alzheimer's disease. The putative molecular mechanisms involved in these associations are however not clear. The aim of this systematic review...... were limited by very low sample numbers. Finally, different assays for amyloid-beta were utilized in the different studies, thus hampering comparisons. Conclusion: To unravel possible risk relations and causalities between affective disorder and Alzheimer's disease and to determine how amyloid...

Individualized quantification of brain {beta}-amyloid burden: results of a proof of mechanism phase 0 florbetaben PET trial in patients with Alzheimer's disease and healthy controls

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Barthel, Henryk; Luthardt, Julia; Becker, Georg; Patt, Marianne; Sattler, Bernhard; Schildan, Andreas; Hesse, Swen; Meyer, Philipp M.; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Hammerstein, Eva; Hartwig, Kristin; Gertz, Hermann-Josef [University of Leipzig, Department of Psychiatry, Leipzig (Germany); Eggers, Birk [Arzneimittelforschung Leipzig GmbH, Leipzig (Germany); Wolf, Henrike [University of Leipzig, Department of Psychiatry, Leipzig (Germany); University of Zurich, Department of Psychiatry, Zurich (Switzerland); Zimmermann, Torsten; Reischl, Joachim; Rohde, Beate; Reininger, Cornelia [Bayer Healthcare, Berlin (Germany)

2011-09-15

Complementing clinical findings with those generated by biomarkers - such as {beta}-amyloid-targeted positron emission tomography (PET) imaging - has been proposed as a means of increasing overall accuracy in the diagnosis of Alzheimer's disease (AD). Florbetaben ([{sup 18}F]BAY 94-9172) is a novel {beta}-amyloid PET tracer currently in global clinical development. We present the results of a proof of mechanism study in which the diagnostic efficacy, pharmacokinetics, safety and tolerability of florbetaben were assessed. The value of various quantitative parameters derived from the PET scans as potential surrogate markers of cognitive decline was also investigated. Ten patients with mild-moderate probable AD (DSM-IV and NINCDS-ADRDA criteria) and ten age-matched ({>=} 55 years) healthy controls (HCs) were administered a single dose of 300 MBq florbetaben, which contained a tracer mass dose of < 5 {mu}g. The 70-90 min post-injection brain PET data were visually analysed by three blinded experts. Quantitative assessment was also performed via MRI-based, anatomical sampling of predefined volumes of interest (VOI) and subsequent calculation of standardized uptake value (SUV) ratios (SUVRs, cerebellar cortex as reference region). Furthermore, single-case, voxelwise analysis was used to calculate individual ''whole brain {beta}-amyloid load''. Visual analysis of the PET data revealed nine of the ten AD, but only one of the ten HC brains to be {beta}-amyloid positive (p = 0.001), with high inter-reader agreement (weighted kappa {>=} 0.88). When compared to HCs, the neocortical SUVRs were significantly higher in the ADs (with descending order of effect size) in frontal cortex, lateral temporal cortex, occipital cortex, anterior and posterior cingulate cortices, and parietal cortex (p = 0.003-0.010). Voxel-based group comparison confirmed these differences. Amongst the PET-derived parameters, the Statistical Parametric Mapping-based whole brain

Memantine reverses social withdrawal induced by ketamine in rats.

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Uribe, Ezequiel; Landaeta, José; Wix, Richard; Eblen, Antonio

2013-03-01

The objective of this study was to determine the effect of memantine on schizophrenia-like symptoms in a ketamine-induced social withdrawal model in rats. We examined therapeutic effects of memantine, an NMDA antagonist, and haloperidol, a classic antipsychotic drug, on this behavioral model. Administration of memantine (10 or 15 mg·kg(-1)) significantly reduced ketamine-induced social withdrawal, and this effect was more effective than that of haloperidol (0.25 mg·kg(-1)) by restoring the social interaction between rats with no modification in general motor activity. These results suggest that memantine could have a therapeutic potential for schizophrenia.

Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes.

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Tang, Weihao; Tam, Joshua H K; Seah, Claudia; Chiu, Justin; Tyrer, Andrea; Cregan, Sean P; Meakin, Susan O; Pasternak, Stephen H

2015-07-14

Alzheimer's disease (AD) is characterized by the deposition of Beta-Amyloid (Aβ) peptides in the brain. Aβ peptides are generated by cleavage of the Amyloid Precursor Protein (APP) by the β - and γ - secretase enzymes. Although this process is tightly linked to the internalization of cell surface APP, the compartments responsible are not well defined. We have found that APP can be rapidly internalized from the cell surface to lysosomes, bypassing early and late endosomes. Here we show by confocal microscopy and electron microscopy that this pathway is mediated by macropinocytosis. APP internalization is enhanced by antibody binding/crosslinking of APP suggesting that APP may function as a receptor. Furthermore, a dominant negative mutant of Arf6 blocks direct transport of APP to lysosomes, but does not affect classical endocytosis to endosomes. Arf6 expression increases through the hippocampus with the development of Alzheimer's disease, being expressed mostly in the CA1 and CA2 regions in normal individuals but spreading through the CA3 and CA4 regions in individuals with pathologically diagnosed AD. Disruption of lysosomal transport of APP reduces both Aβ40 and Aβ42 production by more than 30 %. Our findings suggest that the lysosome is an important site for Aβ production and that altering APP trafficking represents a viable strategy to reduce Aβ production.

Disrupting beta-amyloid aggregation for Alzheimer disease treatment.

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Estrada, L D; Soto, C

2007-01-01

Alzheimer's disease is a devastating degenerative disorder for which there is no cure or effective treatment. Although the etiology of Alzheimer's disease is not fully understood, compelling evidence indicates that deposition of aggregates composed by a misfolded form of the amyloid beta peptide (Abeta) is the central event in the disease pathogenesis. Therefore, an attractive therapeutic strategy is to prevent or reverse Abeta misfolding and aggregation. Diverse strategies have been described to identify inhibitors of this process, including screening of libraries of small molecules chemical compounds, rational design of synthetic peptides, assessment of natural Abeta-binding proteins and stimulation of the immune system by vaccination. In this article we describe these different approaches, their principles and their potential strengths and weaknesses. Overall the available data suggest that the development of drugs to interfere with Abeta misfolding and aggregation is a feasible target that hold great promise for the treatment of Alzheimer's disease.

Interhemispheric EEG differences in olfactory bulbectomized rats with different cognitive abilities and brain beta-amyloid levels.

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Bobkova, Natalia; Vorobyov, Vasily; Medvinskaya, Natalia; Aleksandrova, Irina; Nesterova, Inna

2008-09-26

Alterations in electroencephalogram (EEG) asymmetry and deficits in interhemispheric integration of information have been shown in patients with Alzheimer's disease (AD). However, no direct evidence of an association between EEG asymmetry, morphological markers in the brain, and cognition was found either in AD patients or in AD models. In this study we used rats with bilateral olfactory bulbectomy (OBX) as one of the AD models and measured their learning/memory abilities, brain beta-amyloid levels and EEG spectra in symmetrical frontal and occipital cortices. One year after OBX or sham-surgery, the rats were tested with the Morris water paradigm and assigned to three groups: sham-operated rats, SO, and OBX rats with virtually normal, OBX(+), or abnormal, OBX(-), learning (memory) abilities. In OBX vs. SO, the theta EEG activity was enhanced to a higher extent in the right frontal cortex and in the left occipital cortex. This produced significant interhemispheric differences in the frontal cortex of the OBX(-) rats and in the occipital cortex of both OBX groups. The beta1 EEG asymmetry in SO was attenuated in OBX(+) and completely eliminated in OBX(-). OBX produced highly significant beta2 EEG decline in the right frontal cortex, with OBX(-)>OBX(+) rank order of strength. The beta-amyloid level, examined by post-mortem immunological DOT-analysis in the cortex-hippocampus samples, was about six-fold higher in OBX(-) than in SO, but significantly less (enhanced by 82% vs. SO) in OBX(+) than in OBX(-). The involvement of the brain mediatory systems in the observed EEG asymmetry differences is discussed.

Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta.

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Griciuc, Ana; Serrano-Pozo, Alberto; Parrado, Antonio R; Lesinski, Andrea N; Asselin, Caroline N; Mullin, Kristina; Hooli, Basavaraj; Choi, Se Hoon; Hyman, Bradley T; Tanzi, Rudolph E

2013-05-22

The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer's disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cell cultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reduced in APP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33 inhibition could represent a novel therapy for AD. Copyright © 2013 Elsevier Inc. All rights reserved.

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

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Zhang, Xueli; Tian, Yanli; Zhang, Can; Tian, Xiaoyu; Ross, Alana W.; Moir, Robert D.; Sun, Hongbin; Tanzi, Rudolph E.; Moore, Anna; Ran, Chongzhao

2015-01-01

Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer’s disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17–treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development. PMID:26199414

Impact of amyloid imaging on drug development in Alzheimer's disease

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Mathis, Chester A. [Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States)], E-mail: mathisca@upmc.edu; Lopresti, Brian J. [Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Klunk, William E. [Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States)

2007-10-15

Imaging agents capable of assessing amyloid-beta (A{beta}) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect A{beta} plaques in the brain as well as to help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several A{beta} imaging agents are currently underway. We reported the first PET studies of the carbon 11-labeled thioflavin-T derivative Pittsburgh Compound B in 2004, and this work has subsequently been extended to include a variety of subject groups, including AD patients, mild cognitive impairment patients and healthy controls. The ability to quantify regional A{beta} plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of A{beta} plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.

PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes.

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Wang, Hong-Mei; Zhao, Yan-Xin; Zhang, Shi; Liu, Gui-Dong; Kang, Wen-Yan; Tang, Hui-Dong; Ding, Jian-Qing; Chen, Sheng-Di

2010-01-01

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Accumulating data indicate that astrocytes play an important role in the neuroinflammation related to the pathogenesis of AD. It has been shown that microglia and astrocytes are activated in AD brain and amyloid-beta (Abeta) can increase the expression of cyclooxygenase 2 (COX-2), interleukin-1, and interleukin-6. Suppressing the inflammatory response caused by activated astrocytes may help to inhibit the development of AD. Curcumin is a major constituent of the yellow curry spice turmeric and proved to be a potential anti-inflammatory drug in arthritis and colitis. There is a low age-adjusted prevalence of AD in India, a country where turmeric powder is commonly used as a culinary compound. Curcumin has been shown to suppress activated astroglia in amyloid-beta protein precursor transgenic mice. The real mechanism by which curcumin inhibits activated astroglia is poorly understood. Here we report that the expression of COX-2 and glial fibrillary acidic protein were enhanced and that of peroxisome proliferator-activated receptor gamma (PPARgamma) was decreased in Abeta(25-35)-treated astrocytes. In line with these results, nuclear factor-kappaB translocation was increased in the presence of Abeta. All these can be reversed by the pretreatment of curcumin. Furthermore, GW9662, a PPARgamma antagonist, can abolish the anti-inflammatory effect of curcumin. These results show that curcumin might act as a PPARgamma agonist to inhibit the inflammation in Abeta-treated astrocytes.

Amyloid Beta and Tau as Alzheimer's Disease Blood Biomarkers: Promise From New Technologies.

Science.gov (United States)

Lue, Lih-Fen; Guerra, Andre; Walker, Douglas G

2017-07-01

The utility of the levels of amyloid beta (Aβ) peptide and tau in blood for diagnosis, drug development, and assessment of clinical trials for Alzheimer's disease (AD) has not been established. The lack of availability of ultra-sensitive assays is one critical issue that has impeded progress. The levels of Aβ species and tau in plasma and serum are much lower than levels in cerebrospinal fluid. Furthermore, plasma or serum contain high levels of assay-interfering factors, resulting in difficulties in the commonly used singulex or multiplex ELISA platforms. In this review, we focus on two modern immune-complex-based technologies that show promise to advance this field. These innovative technologies are immunomagnetic reduction technology and single molecule array technology. We describe the technologies and discuss the published studies using these technologies. Currently, the potential of utilizing these technologies to advance Aβ and tau as blood-based biomarkers for AD requires further validation using already collected large sets of samples, as well as new cohorts and population-based longitudinal studies.

PB1-F2 influenza A virus protein adopts a beta-sheet conformation and forms amyloid fibers in membrane environments.

Science.gov (United States)

Chevalier, Christophe; Al Bazzal, Ali; Vidic, Jasmina; Février, Vincent; Bourdieu, Christiane; Bouguyon, Edwige; Le Goffic, Ronan; Vautherot, Jean-François; Bernard, Julie; Moudjou, Mohammed; Noinville, Sylvie; Chich, Jean-François; Da Costa, Bruno; Rezaei, Human; Delmas, Bernard

2010-04-23

The influenza A virus PB1-F2 protein, encoded by an alternative reading frame in the PB1 polymerase gene, displays a high sequence polymorphism and is reported to contribute to viral pathogenesis in a sequence-specific manner. To gain insights into the functions of PB1-F2, the molecular structure of several PB1-F2 variants produced in Escherichia coli was investigated in different environments. Circular dichroism spectroscopy shows that all variants have a random coil secondary structure in aqueous solution. When incubated in trifluoroethanol polar solvent, all PB1-F2 variants adopt an alpha-helix-rich structure, whereas incubated in acetonitrile, a solvent of medium polarity mimicking the membrane environment, they display beta-sheet secondary structures. Incubated with asolectin liposomes and SDS micelles, PB1-F2 variants also acquire a beta-sheet structure. Dynamic light scattering revealed that the presence of beta-sheets is correlated with an oligomerization/aggregation of PB1-F2. Electron microscopy showed that PB1-F2 forms amorphous aggregates in acetonitrile. In contrast, at low concentrations of SDS, PB1-F2 variants exhibited various abilities to form fibers that were evidenced as amyloid fibers in a thioflavin T assay. Using a recombinant virus and its PB1-F2 knock-out mutant, we show that PB1-F2 also forms amyloid structures in infected cells. Functional membrane permeabilization assays revealed that the PB1-F2 variants can perforate membranes at nanomolar concentrations but with activities found to be sequence-dependent and not obviously correlated with their differential ability to form amyloid fibers. All of these observations suggest that PB1-F2 could be involved in physiological processes through different pathways, permeabilization of cellular membranes, and amyloid fiber formation.

Immunotherapy of Alzheimer's disease (AD): from murine models to anti-amyloid beta (Abeta) human monoclonal antibodies.

Science.gov (United States)

Geylis, Valeria; Steinitz, Michael

2006-01-01

The deposition of amyloid beta (Abeta) protein is a key pathological feature in Alzheimer's disease (AD). In murine models of AD, both active and passive immunization against Abeta induce a marked reduction in amyloid brain burden and an improvement in cognitive functions. Preliminary results of a prematurely terminated clinical trial where AD patients were actively vaccinated with aggregated Abeta bear resemblance to those documented in murine models. Passive immunization of AD patients with anti-Abeta antibodies, in particular human antibodies, is a strategy that provides a more cautious management and control of any undesired side effects. Sera of all healthy adults contain anti-Abeta IgG autoimmune antibodies. Hence antigen-committed human B-cells are easily immortalized by Epstein-Barr virus (EBV) into anti-Abeta secreting cell lines. Two anti-Abeta human monoclonal antibodies which we recently prepared bind to the N-terminus of Abeta peptide and were shown to stain amyloid plaques in non-fixed brain sections from an AD patient. It is anticipated that specifically selected anti-Abeta human monoclonal antibodies could reduce and inhibit deposits of amyloid in brain while avoiding the cognitive decline that characterizes AD. In the future, this type of antibody may prove to be a promising immune therapy for the disease.

Imaging characteristic of dual-phase 18F-florbetapir (AV-45/Amyvid) PET for the concomitant detection of perfusion deficits and beta-amyloid deposition in Alzheimer's disease and mild cognitive impairment

International Nuclear Information System (INIS)

Lin, Kun-Ju; Hsiao, Ing-Tsung; Hsieh, Chia-Ju; Wey, Shiaw-Pyng; Yen, Tzu-Chen; Hsu, Jung-Lung; Huang, Chin-Chang; Huang, Kuo-Lun

2016-01-01

We investigated dual-phase 18 F-florbetapir (AV-45/Amyvid) PET imaging for the concomitant detection of brain perfusion deficits and beta-amyloid deposition in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), and in cognitively healthy controls (HCs). A total of 82 subjects (24 AD patients, 44 MCI patients and 14 HCs) underwent both dual-phase 18 F-AV-45 PET and MRI imaging. Dual-phase dynamic PET imaging consisted of (1) five 1-min scans obtained 1 - 6 min after tracer injection (perfusion 18 F-AV-45 imaging, pAV-45), and (2) ten 1-min scans obtained 50 - 60 min after tracer injection (amyloid 18 F-AV-45 imaging). Amyloid-negative MCI/AD patients were excluded. Volume of interest analysis and statistical parametric mapping of pAV-45 and 18 F-AV-45 images were performed to investigate the perfusion deficits and the beta-amyloid burden in the three study groups. The associations between Mini-Mental State Examination (MMSE) scores and global perfusion deficits and amyloid deposition were investigated with linear and segmental linear correlation analyses. HCs generally had normal pAV-45 findings, whereas perfusion deficits were evident in the hippocampus, and temporal, parietal and middle frontal cortices in both MCI and AD patients. The motor-sensory cortex was relatively preserved. MMSE scores in the entire study cohort were significantly associated with the degree of perfusion impairment as assessed by pAV-45 imaging (r = 0.5156, P < 0.0001). 18 F-AV-45 uptake was significantly higher in AD patients than in the two other study groups. However, the correlation between MMSE scores and 18 F-AV-45 uptake in MCI patients was more of a binary phenomenon and began in MCI patients with MMSE score 23.14 when 18 F-AV-45 uptake was higher and MMSE score lower than in patients with early MCI. Amyloid deposition started in the precuneus and the frontal and temporal regions in early MCI, ultimately reaching the maximum burden in advanced

Impact of amyloid-beta changes on cognitive outcomes in Alzheimer's disease: analysis of clinical trials using a quantitative systems pharmacology model.

Science.gov (United States)

Geerts, Hugo; Spiros, Athan; Roberts, Patrick

2018-02-02

Despite a tremendous amount of information on the role of amyloid in Alzheimer's disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects. We present an advanced mechanism-based and biophysically realistic quantitative systems pharmacology computer model of an Alzheimer-type neuronal cortical network that has been calibrated with Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-Cog) readouts from historical clinical trials and simulated the differential impact of amyloid-beta (Aβ40 and Aβ42) oligomers on glutamate and nicotinic neurotransmission. Preclinical data suggest a beneficial effect of shorter Aβ forms within a limited dose range. Such a beneficial effect of Aβ40 on glutamate neurotransmission in human patients is absolutely necessary to reproduce clinical data on the ADAS-Cog in minimal cognitive impairment (MCI) patients with and without amyloid load, the effect of APOE genotype effect on the slope of the cognitive trajectory over time in placebo AD patients and higher sensitivity to cholinergic manipulation with scopolamine associated with higher Aβ in MCI subjects. We further derive a relationship between units of Aβ load in our model and the standard uptake value ratio from amyloid imaging. When introducing the documented clinical pharmacodynamic effects on Aβ levels for various amyloid-related clinical interventions in patients with low Aβ baseline, the platform predicts an overall significant worsening for passive vaccination with solanezumab, beta-secretase inhibitor verubecestat and gamma-secretase inhibitor semagacestat. In contrast, all three interventions improved cognition in subjects with moderate to high baseline Aβ levels, with verubecestat anticipated to have the greatest effect (around ADAS-Cog value 1.5 points), solanezumab the lowest (0.8 ADAS-Cog value points) and semagacestat in between. This could explain the success of many amyloid

Two distinct β-sheet structures in Italian-mutant amyloid-beta fibrils : a potential link to different clinical phenotypes

NARCIS (Netherlands)

Hubin, Ellen; Deroo, Stéphanie; Schierle, Gabriele Kaminksi; Kaminski, Clemens; Serpell, Louise; Subramaniam, Vinod; van Nuland, Nico; Broersen, Kerensa; Raussens, Vincent; Sarroukh, Rabia

2015-01-01

Most Alzheimer's disease (AD) cases are late-onset and characterized by the aggregation and deposition of the amyloid-beta (Aβ) peptide in extracellular plaques in the brain. However, a few rare and hereditary Aβ mutations, such as the Italian Glu22-to-Lys (E22K) mutation, guarantee the development

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

Science.gov (United States)

Revett, Timothy J.; Baker, Glen B.; Jhamandas, Jack; Kar, Satyabrata

2013-01-01

Alzheimer disease is the most prevalent form of dementia globally and is characterized premortem by a gradual memory loss and deterioration of higher cognitive functions and postmortem by neuritic plaques containing amyloid β peptide and neurofibrillary tangles containing phospho-tau protein. Glutamate is the most abundant neurotransmitter in the brain and is essential to memory formation through processes such as long-term potentiation and so might be pivotal to Alzheimer disease progression. This review discusses how the glutamatergic system is impaired in Alzheimer disease and how interactions of amyloid β and glutamate influence synaptic function, tau phosphorylation and neurodegeneration. Interestingly, glutamate not only influences amyloid β production, but also amyloid β can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression. Finally, we describe how the glutamate receptor antagonist, memantine, has been used in the treatment of individuals with Alzheimer disease and discuss its effectiveness. PMID:22894822

Correlations between serum levels of beta amyloid, cerebrospinal levels of tau and phospho tau, and delayed response tasks in young and aged cynomolgus monkeys (Macaca fascicularis)

DEFF Research Database (Denmark)

Darusman, Huda Shalahudin; Sajuthi, D; Kalliokoski, O

2013-01-01

In an attempt to explore cynomolgus monkeys as an animal model for Alzheimer's disease, the present study focused on the Alzheimer's biomarkers beta amyloid 1-42 (Aβ42 ) in serum, and total tau (t-tau) and phosphorylated tau (p-tau) levels in cerebrospinal fluid.......In an attempt to explore cynomolgus monkeys as an animal model for Alzheimer's disease, the present study focused on the Alzheimer's biomarkers beta amyloid 1-42 (Aβ42 ) in serum, and total tau (t-tau) and phosphorylated tau (p-tau) levels in cerebrospinal fluid....

Einfluß einer In-vitro- und In-vivo-Cholesterol-Modulation in Hirnmembranen auf die zellulären Effekte von Amyloid-beta-Peptid

OpenAIRE

Kirsch, Christopher

2003-01-01

Die exzessive Bildung und Ablagerung von aggregiertem Amyloid beta-Peptid im Gehirn von Alzheimer Patienten wird allgemein als zentrales Ereignis im Rahmen des Neurodegenerationsprozesses der Alzheimer Demenz betrachtet. Der Amyloid-Stoffwechsel ist dabei in sehr vielfältiger Weise mit dem zellulären Cholesterol-Stoffwechsel verknüpft. Hohe Cholesterolspiegel in spezifischen Membrandomänen wie Lipid-Rafts forcieren sehr wahrscheinlich die zelluläre Produktion als auch die Fibrillogenese von A...

Other Species in the Aqueous Environment of a Peptide Can Invert its Intrinsic Solvated Polyproline II/Beta Propensity: Implications for Amyloid Formation.

Science.gov (United States)

Mirkin, Noemi G; Krimm, Samuel

2016-02-02

As we have previously shown, the predominance of the polyproline II conformation in the circular dichroism spectra of aqueous polypeptides is related to its lower energy than that of the beta conformation. In order to test whether this is still the case in the presence of additional components in the medium, we have calculated the energy difference between these two conformations in an alanine-dipeptide/twelve-water system without and with the addition of an HCl molecule. We find in the latter case that the beta conformer is of lower energy than the polyproline II. Energy profiles near the minima in both cases also permit conclusions about the relative entropies of these structures. These results emphasize the importance of considering the peptide-plus-medium state as the relevant entity in determining the structural properties of such systems. Such an inversion could be relevant to the formation of amyloid and could thus lead to new strategies for studying its role in the development of neurodegenerative diseases. This article is protected by copyright. All rights reserved. © 2016 Wiley Periodicals, Inc.

No association of cortical amyloid load and EEG connectivity in older people with subjective memory complaints

Directory of Open Access Journals (Sweden)

Stefan Teipel

2018-01-01

Full Text Available Changes in functional connectivity of cortical networks have been observed in resting-state EEG studies in healthy aging as well as preclinical and clinical stages of AD. Little information, however, exists on associations between EEG connectivity and cortical amyloid load in people with subjective memory complaints. Here, we determined the association of global cortical amyloid load, as measured by florbetapir-PET, with functional connectivity based on the phase-lag index of resting state EEG data for alpha and beta frequency bands in 318 cognitively normal individuals aged 70–85 years with subjective memory complaints from the INSIGHT-preAD cohort. Within the entire group we did not find any significant associations between global amyloid load and phase-lag index in any frequency band. Assessing exclusively the subgroup of amyloid-positive participants, we found enhancement of functional connectivity with higher global amyloid load in the alpha and a reduction in the beta frequency bands. In the amyloid-negative participants, higher amyloid load was associated with lower connectivity in the low alpha band. However, these correlations failed to reach significance after controlling for multiple comparisons. The absence of a strong amyloid effect on functional connectivity may represent a selection effect, where individuals remain in the cognitively normal group only if amyloid accumulation does not impair cortical functional connectivity.

Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta

Science.gov (United States)

Griciuc, Ana; Serrano-Pozo, Alberto; Parrado, Antonio R.; Lesinski, Andrea N.; Asselin, Caroline N.; Mullin, Kristina; Hooli, Basavaraj; Choi, Se Hoon; Hyman, Bradley T.; Tanzi, Rudolph E.

2013-01-01

SUMMARY The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer’s disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cell cultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reduced in APPSwe/PS1ΔE9/CD33−/− mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33 inhibition could represent a novel therapy for AD. PMID:23623698

Effects of Capsule Yi -Zhi on learning and memory disorder and beta-amyloid peptide induced neurotoxicity in rats

Institute of Scientific and Technical Information of China (English)

XUJiang-Ping; WUHang-Yu; LILin

2004-01-01

AIM To investigate the effects of Capsule Yi-Zhi (CYZ) on learning and memory disorder and beta-amyloid protein induced neurotoxieity in rats. Methods Various doses of CYZ were administered to Sprague-Dawley (SD) rats for 8 days, twice a day. Then scopolamine hydrobromide (Sco) intraperitoneal injection was performed on each rat and the

Cognitive changes under memantine according to vitamin D status in Alzheimer patients: An exposed/unexposed cohort pilot study.

Science.gov (United States)

Lemire, Pauline; Brangier, Antoine; Beaudenon, Melinda; Duval, Guillaume T; Annweiler, Cedric

2018-01-01

Memantine is a symptomatic treatment that partially prevents cognitive decline in Alzheimer disease (AD). The neuroprotective effects of memantine and vitamin D may potentiate each other, with benefits for cognition. The objective of this exposed/unexposed pilot study was to determine the cognitive changes among AD patients using memantine according to the presence or absence of vitamin D deficiency (VDD). Fifty-eight AD patients followed in a memory clinic during 6 months between 2009 and 2014 (mean±standard deviation, 82.9±5.0years; 56.9%female) were separated into four groups according to VDD (i.e., serum 25-hydroxyvitamin D≤25nM) at M0 and M6 (i.e., Group 1: no VDD-M0, no VDD-M6; Group 2: VDD-M0, no VDD-M6; Group 3: no VDD-M0, VDD-M6; Group 4: VDD-M0, VDD-M6). The 6-month cognitive change was examined with the Mini-Mental State Examination (MMSE) score in the 4 groups according to the use of memantine. Age, gender, body mass index, IADL score, GDS score, and use of pchychoactive drugs were measured at baseline. We found that participants using memantine had a lower MMSE score at M0 compared to those without memantine (P=0.006). After 6 months of follow-up, there was a memantine-related improvement of the MMSE score only in the participants with VDD-M6. This was significant in Group 3 with no VDD-M0 (P=0.039), but not in Group 4 who already had VDD-M0. Similarly, using memantine was associated with a 6-month improvement of MMSE only in Group 3 in whom VDD appeared during the follow-up (β=8.8, P=0.044). In conclusion, the use of memantine was associated with improved cognitive performance after 6 months of treatment in the presence of VDD at M6. Memantine may prevent the cognitive decline that accompanies the onset of VDD, which prompts to give to AD patients a regimen combining both memantine and vitamin D supplements. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synthesis, Molecular Modelling and Biological Evaluation of Novel Heterodimeric, Multiple Ligands Targeting Cholinesterases and Amyloid Beta

Directory of Open Access Journals (Sweden)

Michalina Hebda

2016-03-01

Full Text Available Cholinesterases and amyloid beta are one of the major biological targets in the search for a new and efficacious treatment of Alzheimer’s disease. The study describes synthesis and pharmacological evaluation of new compounds designed as dual binding site acetylcholinesterase inhibitors. Among the synthesized compounds, two deserve special attention—compounds 42 and 13. The former is a saccharin derivative and the most potent and selective acetylcholinesterase inhibitor (EeAChE IC50 = 70 nM. Isoindoline-1,3-dione derivative 13 displays balanced inhibitory potency against acetyl- and butyrylcholinesterase (BuChE (EeAChE IC50 = 0.76 μM, EqBuChE IC50 = 0.618 μM, and it inhibits amyloid beta aggregation (35.8% at 10 μM. Kinetic studies show that the developed compounds act as mixed or non-competitive acetylcholinesterase inhibitors. According to molecular modelling studies, they are able to interact with both catalytic and peripheral active sites of the acetylcholinesterase. Their ability to cross the blood-brain barrier (BBB was confirmed in vitro in the parallel artificial membrane permeability BBB assay. These compounds can be used as a solid starting point for further development of novel multifunctional ligands as potential anti-Alzheimer’s agents.

Direct interaction of beta-amyloid with Na,K-ATPase as a putative regulator of the enzyme function

Science.gov (United States)

Petrushanko, Irina Yu.; Mitkevich, Vladimir A.; Anashkina, Anastasia A.; Adzhubei, Alexei A.; Burnysheva, Ksenia M.; Lakunina, Valentina A.; Kamanina, Yulia V.; Dergousova, Elena A.; Lopina, Olga D.; Ogunshola, Omolara O.; Bogdanova, Anna Yu.; Makarov, Alexander A.

2016-06-01

By maintaining the Na+ and K+ transmembrane gradient mammalian Na,K-ATPase acts as a key regulator of neuronal electrotonic properties. Na,K-ATPase has an important role in synaptic transmission and memory formation. Accumulation of beta-amyloid (Aβ) at the early stages of Alzheimer’s disease is accompanied by reduction of Na,K-ATPase functional activity. The molecular mechanism behind this phenomenon is not known. Here we show that the monomeric Aβ(1-42) forms a tight (Kd of 3 μM), enthalpy-driven equimolar complex with α1β1 Na,K-ATPase. The complex formation results in dose-dependent inhibition of the enzyme hydrolytic activity. The binding site of Aβ(1-42) is localized in the “gap” between the alpha- and beta-subunits of Na,K-ATPase, disrupting the enzyme functionality by preventing the subunits from shifting towards each other. Interaction of Na,K-ATPase with exogenous Aβ(1-42) leads to a pronounced decrease of the enzyme transport and hydrolytic activity and Src-kinase activation in neuroblastoma cells SH-SY5Y. This interaction allows regulation of Na,K-ATPase activity by short-term increase of the Aβ(1-42) level. However prolonged increase of Aβ(1-42) level under pathological conditions could lead to chronical inhibition of Na,K-ATPase and disruption of neuronal function. Taken together, our data suggest the role of beta-amyloid as a novel physiological regulator of Na,K-ATPase.

The alpha7 nicotinic acetylcholine receptor-selective antagonist, methyllycaconitine, partially protects against beta-amyloid1-42 toxicity in primary neuron-enriched cultures.

Science.gov (United States)

Martin, Shelley E; de Fiebre, Nancy Ellen C; de Fiebre, Christopher M

2004-10-01

Studies have suggested that the neuroprotective actions of alpha7 nicotinic agonists arise from activation of receptors and not from the extensive desensitization which rapidly follows activation. Here, we report that the alpha7-selective nicotinic antagonist, methyllycaconitine (MLA), protects against beta-amyloid-induced neurotoxicity; whereas the alpha4beta2-selective antagonist, dihydro-beta-erythroidine, does not. These findings suggest that neuroprotective actions of alpha7-acting agents arise from receptor inhibition/desensitization and that alpha7 antagonists may be useful neuroprotective agents.

Memantine for treatment of moderate or severe Alzheimer's disease patients in urban China: clinical and economic outcomes from a health economic model.

Science.gov (United States)

Hu, Shanlian; Yu, Xin; Chen, Shengdi; Clay, Emilie; Toumi, Mondher; Milea, Dominique

2015-01-01

To estimate the clinical and economic benefits of memantine treatment initiated in moderate Alzheimer's disease (AD) in China, compared with initiation in severe AD only. A Markov model with a 5-year time horizon simulated moderate patients' progression through health states. Two groups were compared: patients receiving memantine from the moderate stage (i.e., at model entry), continuing treatment when reaching the severe stage; patients initiating memantine only when they developed severe disease. After 5 years, fewer patients receiving memantine from the moderate stage were severe (49%), dependent (59%) or aggressive (47%) compared with moderate patients who initiated treatment from severe stage only (58, 67 and 55%, respectively). Total cost of care was lower for treatment from moderate stage (67 billion RMB) when compared with treatment from severe stage (73 billion RMB). In China, AD treatment with memantine from the moderate stage could result in substantial cost savings.

Amyloid Imaging in Aging and Dementia: Testing the Amyloid Hypothesis In Vivo

Directory of Open Access Journals (Sweden)

G. D. Rabinovici

2009-01-01

Full Text Available Amyloid imaging represents a major advance in neuroscience, enabling the detection and quantification of pathologic protein aggregations in the brain. In this review we survey current amyloid imaging techniques, focusing on positron emission tomography (PET with ^{11}carbon-labelled Pittsburgh Compound-B (11C-PIB, the most extensively studied and best validated tracer. PIB binds specifically to fibrillar beta-amyloid (Aβ deposits, and is a sensitive marker for Aβ pathology in cognitively normal older individuals and patients with mild cognitive impairment (MCI and Alzheimer’s disease (AD. PIB-PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid imaging studies support a model in which amyloid deposition is an early event on the path to dementia, beginning insidiously in cognitively normal individuals, and accompanied by subtle cognitive decline and functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression.

X11beta rescues memory and long-term potentiation deficits in Alzheimer's disease APPswe Tg2576 mice.

LENUS (Irish Health Repository)

Mitchell, Jacqueline C

2009-12-01

Increased production and deposition of amyloid beta-protein (Abeta) are believed to be key pathogenic events in Alzheimer\\'s disease. As such, routes for lowering cerebral Abeta levels represent potential therapeutic targets for Alzheimer\\'s disease. X11beta is a neuronal adaptor protein that binds to the intracellular domain of the amyloid precursor protein (APP). Overexpression of X11beta inhibits Abeta production in a number of experimental systems. However, whether these changes to APP processing and Abeta production induced by X11beta overexpression also induce beneficial effects to memory and synaptic plasticity are not known. We report here that X11beta-mediated reduction in cerebral Abeta is associated with normalization of both cognition and in vivo long-term potentiation in aged APPswe Tg2576 transgenic mice that model the amyloid pathology of Alzheimer\\'s disease. Overexpression of X11beta itself has no detectable adverse effects upon mouse behaviour. These findings support the notion that modulation of X11beta function represents a therapeutic target for Abeta-mediated neuronal dysfunction in Alzheimer\\'s disease.

Memantine facilitates memory consolidation and reconsolidation in the day-old chick.

Science.gov (United States)

Samartgis, Jodi R; Schachte, Leslie; Hazi, Agnes; Crowe, Simon F

2012-05-01

Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist that has been approved for the treatment of the cognitive deficits noted in Alzheimer's disease. While there is a body of research that supports memantine's facilitative action upon memory compromise, this series of studies aimed to investigate the effects of this drug in healthy animals with intact memory functioning. A 0.1 mM dose of memantine injected immediately after a weakly aversive training event (i.e. 20% v/v methyl anthranilate) was found to enhance passive avoidance learning for this event in day-old chicks up to 24 h following training. The same dose of memantine was also observed to enhance memory for the training event when it was administered in conjunction with a reminder trial. These results suggest that memantine is capable of facilitating both memory consolidation as well as memory reconsolidation. It was concluded that memantine's mechanism may involve the short-term or intermediate memory phases of the Gibbs and Ng model of memory, and that the current findings represent enhancement of intact memory, rather than amelioration of memory compromise. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ß production.

Science.gov (United States)

Bordji, Karim; Becerril-Ortega, Javier; Nicole, Olivier; Buisson, Alain

2010-11-24

Calcium is a key mediator controlling essential neuronal functions depending on electrical activity. Altered neuronal calcium homeostasis affects metabolism of amyloid precursor protein (APP), leading to increased production of β-amyloid (Aβ), and contributing to the initiation of Alzheimer's disease (AD). A linkage between excessive glutamate receptor activation and neuronal Aβ release was established, and recent reports suggest that synaptic and extrasynaptic NMDA receptor (NMDAR) activation may have distinct consequences in plasticity, gene regulation, and neuronal death. Here, we report for the first time that prolonged activation of extrasynaptic NMDAR, but not synaptic NMDAR, dramatically increased the neuronal production of Aβ. This effect was preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing APPs (KPI-APPs), isoforms exhibiting an important amyloidogenic potential. Conversely, after synaptic NMDAR activation, we failed to detect any KPI-APP expression and neuronal Aβ production was not modified. Calcium imaging data showed that intracellular calcium concentration after extrasynaptic NMDAR stimulation was lower than after synaptic activation. This suggests distinct signaling pathways for each pool of receptors. We found that modification of neuronal APP expression pattern triggered by extrasynaptic NMDAR activation was regulated at an alternative splicing level involving calcium-/calmodulin-dependent protein kinase IV, but overall APP expression remained identical. Finally, memantine dose-dependently inhibited extrasynaptic NMDAR-induced KPI-APPs expression as well as neuronal Aβ release. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR promotes amyloidogenic KPI-APP expression leading to neuronal Aβ release, representing a causal risk factor for developing AD.

The soluble transcobalamin receptor (sCD320) is present in cerebrospinal fluid and correlates to dementia-related biomarkers tau proteins and amyloid-beta

DEFF Research Database (Denmark)

Abuyaman, Omar; Nexo, Ebba

2015-01-01

BACKGROUND: Cellular uptake of vitamin B12 (B12) demands binding of the vitamin to transcobalamin (TC) and recognition of TC-B12 (holoTC) by the receptor CD320. Recently, we identified a soluble form of CD320 (sCD320) in human plasma. Here we present data on the occurrence of this soluble receptor...... phospho-tau (181P) (p-tau), total tau (t-tau) and amyloid-beta 1-42 (Aβ) (n = 177) employing commercial ELISA kits (Innogenetics Company). Size exclusion chromatography was performed on a Superdex 200 column. RESULTS: The median sCD320 concentration in CSF (14 pmol/L) is around five times lower than...

Ameliorating effect of anti-Alzheimer’s drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer’s disease

Science.gov (United States)

Elgharabawy, Rehab M; AL-Najjar, Amal H

2017-01-01

Mild to severe forms of nervous system damage were exhibited by approximately 60–70% of diabetics. It is important to understand the association between type 2 diabetes mellitus and Alzheimer’s disease. The aim of the present work is to understand the bidirectional association between type 2 diabetes and Alzheimer’s disease pathogenesis, that was monitored by glycaemic status, lipid profile, amyloid beta 40 and 42 (Aβ40 and Aβ42), C-reactive protein, total creatine kinase, total lactate dehydrogenase, D-dimer and magnesium measurements, to assess the association between theses biochemical markers and each other, to estimate the possibility of utilizing the amyloid beta as biochemical marker of T2D in Alzheimer's patients, and to evaluate the effect of piracetam and memantine drugs on diabetes mellitus. This study involved 120 subjects divided into 20 healthy control (group I), 20 diabetic patients (group II), 20 Alzheimer’s patients (group III), 20 diabetic Alzheimer's patients with symptomatic treatment (group IV), 20 diabetic Alzheimer's patients treated with memantine (group V), and 20 diabetic Alzheimer's patients treated with piracetam (group VI). The demographic characteristics, diabetic index, and lipid profile were monitored. Plasma amyloid beta 40 and amyloid beta 42, C-reactive protein, total creatine kinase, total lactate dehydrogenase, D-dimer, and magnesium were assayed. The levels of amyloid beta 40 and amyloid beta 42 were significantly elevated in diabetic Alzheimer's patients with symptomatic treatment (group IV) compared to group II (by 50.5 and 7.5 fold, respectively) and group III (by 25.4 and 2.8 fold, respectively). In groups II, III, IV, V and VI, significant and positive associations were monitored between insulin and amyloid beta 40, amyloid beta 42, C-reactive protein, total creatine kinase, and D-dimer. Diabetic markers were significantly decreased in diabetic Alzheimer’s patients treated with anti-Alzheimer’s drugs

Imaging characteristic of dual-phase {sup 18}F-florbetapir (AV-45/Amyvid) PET for the concomitant detection of perfusion deficits and beta-amyloid deposition in Alzheimer's disease and mild cognitive impairment

Energy Technology Data Exchange (ETDEWEB)

Lin, Kun-Ju; Hsiao, Ing-Tsung; Hsieh, Chia-Ju; Wey, Shiaw-Pyng; Yen, Tzu-Chen [Linkou Chang Gung Memorial Hospital and University, Department of Nuclear Medicine and Molecular Imaging Center, Taoyuan (China); Chang Gung University, Department of Medical Imaging and Radiological Sciences and Healthy Aging Research Center, Taoyuan (China); Hsu, Jung-Lung [Linkou Chang Gung Memorial Hospital, Section of Dementia and Cognitive Impairment, Department of Neurology, Taoyuan (China); Taipei Medical University, Graduate Institute of Humanities in Medicine, Taipei (China); Huang, Chin-Chang; Huang, Kuo-Lun [Linkou Chang Gung Memorial Hospital and University, Department of Neurology, Taoyuan (China)

2016-07-15

We investigated dual-phase {sup 18}F-florbetapir (AV-45/Amyvid) PET imaging for the concomitant detection of brain perfusion deficits and beta-amyloid deposition in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI), and in cognitively healthy controls (HCs). A total of 82 subjects (24 AD patients, 44 MCI patients and 14 HCs) underwent both dual-phase {sup 18}F-AV-45 PET and MRI imaging. Dual-phase dynamic PET imaging consisted of (1) five 1-min scans obtained 1 - 6 min after tracer injection (perfusion {sup 18}F-AV-45 imaging, pAV-45), and (2) ten 1-min scans obtained 50 - 60 min after tracer injection (amyloid {sup 18}F-AV-45 imaging). Amyloid-negative MCI/AD patients were excluded. Volume of interest analysis and statistical parametric mapping of pAV-45 and {sup 18}F-AV-45 images were performed to investigate the perfusion deficits and the beta-amyloid burden in the three study groups. The associations between Mini-Mental State Examination (MMSE) scores and global perfusion deficits and amyloid deposition were investigated with linear and segmental linear correlation analyses. HCs generally had normal pAV-45 findings, whereas perfusion deficits were evident in the hippocampus, and temporal, parietal and middle frontal cortices in both MCI and AD patients. The motor-sensory cortex was relatively preserved. MMSE scores in the entire study cohort were significantly associated with the degree of perfusion impairment as assessed by pAV-45 imaging (r = 0.5156, P < 0.0001). {sup 18}F-AV-45 uptake was significantly higher in AD patients than in the two other study groups. However, the correlation between MMSE scores and {sup 18}F-AV-45 uptake in MCI patients was more of a binary phenomenon and began in MCI patients with MMSE score 23.14 when {sup 18}F-AV-45 uptake was higher and MMSE score lower than in patients with early MCI. Amyloid deposition started in the precuneus and the frontal and temporal regions in early MCI, ultimately

Combining hypobaric hypoxia or hyperbaric oxygen postconditioning with memantine reduces neuroprotection in 7-day-old rat hypoxia-ischemia.

Science.gov (United States)

Gamdzyk, Marcin; Ziembowicz, Apolonia; Bratek, Ewelina; Salinska, Elzbieta

2016-10-01

Perinatal hypoxia-ischemia causes brain injury in neonates, but a fully successful treatment to prevent changes in the brain has yet to be developed. The aim of this study was to evaluate the effect of combining memantine treatment with HBO (2.5 ATA) or HH (0.47 ATA) on neonatal hypoxia-ischemia brain injury. 7-day old rats were subjected to hypoxia-ischemia (H-I) and treated with combination of memantine and HBO or HH. The brain damage was evaluated by examination of infarct area and the number of apoptotic cells in CA1 region of hippocampus. Additionally, the level of reactive oxygen species (ROS) was measured. Memantine, HBO or HH postconditioning applied at short time (1-6h) after H-I, and repeated for two subsequent days, resulted in significant neuroprotection. The reduction in ipsilateral hemisphere weight deficit and in the size of infarct area was observed 14days after H-I. A reduction in apoptosis and ROS level was also observed. Combining memantine with HBO or HH resulted in a loss of neuroprotection. Our results show that, combining HBO or HH postconditioning with memantine produce no additive increase in the neuroprotective effect. On the contrary, combining the treatments resulted in lower neuroprotection in comparison to the effects of memantine, HBO or HH alone. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Zn(II)- and Cu(II)-induced non-fibrillar aggregates of amyloid-beta (1-42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators.

Science.gov (United States)

Tõugu, Vello; Karafin, Ann; Zovo, Kairit; Chung, Roger S; Howells, Claire; West, Adrian K; Palumaa, Peep

2009-09-01

Aggregation of amyloid-beta (Abeta) peptides is a central phenomenon in Alzheimer's disease. Zn(II) and Cu(II) have profound effects on Abeta aggregation; however, their impact on amyloidogenesis is unclear. Here we show that Zn(II) and Cu(II) inhibit Abeta(42) fibrillization and initiate formation of non-fibrillar Abeta(42) aggregates, and that the inhibitory effect of Zn(II) (IC(50) = 1.8 micromol/L) is three times stronger than that of Cu(II). Medium and high-affinity metal chelators including metallothioneins prevented metal-induced Abeta(42) aggregation. Moreover, their addition to preformed aggregates initiated fast Abeta(42) fibrillization. Upon prolonged incubation the metal-induced aggregates also transformed spontaneously into fibrils, that appear to represent the most stable state of Abeta(42). H13A and H14A mutations in Abeta(42) reduced the inhibitory effect of metal ions, whereas an H6A mutation had no significant impact. We suggest that metal binding by H13 and H14 prevents the formation of a cross-beta core structure within region 10-23 of the amyloid fibril. Cu(II)-Abeta(42) aggregates were neurotoxic to neurons in vitro only in the presence of ascorbate, whereas monomers and Zn(II)-Abeta(42) aggregates were non-toxic. Disturbed metal homeostasis in the vicinity of zinc-enriched neurons might pre-dispose formation of metal-induced Abeta aggregates, subsequent fibrillization of which can lead to amyloid formation. The molecular background underlying metal-chelating therapies for Alzheimer's disease is discussed in this light.

The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo.

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Xie, Zhongcong; Culley, Deborah J; Dong, Yuanlin; Zhang, Guohua; Zhang, Bin; Moir, Robert D; Frosch, Matthew P; Crosby, Gregory; Tanzi, Rudolph E

2008-12-01

An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid beta-protein (Abeta) in cultured cells. However, the in vivo relevance has not been addressed. We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction. Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Abeta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo. Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation.

Influence of scan duration on the accuracy of {beta}-amyloid PET with florbetaben in patients with Alzheimer's disease and healthy volunteers

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Tiepolt, Solveig; Barthel, Henryk; Butzke, Daniel; Hesse, Swen; Patt, Marianne; Sabri, Osama [University of Leipzig, Department of Nuclear Medicine, Leipzig (Germany); Gertz, Hermann-Josef [University of Leipzig, Department of Psychiatry, Leipzig (Germany); Reininger, Cornelia [Bayer Pharma AG, Global Clinical Development, Berlin (Germany)

2013-02-15

Florbetaben is a {beta}-amyloid-targeted PET tracer with significant potential for augmenting the toolbox in the clinical diagnosis of Alzheimer's disease (AD). In dementia imaging, shortening of scan duration may simplify future clinical use. The aim of this retrospective study was to investigate the effect of scan duration on diagnostic accuracy. PET scans obtained from 25 AD patients and 25 healthy volunteers (HVs) were analysed. In each subject, scans of three different durations (5, 10 and 20 min; all starting 90 min after injection) were obtained, randomized, and visually assessed by three experts blinded to the subject's identity and group affiliation. Presence/absence of {beta}-amyloid and diagnostic confidence (0-100 %) were scored, and 10 % of the scans were re-read. Further, randomly selected datasets of ten AD patients and ten HVs were quantified using an established VOI-based approach and using a voxel-based approach. The sensitivity and specificity of the blinded read were 80 % and 96 %, respectively, for all scan durations. Diagnostic confidence was high (97 {+-} 6 %, 97 {+-} 6 % and 95 {+-} 8 % for the 20-min, 10-min and 5-min scans, respectively; n.s.), as was interreader agreement (kappa{sub 20} {sub min} = 0.94, kappa{sub 10} {sub min} = 0.94, kappa{sub 5} {sub min} = 0.89; n.s.). Intrareader agreement was highest for the 20-min scan (kappa = 1.00) and lower for the 10-min scan (kappa = 0.71) and 5-min scan (kappa = 0.80; p = 0.002 and 0.003 vs. the 20-min scan). For all scan durations, composite SUVRs (Cohen's d effect size 4.5, 3.9 and 4.8 for the 5-min, 10-min and 20-min scans; p < 0.0001 each) and individual brain volumes affected by {beta}-amyloid (Cohen's d effect size 1.6, 1.8 and 2.0 for the 5-min, 10-min and 20-min scans; p < 0.005 each) were significantly higher in AD patients than in HVs. Reduction in scan duration did not relevantly affect the accuracy of florbetaben PET scans in discriminating between AD patients

Differential regulation of GluA1 expression by ketamine and memantine.

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Zhang, Ke; Yamaki, Vitor Nagai; Wei, Zhisheng; Zheng, Yu; Cai, Xiang

2017-01-01

Evidence from preclinical and clinical studies shows that ketamine, a noncompetitive NMDA receptor antagonist, exerts rapid and sustained antidepressant responses. However, ketamine's psychotomimetic side effects and abuse liability limit the clinical use of the compound. Interestingly, memantine, another NMDA receptor channel blocker, processes no defined antidepressant property but is much safer and clinical tolerated. Understanding why ketamine but not memantine exhibits rapid antidepressant responses is important to elucidate the cellular signaling underlying the fast antidepressant actions of ketamine and to design a new safer generation of fast-acting antidepressants. Here we show that ketamine but memantine caused a rapid and sustained antidepressant-like responses in forced swim test (FST). Both drugs enhanced GluA1 S845 phosphorylation and potentiated Schaffer collateral-CA1 synaptic transmission. However, ketamine but not memantine elevated the expression of GluA1. Incubating acutely prepared hippocampal slices with ketamine but not memantine enhanced mTOR phosphorylation in a time course parallel to the time course of GluA1 elevation. Our results suggest that distinct properties in regulation of mTOR phosphorylation and synaptic protein expression may underlie the differential effectiveness of ketamine and memantine in their antidepressant responses. Copyright © 2016 Elsevier B.V. All rights reserved.

Enhancement of long-term spatial memory in adult rats by the noncompetitive NMDA receptor antagonists, memantine and neramexane.

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Zoladz, Phillip R; Campbell, Adam M; Park, Collin R; Schaefer, Daniela; Danysz, Wojciech; Diamond, David M

2006-10-01

Memantine and neramexane are noncompetitive NMDA receptor antagonists which have been investigated for their promising effects in aiding memory in people with dementia. Memantine is approved for the treatment of Alzheimer's disease, and neramexane is currently under development for this indication. Therefore, the present study provided a comparative assessment of the effects of equimolar doses of memantine and neramexane on spatial (hippocampus-dependent) memory. Adult male rats were given only 3 training trials to learn the location of a hidden platform in a water maze. In control (vehicle-injected) rats, this minimal amount of training produced intact short-term (15 min), but poor long-term (24 h), memory. Pre-training administration of memantine or neramexane produced a dose-dependent enhancement of long-term memory. Pharmacokinetic experiments with equimolar doses of both agents indicated that lower plasma levels of neramexane were more effective than memantine at enhancing memory. The effective doses of both agents in the current study produced plasma levels (and extrapolated brain CSF levels) within a range of activity at NMDA receptors and plasma levels seen in patients with Alzheimer's disease. These findings provide support for the use of neramexane as a pharmacological intervention in the treatment of dementia.

A placebo-controlled study of memantine (Ebixa) in dementia of Wernicke-Korsakoff syndrome.

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Rustembegović, Avdo; Kundurović, Zlata; Sapcanin, Aida; Sofic, Emin

2003-01-01

We evaluated the responses of 16 patients to preliminarily explore the spectrum of effectiveness and tolerability of the memantine, and NMDA antagonist, in the treatment of dementia in Wernicke-Korsakoff syndrome. In this study, for the first time in dementia of Wernicke-Korsakoff syndrome, the response to memantine was assessed. 16 patients with median age of 64 years and median body weight of 77 kg were treated with memantine 10 mg twice daily for up to 28 weeks. Clinical global impressions (CGI), and Mini Mental Status Examination (MMSE) were performed during the treatment period (after 2, 4, and 28 weeks). Efficacy measures also included the ADCS-Activities of Daily Living scale (ADCS-ADL). At 28 weeks, the ADCS-ADL showed significantly less deterioration in memantine treated patients compared with placebo (-2.3 compared with -4.3: p = 0.005). The results of MMSE demonstrate a significant and clinically relevant benefit for memantine relative to placebo as shown by positive outcomes in cognitive and functional assessments. Memantine (10 mg) was safe and well tolerated. The preliminarily findings of this study with 16 patients suggested that memantine is effective in the treatment of dementia in Wernicke-Korsakoff syndrome.

Neurodegenerative cerebrospinal fluid biomarkers tau and amyloid beta predict functional, quality of life, and neuropsychological outcomes after aneurysmal subarachnoid hemorrhage.

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Joswig, Holger; Korte, Wolfgang; Früh, Severin; Epprecht, Lorenz; Hildebrandt, Gerhard; Fournier, Jean-Yves; Stienen, Martin Nikolaus

2018-04-01

Cerebrospinal fluid (CSF) biomarkers might be useful in predicting outcome after aneurysmal subarachnoid hemorrhage (aSAH). It was the aim to determine whether tau and amyloid beta CSF concentrations predict functional, health-related quality of life (hrQoL), and neuropsychological outcomes after aSAH. Ventricular CSF was obtained from n = 24 aSAH patients at admission (D0), day 2 (D2), and day 6 (D6). CSF total (t)Tau, phosphorylated (p)Tau (181P) , and amyloid beta (1-40 and 1-42) (Aβ40/Aβ42) levels were compared between patients with favorable and unfavorable functional (modified Rankin Scale (mRS)), hrQoL (Euro-Qol (EQ-5D)), and neuropsychological outcomes at 3 (3 m) and 12 months (12 m). Patients with unfavorable functional (mRS 4-6) and hrQoL outcome (EQ-5D z-score ≤ - 1.0) at 3 and 12 m had higher CSF tTau/pTau and lower Aβ40/Aβ42 at D0, D2, and D6 with varying degrees of statistical significance. In terms of predicting neuropsychological outcome, CSF pTau showed a statistically significant correlation with the z-scores of executive function (r = - 0.7486, p = 0.008), verbal memory (r = - 0.8101, p = 0.002), attention (r = - 0.6498, p = 0.030), and visuospatial functioning (r = - 0.6944, p = 0.017) at 3 m. At 12 m, CSF pTau had statistically significant correlations with the z-scores of verbal memory (r = - 0.7473, p = 0.008) and visuospatial functioning (r = - 0.6678, p = 0.024). In conclusion, higher tTau/pTau and lower Aβ40/Aβ42 CSF levels predict unfavorable long-term functional and hrQoL outcomes. Neuropsychological deficits correlate with increased CSF tTau and pTau concentrations.

Origin of life. Primordial genetics: Information transfer in a pre-RNA world based on self-replicating beta-sheet amyloid conformers.

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Maury, Carl Peter J

2015-10-07

The question of the origin of life on Earth can largely be reduced to the question of what was the first molecular replicator system that was able to replicate and evolve under the presumably very harsh conditions on the early Earth. It is unlikely that a functional RNA could have existed under such conditions and it is generally assumed that some other kind of information system preceded the RNA world. Here, I present an informational molecular system that is stable, self-replicative, environmentally responsive, and evolvable under conditions characterized by high temperatures, ultraviolet and cosmic radiation. This postulated pregenetic system is based on the amyloid fold, a functionally unique polypeptide fold characterized by a cross beta-sheet structure in which the beta strands are arranged perpendicular to the fiber axis. Beside an extraordinary structural robustness, the amyloid fold possesses a unique ability to transmit information by a three-dimensional templating mechanism. In amyloidogenesis short peptide monomers are added one by one to the growing end of the fiber. From the same monomeric subunits several structural variants of amyloid may be formed. Then, in a self-replicative mode, a specific amyloid conformer can act as a template and confer its spatially encoded information to daughter molecular entities in a repetitive way. In this process, the specific conformational information, the spatially changed organization, is transmitted; the coding element is the steric zipper structure, and recognition occurs by amino acid side chain complementarity. The amyloid information system fulfills several basic requirements of a primordial evolvable replicator system: (i) it is stable under the presumed primitive Earth conditions, (ii) the monomeric building blocks of the informational polymer can be formed from available prebiotic compounds, (iii) the system is self-assembling and self-replicative and (iv) it is adaptive to changes in the environment and

Diagnostic radionuclide imaging of amyloid: biological targeting by circulating human serum amyloid P component

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Hawkins, P.N.; Lavender, J.P.; Myers, M.J.; Pepys, M.B.

1988-06-25

The specific molecular affinity of the normal plasma protein, serum amyloid P component (SAP), for all known types of amyloid fibrils was used to develop a new general diagnostic method for in-vivo radionuclide imaging of amyloid deposits. After intravenous injection of /sup 123/I-labelled purified human SAP there was specific uptake into amyloid deposits in all affected patients, 7 with systematic AL amyloid, 5 with AA amyloid, and 2 with ..beta../sub 2/M amyloid, in contrast to the complete absence of any tissue localisation in 5 control subjects. Distinctive high-resolution scintigraphic images, even of minor deposits in the carpal regions, bone marrow, or adrenals, were obtained. This procedure should yield much information on the natural history and the management of amyloidosis, the presence of which has hitherto been confirmed only by biopsy. Clearance and metabolic studies indicated that, in the presence of extensive amyloidosis, the rate of synthesis of SAP was greatly increased despite maintenance of normal plasma levels. Futhermore, once localised to amyloid deposits the /sup 123/I-SAP persisted for long periods and was apparently protected from its normal rapid degradation. These findings shed new light on the pathophysiology of amyloid and may have implications for therapeutic strategies based upon specific molecular targeting with SAP.

Memory and mood during MDMA intoxication, with and without memantine pretreatment.

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de Sousa Fernandes Perna, E B; Theunissen, E L; Kuypers, K P C; Heckman, P; de la Torre, R; Farre, M; Ramaekers, J G

2014-12-01

Previous studies have shown that single doses of MDMA can affect mood and impair memory in humans. The neuropharmacological mechanisms involved in MDMA-induced memory impairment are not clear. Memantine, an NMDA and alpha 7 nicotinic acetylcholine (ACh) receptor antagonist, was able to reverse MDMA-induced memory impairment in rats. This study investigated whether treatment with memantine can prevent MDMA-induced memory impairment in humans. 15 subjects participated in a double-blind, placebo controlled, within-subject design. Subjects received both pre-treatment (placebo/memantine 20 mg) (T1) and treatment (placebo/MDMA 75 mg) (T2) on separate test days. T1 preceded T2 by 120 min. Memory function was assessed 90 min after T2 by means of a Visual Verbal Learning Task, a Prospective Memory Task, the Sternberg Memory Task and the Abstract Visual Pattern Learning Task. Profile of Mood State and psychomotor performance were also assessed to control whether MDMA and memantine interactions would selectively pertain to memory or transfer to other domains as well. MDMA significantly impaired performance in the visual verbal learning task and abstract visual pattern learning task. Pre-treatment with memantine did not prevent MDMA-induced memory impairment in these two tasks. Both positive (vigour, arousal, elation) and negative mood effects (anxiety) were increased by MDMA. The responses were not altered by pretreatment with memantine which had no effect on memory or mood when given alone. These preliminary results suggest that memantine does not reverse MDMA-induced memory impairment and mood in humans. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Liquid Crystal Enabled Early Stage Detection of Beta Amyloid Formation on Lipid Monolayers

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Sadati, Monirosadat [Institute for Molecular Engineering, University of Chicago, Chicago IL 60637 USA; Apik, Aslin Izmitli [Chemical and Biological Engineering, University of Wisconsin, Madison WI 53706 USA; Armas-Perez, Julio C. [Institute for Molecular Engineering, University of Chicago, Chicago IL 60637 USA; Martinez-Gonzalez, Jose [Institute for Molecular Engineering, University of Chicago, Chicago IL 60637 USA; Hernandez-Ortiz, Juan P. [Institute for Molecular Engineering, University of Chicago, Chicago IL 60637 USA; Departamento de Materiales y Minerales, Facultad de Minas, Universidad Nacional de Colombia, Sede Medellín, Calle 75 # 79A-51, Bloque M17 Medellín Colombia; Abbott, Nicholas L. [Chemical and Biological Engineering, University of Wisconsin, Madison WI 53706 USA; de Pablo, Juan J. [Institute for Molecular Engineering, University of Chicago, Chicago IL 60637 USA; Argonne National Laboratory, Argonne IL 60439 USA

2015-09-09

Liquid crystals (LCs) can serve as sensitive reporters of interfacial events, and this property has been used for sensing of synthetic or biological toxins. Here it is demonstrated that LCs can distinguish distinct molecular motifs and exhibit a specific response to beta-sheet structures. That property is used to detect the formation of highly toxic protofibrils involved in neurodegenerative diseases, where it is crucial to develop methods that probe the early-stage aggregation of amyloidogenic peptides in the vicinity of biological membranes. In the proposed method, the amyloid fibrils formed at the lipid-decorated LC interface can change the orientation of LCs and form elongated and branched structures that are amplified by the mesogenic medium; however, nonamyloidogenic peptides form ellipsoidal domains of tilted LCs. Moreover, a theoretical and computational analysis is used to reveal the underlying structure of the LC, thereby providing a detailed molecular-level view of the interactions and mechanisms responsible for such motifs. The corresponding signatures can be detected at nanomolar concentrations of peptide by polarized light microscopy and much earlier than the ones that can be identified by fluorescence-based techniques. As such, it offers the potential for early diagnoses of neurodegenerative diseases and for facile testing of inhibitors of amyloid formation.

Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease

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Roger J. Mullins

2017-05-01

Full Text Available Current hypotheses and theories regarding the pathogenesis of Alzheimer’s disease (AD heavily implicate brain insulin resistance (IR as a key factor. Despite the many well-validated metrics for systemic IR, the absence of biomarkers for brain-specific IR represents a translational gap that has hindered its study in living humans. In our lab, we have been working to develop biomarkers that reflect the common mechanisms of brain IR and AD that may be used to follow their engagement by experimental treatments. We present two promising biomarkers for brain IR in AD: insulin cascade mediators probed in extracellular vesicles (EVs enriched for neuronal origin, and two-dimensional magnetic resonance spectroscopy (MRS measures of brain glucose. As further evidence for a fundamental link between brain IR and AD, we provide a novel analysis demonstrating the close spatial correlation between brain expression of genes implicated in IR (using Allen Human Brain Atlas data and tau and beta-amyloid pathologies. We proceed to propose the bold hypotheses that baseline differences in the metabolic reliance on glycolysis, and the expression of glucose transporters (GLUT and insulin signaling genes determine the vulnerability of different brain regions to Tau and/or Amyloid beta (Aβ pathology, and that IR is a critical link between these two pathologies that define AD. Lastly, we provide an overview of ongoing clinical trials that target IR as an angle to treat AD, and suggest how biomarkers may be used to evaluate treatment efficacy and target engagement.

Amyloid-degrading ability of nattokinase from Bacillus subtilis natto.

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Hsu, Ruei-Lin; Lee, Kung-Ta; Wang, Jung-Hao; Lee, Lily Y-L; Chen, Rita P-Y

2009-01-28

More than 20 unrelated proteins can form amyloid fibrils in vivo which are related to various diseases, such as Alzheimer's disease, prion disease, and systematic amyloidosis. Amyloid fibrils are an ordered protein aggregate with a lamellar cross-beta structure. Enhancing amyloid clearance is one of the targets of the therapy of these amyloid-related diseases. Although there is debate on whether the toxicity is due to amyloids or their precursors, research on the degradation of amyloids may help prevent or alleviate these diseases. In this study, we explored the amyloid-degrading ability of nattokinase, a fibrinolytic subtilisin-like serine protease, and determined the optimal conditions for amyloid hydrolysis. This ability is shared by proteinase K and subtilisin Carlsberg, but not by trypsin or plasmin.

Tuning the stereo-hindrance of a curcumin scaffold for the selective imaging of the soluble forms of amyloid beta species.

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Li, Yuyan; Yang, Jian; Liu, Hongwu; Yang, Jing; Du, Lei; Feng, Haiwei; Tian, Yanli; Cao, Jianqin; Ran, Chongzhao

2017-11-01

Amyloid peptides and proteins are associated with the pathologies of numerous diseases. In the progression of a disease, amyloids exist in soluble and insoluble forms, which are the dominant species at different stages of the disease and they have different degrees of toxicity. However, differentiating between the soluble and insoluble forms is very challenging with small molecule probes due to multiple obstacles that need to be overcome. Inspired by the recognition principle of antibodies for sAβ, we hypothesized that the accessibility/tightness of soluble and insoluble amyloids could be utilized to design imaging probes to recognize different amyloid forms and the stereo-hindrance tuning strategy could be used to design imaging probes for selectively detecting the soluble amyloid beta (sAβ) species in Alzheimer's disease (AD). Herein, we demonstrated that tuning the stereo-hindrance of the phenoxy-alkyl chains at the 4-position of a curcumin scaffold could lead to certain selectivity for sAβ over insoluble Aβs (insAβ). Among the designed compounds, CRANAD-102 showed a 68-fold higher affinity for sAβ than for insAβ (7.5 ± 10 nM vs. 505.9 ± 275.9 nM). Moreover, our imaging data indicated that CRANAD-102 was indeed capable of detecting sAβ in vivo using 4 month old APP/PS1 mice, in which sAβ is the predominant species in the brain. In addition, we also demonstrated that CRANAD-102 could be used to monitor the increase in sAβ loading from the ages of 4 months old to 12 months old. We believe that CRANAD-102 can be a useful probe for selectively detecting sAβ species in AD and that our probe designing strategy can be applied to other amyloids and will have tremendous impact on AD drug development and other amyloid research.

The effects of memantine on behavioral disturbances in patients with Alzheimer's disease: a meta-analysis

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Kishi T

2017-07-01

Full Text Available Taro Kishi,* Shinji Matsunaga,* Nakao Iwata Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan *These authors contributed equally to this work Background: Memantine is effective in the treatment of behavioral disturbances in patients with Alzheimer’s disease. It has not yet been fully determined which behavioral disturbances respond best to memantine.Methods: We conducted a meta-analysis of memantine vs control (placebo or usual care for the treatment of individual behavioral disturbances (delusion, hallucination, agitation/aggression, dysphoria, anxiety/phobia, euphoria, apathy, disinhibition, irritability/lability, aberrant motor activity/activity disturbances, nighttime disturbance/diurnal rhythm disturbances, and eating disturbances. Randomized controlled studies of memantine in patients with Alzheimer’s disease were included in this study. To evaluate these outcomes, standardized mean difference (SMD, with 95% confidence intervals (95% CIs, based upon a random-effects model was evaluated in the meta-analysis.Results: A total of 11 studies (n=4,261; memantine vs placebo: N=4, n=1,500; memantine + cholinesterase inhibitors [M + ChEIs] vs ChEIs: N=7, n=2,761 were included in the meta-analysis. Compared to control, memantine showed significant improvement in agitation/aggression (SMD =-0.11; 95% CIs =-0.20, -0.03; P=0.01; I2=47%, delusion (SMD =-0.12; 95% CIs =-0.18, -0.06; P=0.0002; I2=0%, disinhibition (SMD =-0.08; 95% CIs =-0.15, -0.00; P=0.04; I2=0%, and nighttime disturbance/diurnal rhythm disturbances (SMD =-0.10; 95% CIs =-0.18, -0.02; P=0.02; I2=36%. Memantine was also marginally superior to control in hallucination (SMD =-0.06; 95% CIs =-0.12, 0.01; P=0.07; I2=0% and irritability/lability (SMD =-0.09; 95% CIs =-0.19, 0.01; P=0.07; I2=42%. Memantine is similar to control in dysphoria, anxiety/phobia, euphoria, apathy, and eating disturbance.Conclusion: The meta-analysis suggest

A role for 12/15 lipoxygenase in the amyloid beta precursor protein metabolism.

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Succol, Francesca; Praticò, Domenico

2007-10-01

12/15 Lipoxygenase (12/15LO) protein levels and activity are increased in pathologically affected regions of Alzheimer's disease (AD) brains, compared with controls. Its metabolic products are elevated in cerebrospinal fluid of patients with AD and individuals with mild cognitive impairment, suggesting that this enzyme may be involved early in AD pathogenesis. Herein, we investigate the effect of pharmacologic inhibition of 12/15LO on the amyloid beta precursor protein (APP) metabolism. To this end, we used CHO and N2A cells stably expressing human APP with the Swedish mutant, and two structurally distinct and selective 12/15LO inhibitors, PD146176 and CDC. Our results demonstrated that both drugs dose-dependently reduced Abeta formation without affecting total APP levels. Interestingly, in the same cells we observed a significant reduction in secreted (s)APPbeta and beta-secretase (BACE), but not sAPPalpha and ADAM10 protein levels. Together, these data show for the first time that this enzymatic pathway influences Abeta formation whereby modulating the BACE proteolytic cascade. We conclude that specific pharmacologic inhibition of 12/15LO could represent a novel therapeutic target for treating or preventing AD pathology in humans.

Preventive immunization of aged and juvenile non-human primates to beta-amyloid

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Kofler Julia

2012-05-01

Full Text Available Abstract Background Immunization against beta-amyloid (Aβ is a promising approach for the treatment of Alzheimer’s disease, but the optimal timing for the vaccination remains to be determined. Preventive immunization approaches may be more efficacious and associated with fewer side-effects; however, there is only limited information available from primate models about the effects of preclinical vaccination on brain amyloid composition and the neuroinflammatory milieu. Methods Ten non-human primates (NHP of advanced age (18–26 years and eight 2-year-old juvenile NHPs were immunized at 0, 2, 6, 10 and 14 weeks with aggregated Aβ42 admixed with monophosphoryl lipid A as adjuvant, and monitored for up to 6 months. Anti-Aβ antibody levels and immune activation markers were assessed in plasma and cerebrospinal fluid samples before and at several time-points after immunization. Microglial activity was determined by [11C]PK11195 PET scans acquired before and after immunization, and by post-mortem immunohistochemical and real-time PCR evaluation. Aβ oligomer composition was assessed by immunoblot analysis in the frontal cortex of aged immunized and non-immunized control animals. Results All juvenile animals developed a strong and sustained serum anti-Aβ IgG antibody response, whereas only 80 % of aged animals developed detectable antibodies. The immune response in aged monkeys was more delayed and significantly weaker, and was also more variable between animals. Pre- and post-immunization [11C]PK11195 PET scans showed no evidence of vaccine-related microglial activation. Post-mortem brain tissue analysis indicated a low overall amyloid burden, but revealed a significant shift in oligomer size with an increase in the dimer:pentamer ratio in aged immunized animals compared with non-immunized controls (P  Conclusions Our results indicate that preventive Aβ immunization is a safe therapeutic approach lacking adverse CNS immune system

Detection of Alzheimer's amyloid beta aggregation by capturing molecular trails of individual assemblies

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Vestergaard, Mun'delanji; Hamada, Tsutomu; Saito, Masato; Yajima, Yoshifumi; Kudou, Monotori; Tamiya, Eiichi; Takagi, Masahiro

2008-01-01

Assembly of Amyloid beta (Aβ) peptides, in particular Aβ-42 is central to the formation of the amyloid plaques associated with neuro-pathologies such as Alzheimer's disease (AD). Molecular assembly of individual Aβ-42 species was observed using a simple fluorescence microscope. From the molecular movements (aka Brownian motion) of the individual peptide assemblies, we calculated a temporal evolution of the hydrodynamic radius (R H ) of the peptide at physiological temperature and pH. The results clearly show a direct relationship between R H of Aβ-42 and incubation period, corresponding to the previously reported peptide's aggregation kinetics. The data correlates highly with in solution-based label-free electrochemical detection of the peptide's aggregation, and Aβ-42 deposited on a solid surface and analysed using atomic force microscopy (AFM). To the best of our knowledge, this is the first analysis and characterisation of Aβ aggregation based on capturing molecular trails of individual assemblies. The technique enables both real-time observation and a semi-quantitative distribution profile of the various stages of Aβ assembly, at microM peptide concentration. Our method is a promising candidate for real-time observation and analysis of the effect of other pathologically-relevant molecules such as metal ions on pathways to Aβ oligomerisation and aggregation. The method is also a promising screening tool for AD therapeutics that target Aβ assembly.

Changes of Functional and Directed Resting-State Connectivity Are Associated with Neuronal Oscillations, ApoE Genotype and Amyloid Deposition in Mild Cognitive Impairment

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Lars Michels

2017-09-01

Full Text Available The assessment of effects associated with cognitive impairment using electroencephalography (EEG power mapping allows the visualization of frequency-band specific local changes in oscillatory activity. In contrast, measures of coherence and dynamic source synchronization allow for the study of functional and effective connectivity, respectively. Yet, these measures have rarely been assessed in parallel in the context of mild cognitive impairment (MCI and furthermore it has not been examined if they are related to risk factors of Alzheimer’s disease (AD such as amyloid deposition and apolipoprotein ε4 (ApoE allele occurrence. Here, we investigated functional and directed connectivities with Renormalized Partial Directed Coherence (RPDC in 17 healthy controls (HC and 17 participants with MCI. Participants underwent ApoE-genotyping and Pittsburgh compound B positron emission tomography (PiB-PET to assess amyloid deposition. We observed lower spectral source power in MCI in the alpha and beta bands. Coherence was stronger in HC than MCI across different neuronal sources in the delta, theta, alpha, beta and gamma bands. The directed coherence analysis indicated lower information flow between fronto-temporal (including the hippocampus sources and unidirectional connectivity in MCI. In MCI, alpha and beta RPDC showed an inverse correlation to age and gender; global amyloid deposition was inversely correlated to alpha coherence, RPDC and beta and gamma coherence. Furthermore, the ApoE status was negatively correlated to alpha coherence and RPDC, beta RPDC and gamma coherence. A classification analysis of cognitive state revealed the highest accuracy using EEG power, coherence and RPDC as input. For this small but statistically robust (Bayesian power analyses sample, our results suggest that resting EEG related functional and directed connectivities are sensitive to the cognitive state and are linked to ApoE and amyloid burden.

SERUM ANALYSIS OF AMYLOID BETA-PROTEIN 1-40 IN HEALTHY SUBJECTS, AUTISTIC CHILDREN AND ALZHEIMER’S PATIENTS

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Vijendra K. SINGH

2008-06-01

Full Text Available Amyloid beta-protein1-40 (AP40 is a low molecu­lar weight peptide produced throughout life during normal cell metabolism and neurodegenerative diseases. Owing to its neurotrophic and neurotoxic effects, the present study was conducted to evalu­ate serum levels of AP40 in healthy subjects, au­tistic children and Alzheimer’s disease patients. Serum AP40 was measured by enzyme-linked im­munosorbent assay (ELISA. AP40 was signifi­cantly higher in normal children compared to nor­mal older controls, in normal children compared to autistic children, and in autistic children compared to Alzheimer’s patients (p value was less than 0.05 for all groups. This finding suggests an age-re­lated decline of serum AP40 in normal aging, as well as in autism and Alzheimer’s disease. This decline may result from abnormal processing of amyloid beta-protein precursor (APP during nor­mal aging and age-related diseases such as autism in children and Alzheimer’s disease in elderly. Possible explanations for this decline may include age-related increased interactions of AP40 with cytoskeletal proteins for brain tissue deposition, increased serine proteases for APP metabolism or hyperimmune reaction (antibodies to AP40 for removal of circulating AP40. To conclude, the AP40 metabolism declines with normal aging and in addition to its role in Alzheimer’s disease this protein might also be a contributing factor in au­tism.

First-principles calculation of structural and electronic properties of memantine (Alzheimer's disease) and adamantane (anti-flu) drugs

Science.gov (United States)

Middleton, Kirsten; Zhang, Guoping; George, Thomas F.

2012-02-01

Memantine is currently used as a treatment for mild to severe Alzheimer's disease, although its functionality is complicated. Using various density functional theory calculations and basis sets, we first examine memantine alone and then add ions which are present in the human body. This provides clues as to how the compound may react in the calcium ion channel, where it is believed to treat the disease. In order to understand the difference between calcium and magnesium ions interacting with memantine, we compute the electron affinity of each complex. We find that memantine is more strongly attracted to magnesium ions than calcium ions within the channel. By observing the HOMO-LUMO gap within memantine in comparison to adamantane, we find that memantine is more excitable than the anti-flu drug. We believe these factors to affect the efficiency of memantine as a treatment of Alzheimer's disease.

Indirubin-3′-monoxime suppresses amyloid-beta-induced apoptosis by inhibiting tau hyperphosphorylation

Institute of Scientific and Technical Information of China (English)

Shu-gang Zhang; Xiao-shan Wang; Ying-dong Zhang; Qing Di; Jing-ping Shi; Min Qian; Li-gang Xu; Xing-jian Lin; Jie Lu

2016-01-01

Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apopto-sis in Alzheimer’s disease. Here, we found that indirubin-3′-monoxime improved the morphology and increased the survival rate of SH-SY5Y cells exposed to amyloid-beta 25–35 (Aβ25–35), and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3′-monoxime inhibited phosphorylation of glycogen synthase kinase-3β (GSK-3β). Our results suggest that in-dirubin-3′-monoxime reduced Aβ25–35-induced apoptosis by suppressing tau hyperphosphorylationvia a GSK-3β-mediated mechanism. Indirubin-3′-monoxime is a promising drug candidate for Alzheimer’s disease.

Cellular and substrate adhesion molecules (integrins) and their ligands in cerebral amyloid plaques in Alzheimer's disease

NARCIS (Netherlands)

Eikelenboom, P.; Zhan, S. S.; Kamphorst, W.; van der Valk, P.; Rozemuller, J. M.

1994-01-01

Integrins belonging to different subfamilies can be identified immunohistochemically in cerebral amyloid plaques. Monoclonal antibodies against the VLA family beta 1-integrins show staining of the corona of classical amyloid plaques for beta 1, alpha 3 and alpha 6. Immunostaining reveal also the

Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease

DEFF Research Database (Denmark)

Steen Jensen, Camilla; Portelius, Erik; Siersma, Volkert

2016-01-01

BACKGROUND: Physical exercise may have some effect on cognition in patients with Alzheimer disease (AD). However, the underlying biochemical effects are unclear. Animal studies have shown that amyloid beta (Aβ), one of the pathological hallmarks of AD, can be altered with high levels of physical...... of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study we analyzed cerebrospinal fluid samples for Aβ species, total tau (t-tau), phosphorylated tau (p-tau) and soluble amyloid precursor protein (sAPP) species. We also assessed the patients...

Memantine mediates neuroprotection via regulating neurovascular unit in a mouse model of focal cerebral ischemia.

Science.gov (United States)

Chen, Zheng-Zhen; Yang, Dan-Dan; Zhao, Zhan; Yan, Hui; Ji, Juan; Sun, Xiu-Lan

2016-04-01

Memantine is a low-moderate affinity and uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist, which is also a potential neuroprotectant in acute ischemic stroke for its particular action profiles. The present study was to reveal the mechanisms involved in the neuroprotection of memantine. We used a mouse model of permanent focal cerebral ischemia via middle cerebral artery occlusion to verify our hypothesis. 2,3,5-Triphenyltetrazolium chloride staining was used to compare infarct size. The amount of astrocytes and the somal volume of the microglia cell body were analyzed by immunohistochemistry and stereological estimates. Western blotting was used to determine the protein expressions. Memantine prevented cerebral ischemia-induced brain infarct and neuronal injury, and reduced oxygen-glucose deprivation-induced cortical neuronal apoptosis. Moreover, memantine reduced the amount of the damaged astrocytes and over activated microglia after 24h of ischemia. In the early phase of ischemia, higher production of MMP-9 was observed, and thereby collagen IV was dramatically disrupted. Meanwhile, the post-synaptic density protein 95(PSD-95) was also severely cleavaged. Memantine decreased MMP-9 secretion, prevented the degradation of collagen IV in mouse brain. PSD-95 cleavage was also inhibited by memantine. These results suggested that memantine exerted neuroprotection effects in acute ischemic brain damage, partially via improving the functions of neurovascular unit. Taking all these findings together, we consider that memantine might be a promising protective agent against ischemic stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

Controlling amyloid-beta peptide(1-42) oligomerization and toxicity by fluorinated nanoparticles.

Science.gov (United States)

Saraiva, Ana M; Cardoso, Isabel; Pereira, M Carmo; Coelho, Manuel A N; Saraiva, Maria João; Möhwald, Helmuth; Brezesinski, Gerald

2010-09-03

The amyloid-beta peptide (Abeta) is a major fibrillar component of neuritic plaques in Alzheimer's disease brains and is related to the pathogenesis of the disease. Soluble oligomers that precede fibril formation have been proposed as the main neurotoxic species that contributes to neurodegeneration and dementia. We hypothesize that oligomerization and cytotoxicity can be repressed by nanoparticles (NPs) that induce conformational changes in Abeta42. We show here that fluorinated and hydrogenated NPs with different abilities to change Abeta42 conformation influence oligomerization as assessed by atomic force microscopy, immunoblot and SDS-PAGE. Fluorinated NPs, which promote an increase in alpha-helical content, exert an antioligomeric effect, whereas hydrogenated analogues do not and lead to aggregation. Cytotoxicity assays confirmed our hypothesis by indicating that the conformational conversion of Abeta42 into an alpha-helical-enriched secondary structure also has antiapoptotic activity, thereby increasing the viability of cells treated with oligomeric species.

Amyloid PET in European and North American cohorts; and exploring age as a limit to clinical use of amyloid imaging

Energy Technology Data Exchange (ETDEWEB)

Chiotis, Konstantinos [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); Carter, Stephen F. [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); University of Manchester, Wolfson Molecular Imaging Centre, Institute of Brain, Behaviour and Mental Health, Manchester (United Kingdom); Farid, Karim [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); APHP, Hotel-Dieu Hospital, Department of Nuclear Medicine, Paris (France); Savitcheva, Irina [Karolinska University Hospital Huddinge, Department of Radiology, Stockholm (Sweden); Nordberg, Agneta [Karolinska Institutet, Department of NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden); Collaboration: for the Diagnostic Molecular Imaging (DiMI) network and the Alzheimer' s Disease Neuroimaging Initiative

2015-09-15

Several radiotracers that bind to fibrillar amyloid-beta in the brain have been developed and used in various patient cohorts. This study aimed to investigate the comparability of two amyloid positron emission tomography (PET) tracers as well as examine how age affects the discriminative properties of amyloid PET imaging. Fifty-one healthy controls (HCs), 72 patients with mild cognitive impairment (MCI) and 90 patients with Alzheimer's disease (AD) from a European cohort were scanned with [11C]Pittsburgh compound-B (PIB) and compared with an age-, sex- and disease severity-matched population of 51 HC, 72 MCI and 84 AD patients from a North American cohort who were scanned with [18F]Florbetapir. An additional North American population of 246 HC, 342 MCI and 138 AD patients with a Florbetapir scan was split by age (55-75 vs 76-93 y) into groups matched for gender and disease severity. PET template-based analyses were used to quantify regional tracer uptake. The mean regional uptake patterns were similar and strong correlations were found between the two tracers across the regions of interest in HC (ρ = 0.671, p = 0.02), amyloid-positive MCI (ρ = 0.902, p < 0.001) and AD patients (ρ = 0.853, p < 0.001). The application of the Florbetapir cut-off point resulted in a higher proportion of amyloid-positive HC and a lower proportion of amyloid-positive AD patients in the older group (28 and 30 %, respectively) than in the younger group (19 and 20 %, respectively). These results illustrate the comparability of Florbetapir and PIB in unrelated but matched patient populations. The role of amyloid PET imaging becomes increasingly important with increasing age in the diagnostic assessment of clinically impaired patients. (orig.)

Amyloid PET in European and North American cohorts; and exploring age as a limit to clinical use of amyloid imaging

International Nuclear Information System (INIS)

Chiotis, Konstantinos; Carter, Stephen F.; Farid, Karim; Savitcheva, Irina; Nordberg, Agneta

2015-01-01

Several radiotracers that bind to fibrillar amyloid-beta in the brain have been developed and used in various patient cohorts. This study aimed to investigate the comparability of two amyloid positron emission tomography (PET) tracers as well as examine how age affects the discriminative properties of amyloid PET imaging. Fifty-one healthy controls (HCs), 72 patients with mild cognitive impairment (MCI) and 90 patients with Alzheimer's disease (AD) from a European cohort were scanned with [11C]Pittsburgh compound-B (PIB) and compared with an age-, sex- and disease severity-matched population of 51 HC, 72 MCI and 84 AD patients from a North American cohort who were scanned with [18F]Florbetapir. An additional North American population of 246 HC, 342 MCI and 138 AD patients with a Florbetapir scan was split by age (55-75 vs 76-93 y) into groups matched for gender and disease severity. PET template-based analyses were used to quantify regional tracer uptake. The mean regional uptake patterns were similar and strong correlations were found between the two tracers across the regions of interest in HC (ρ = 0.671, p = 0.02), amyloid-positive MCI (ρ = 0.902, p < 0.001) and AD patients (ρ = 0.853, p < 0.001). The application of the Florbetapir cut-off point resulted in a higher proportion of amyloid-positive HC and a lower proportion of amyloid-positive AD patients in the older group (28 and 30 %, respectively) than in the younger group (19 and 20 %, respectively). These results illustrate the comparability of Florbetapir and PIB in unrelated but matched patient populations. The role of amyloid PET imaging becomes increasingly important with increasing age in the diagnostic assessment of clinically impaired patients. (orig.)

Heterologous amyloid seeding: revisiting the role of acetylcholinesterase in Alzheimer's disease.

Directory of Open Access Journals (Sweden)

Létitia Jean

2007-07-01

Full Text Available Neurodegenerative diseases associated with abnormal protein folding and ordered aggregation require an initial trigger which may be infectious, inherited, post-inflammatory or idiopathic. Proteolytic cleavage to generate vulnerable precursors, such as amyloid-beta peptide (Abeta production via beta and gamma secretases in Alzheimer's Disease (AD, is one such trigger, but the proteolytic removal of these fragments is also aetiologically important. The levels of Abeta in the central nervous system are regulated by several catabolic proteases, including insulysin (IDE and neprilysin (NEP. The known association of human acetylcholinesterase (hAChE with pathological aggregates in AD together with its ability to increase Abeta fibrilization prompted us to search for proteolytic triggers that could enhance this process. The hAChE C-terminal domain (T40, AChE(575-614 is an exposed amphiphilic alpha-helix involved in enzyme oligomerisation, but it also contains a conformational switch region (CSR with high propensity for conversion to non-native (hidden beta-strand, a property associated with amyloidogenicity. A synthetic peptide (AChE(586-599 encompassing the CSR region shares homology with Abeta and forms beta-sheet amyloid fibrils. We investigated the influence of IDE and NEP proteolysis on the formation and degradation of relevant hAChE beta-sheet species. By combining reverse-phase HPLC and mass spectrometry, we established that the enzyme digestion profiles on T40 versus AChE(586-599, or versus Abeta, differed. Moreover, IDE digestion of T40 triggered the conformational switch from alpha- to beta-structures, resulting in surfactant CSR species that self-assembled into amyloid fibril precursors (oligomers. Crucially, these CSR species significantly increased Abeta fibril formation both by seeding the energetically unfavorable formation of amyloid nuclei and by enhancing the rate of amyloid elongation. Hence, these results may offer an explanation

Poor Memory Performance in Aged Cynomolgus Monkeys with Hippocampal Atrophy, Depletion of Amyloid Beta 1-42 and Accumulation of Tau Proteins in Cerebrospinal Fluid

DEFF Research Database (Denmark)

Darusman, Huda S; Pandelaki, Jacub; Mulyadi, Rahmad

2014-01-01

, aged cynomolgus monkeys were divided into two groups to compare high-performing (n=6) and low-performing (n=6) subjects. Both groups were tested for biomarkers related to Alzheimer's disease and their brains were scanned using structural magnetic resonance imaging. RESULTS: The subjects with poor DRT......BACKGROUND: Due to their similarities in behavior and disease pathology to humans, non-human primate models are desirable to complement small animals as models for the study of age-related dementia. MATERIALS AND METHODS: Based on their performance on delayed response task (DRT) tests of memory...... performance had evidence of atrophy in the hippocampus and cortical areas, significantly lower cerebrospinal fluid levels of amyloid beta amino acid 1-42 (pperforming well on the DRT tests. CONCLUSION: Old, memory...

Long-lasting effect of NMDA receptor antagonist memantine on ethanol-cue association and relapse.

Science.gov (United States)

Vengeliene, Valentina; Olevska, Anastasia; Spanagel, Rainer

2015-12-01

It is well known that the glutamatergic system plays a crucial role in alcohol addiction and especially in relapse-like behaviour. However, results of clinical studies on compounds that influence the activity of the glutamatergic system have been disappointing so far. The aim of our study was to establish treatment conditions under which the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine may produce more reliable treatment effect with respect to alcohol relapse-like behaviour. For this purpose, male Wistar rats were trained to associate several discrete stimuli with ethanol delivery. Thereafter, half of the animals received a brief memory reactivation session followed by two administrations of 20 mg/kg of memantine, while the other half received the same treatment without memory reactivation. Afterwards, a cue-induced ethanol-seeking behaviour test was performed followed by repeated extinction sessions and a reacquisition test. Our data show that administration of memantine reduced responding on the ethanol-associated lever in a cue-induced ethanol-seeking test. This reduction did not depend on whether or not a memory reactivation session was introduced prior to memantine administration. Following extinction, however, reacquisition of ethanol self-administration was only impaired in the group where memantine was given after a short memory reactivation session, showing that this schedule of drug administration produced a long-lasting disruption of the association between the conditioned stimuli and the delivery of ethanol. In conclusion, we show that memantine disrupted the drug-cue association, which consequently interfered with relapse-like behaviour supporting the possibility that memantine is a treatment option for alcoholism. Our data supports the possibility that memantine is a treatment option for alcoholism. However, the effectiveness of this drug seems to lie in its ability to disrupt conditioned behaviours and should be given in conjunction

Functional Amyloid Formation within Mammalian Tissue.

Directory of Open Access Journals (Sweden)

2005-11-01

Full Text Available Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

Functional amyloid formation within mammalian tissue.

Directory of Open Access Journals (Sweden)

Douglas M Fowler

2006-01-01

Full Text Available Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

Astrocytic expression of the Alzheimer's disease beta-secretase (BACE1) is stimulus-dependent

DEFF Research Database (Denmark)

Hartlage-Rübsamen, Maike; Zeitschel, Ulrike; Apelt, Jenny

2003-01-01

The beta-site APP-cleaving enzyme (BACE1) is a prerequisite for the generation of beta-amyloid peptides, which give rise to cerebrovascular and parenchymal beta-amyloid deposits in the brain of Alzheimer's disease patients. BACE1 is neuronally expressed in the brains of humans and experimental...... paradigms studied. In contrast, BACE1 expression by reactive astrocytes was evident in chronic but not in acute models of gliosis. Additionally, we observed BACE1-immunoreactive astrocytes in proximity to beta-amyloid plaques in the brains of aged Tg2576 mice and Alzheimer's disease patients....

Amyloid and tau cerebrospinal fluid biomarkers in HIV infection

Directory of Open Access Journals (Sweden)

Rosengren Lars

2009-12-01

Full Text Available Abstract Background Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF biomarkers related of amyloid and tau metabolism in HIV-infected patients. Methods In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPα and sAPPβ, amyloid beta fragment 1-42 (Aβ1-42, and total and hyperphosphorylated tau (t-tau and p-tau in CSF of 86 HIV-infected (HIV+ subjects, including 21 with AIDS dementia complex (ADC, 25 with central nervous system (CNS opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV- subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease. Results CSF sAPPα and sAPPβ concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Aβ1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections. Conclusions Parallel reductions of CSF sAPPα and sAPPβ in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those

Reducing the Levels of Akt Activation by PDK1 Knock-in Mutation Protects Neuronal Cultures against Synthetic Amyloid-Beta Peptides

Directory of Open Access Journals (Sweden)

Shaobin Yang

2018-01-01

Full Text Available The Akt kinase has been widely assumed for years as a key downstream effector of the PI3K signaling pathway in promoting neuronal survival. This notion was however challenged by the finding that neuronal survival responses were still preserved in mice with reduced Akt activity. Moreover, here we show that the Akt signaling is elevated in the aged brain of two different mice models of Alzheimer Disease. We manipulate the rate of Akt stimulation by employing knock-in mice expressing a mutant form of PDK1 (phosphoinositide-dependent protein kinase 1 with reduced, but not abolished, ability to activate Akt. We found increased membrane localization and activity of the TACE/ADAM17 α-secretase in the brain of the PDK1 mutant mice with concomitant TNFR1 processing, which provided neurons with resistance against TNFα-induced neurotoxicity. Opposite to the Alzheimer Disease transgenic mice, the PDK1 knock-in mice exhibited an age-dependent attenuation of the unfolding protein response, which protected the mutant neurons against endoplasmic reticulum stressors. Moreover, these two mechanisms cooperatively provide the mutant neurons with resistance against amyloid-beta oligomers, and might singularly also contribute to protect these mice against amyloid-beta pathology.

Amyloid beta precursor protein regulates male sexual behavior.

Science.gov (United States)

Park, Jin Ho; Bonthius, Paul J; Tsai, Houng-Wei; Bekiranov, Stefan; Rissman, Emilie F

2010-07-28

Sexual behavior is variable between individuals, ranging from celibacy to sexual addictions. Within normal populations of individual men, ranging from young to middle aged, testosterone levels do not correlate with libido. To study the genetic mechanisms that contribute to individual differences in male sexual behavior, we used hybrid B6D2F1 male mice, which are a cross between two common inbred strains (C57BL/6J and DBA/2J). Unlike most laboratory rodent species in which male sexual behavior is highly dependent upon gonadal steroids, sexual behavior in a large proportion of these hybrid male mice after castration is independent of gonadal steroid hormones and their receptors; thus, we have the ability to discover novel genes involved in this behavior. Gene expression arrays, validation of gene candidates, and transgenic mice that overexpress one of the genes of interest were used to reveal genes involved in maintenance of male sexual behavior. Several genes related to neuroprotection and neurodegeneration were differentially expressed in the hypothalamus of males that continued to mate after castration. Male mice overexpressing the human form of one of these candidate genes, amyloid beta precursor protein (APP), displayed enhanced sexual behavior before castration and maintained sexual activity for a longer duration after castration compared with controls. Our results reveal a novel and unexpected relationship between APP and male sexual behavior. We speculate that declining APP during normal aging in males may contribute to the loss of sexual function.

Cellular demise and inflammatory microglial activation during beta-amyloid toxicity are governed by Wnt1 and canonical signaling pathways.

Science.gov (United States)

Chong, Zhao Zhong; Li, Faqi; Maiese, Kenneth

2007-06-01

Initially described as a modulator of embryogenesis for a number of organ systems, Wnt1 has recently been linked to the development of several neurodegenerative disorders, none being of greater significance than Alzheimer's disease. We therefore examined the ability of Wnt1 to oversee vital pathways responsible for cell survival during beta-amyloid (Abeta1-42) exposure. Here we show that Wnt1 is critical for protection in the SH-SY5Y neuronal cell line against genomic DNA degradation, membrane phosphatidylserine (PS) exposure, and microglial activation, since these neuroprotective attributes of Wnt1 are lost during gene silencing of Wnt1 protein expression. Intimately tied to Wnt1 protection is the presence and activation of Akt1. Pharmacological inhibition of the PI 3-K pathway or gene silencing of Akt1 expression can abrogate the protective capacity of Wnt1. Closely aligned with Wnt1 and Akt1 are the integrated canonical pathways of synthase kinase-3beta (GSK-3beta) and beta-catenin. Through Akt1 dependent pathways, Wnt1 phosphorylates GSK-3beta and maintains beta-catenin integrity to insure its translocation from the cytoplasm to the nucleus to block apoptosis. Our work outlines a highly novel role for Wnt1 and its integration with Akt1, GSK-3beta, and beta-catenin to foster neuronal cell survival and repress inflammatory microglial activation that can identify new avenues of therapy against neurodegenerative disorders.

Behavior of beta-Amyloid 1-16 at the Air-Water Interface at Varying pH by Nonlinear Spectroscopy and Molecular Dynamics Simulations

Czech Academy of Sciences Publication Activity Database

Miller, A. E.; Petersen, P. B.; Hollars, C. H.; Saykally, R. J.; Heyda, Jan; Jungwirth, Pavel

2011-01-01

Roč. 115, č. 23 (2011), s. 5873-5880 ISSN 1089-5639 R&D Projects: GA MŠk LC512; GA ČR GA203/08/0114 Grant - others:NSF(US) 0650950 Institutional research plan: CEZ:AV0Z40550506 Keywords : beta-amyloid * air /water interface * SHG spectroscopy * molecular dynamics Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 2.946, year: 2011

Antagonizing beta-amyloid peptide neurotoxicity of the anti-aging fungus Ganoderma lucidum.

Science.gov (United States)

Lai, Cora Sau-Wan; Yu, Man-Shan; Yuen, Wai-Hung; So, Kwok-Fai; Zee, Sze-Yong; Chang, Raymond Chuen-Chung

2008-01-23

Ganoderma lucidum (Leyss. ex Fr.) Karst. (Lingzhi) is a medicinal fungus used clinically in many Asian countries to promote health and longevity. Synaptic degeneration is another key mode of neurodegeneration in Alzheimer's disease (AD). Recent studies have shown the loss of synaptic density proteins in each individual neuron during the progression of AD. It was recently reported that beta-amyloid (Abeta) could cause synaptic dysfunction and contribute to AD pathology. In this study, we reported that aqueous extract of G. lucidum significantly attenuated Abeta-induced synaptotoxicity by preserving the synaptic density protein, synaptophysin. In addition, G. lucidum aqueous extract antagonized Abeta-triggered DEVD cleavage activities in a dose-dependent manner. Further studies elucidated that phosphorylation of c-Jun N-terminal kinase, c-Jun, and p38 MAP kinase was attenuated by G. lucidum in Abeta-stressed neurons. Taken together, the results prove a hypothesis that anti-aging G. lucidum can prevent harmful effects of the exterminating toxin Abeta in AD.

The nicotinic alpha7 acetylcholine receptor agonist ssr180711 is unable to activate limbic neurons in mice overexpressing human amyloid-beta1-42

DEFF Research Database (Denmark)

Soderman, A.; Spang-Thomsen, Mogens; Hansen, H.

2008-01-01

Recent studies have demonstrated that amyloid-beta1-42 (Abeta1-42) binds to the nicotinergic alpha7 acetylcholine receptor (alpha7 nAChR) and that the application of Abeta1-42 to cells inhibits the function of the alpha7 nAChR. The in vivo consequences of the pharmacological activation of the alp...

Effects of breviscapine on amyloid beta 1-42 induced Alzheimer's disease mice: A HPLC-QTOF-MS based plasma metabonomics study.

Science.gov (United States)

Xia, Hongjun; Wu, Lingling; Chu, Mengying; Feng, Huimin; Lu, Chunliang; Wang, Qinghe; He, Minghai; Ge, Xiaoqun

2017-07-01

Herba Erigerontis has long been used to cure apoplexy hemiplegia and precordial pain in China. In addition, the bioactivities of its total flavonoids-breviscapine included inhibiting amyloid beta (Aβ) fibril formation, antioxidation and metal chelating, which are beneficial to treat Alzheimer's disease (AD). Hence, A HPLC-QTOF-MS based plasma metabonomics approach was applied to investigate the neuroprotective effects of breviscapine on intracerebroventricular injection of aggregated Aβ 1-42 induced AD mice for the first time in the study. Ten potential biomarkers were screened out by multivariate statistical analysis, eight of which were further identified as indoleacrylic acid, C16 sphinganine, LPE (22:6), sulfolithocholic acid, LPC (16:0), PA (22:1/0:0), taurodeoxycholic acid, and PC (0:0/18:0). According to their metabolic pathways, it was supposed that breviscapine ameliorated the learning and memory deficits of AD mice predominantly by regulating phospholipids metabolism, elevating serotonin level and lowering cholesterols content in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

In vitro effects of the anti-Alzheimer drug memantine on the human erythrocyte membrane and molecular models

International Nuclear Information System (INIS)

Zambrano, Pablo; Suwalsky, Mario; Villena, Fernando; Jemiola-Rzeminska, Malgorzata; Strzalka, Kazimierz

2017-01-01

Memantine is a NMDA antagonist receptor clinically used for treating Alzheimer's disease. NMDA receptors are present in the human neurons and erythrocyte membranes. The aim of the present study was to investigate the effects of memantine on human erythrocytes. With this purpose, the drug was developed to in vitro interact with human red cells and bilayers built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE). The latter represent lipids respectively present in both outer and inner monolayers of the red cell membrane. Results obtained by scanning electron microscopy (SEM) showed that memantine changed the normal biconcave shape of red cells to cup-shaped stomatocytes. According to the bilayer-couple hypothesis the drug intercalated into the inner monolayer of the erythrocyte membrane. Experimental results obtained by X-ray diffraction on multibilayers of DMPC and DMPE, and by differential scanning calorimetry on multilamellar vesicles indicated that memantine preferentially interacted with DMPC in a concentration-dependent manner. Thus, it can be concluded that in the low therapeutic plasma concentration of circa 1 μM memantine is located in NMDA receptor channel without affecting the erythrocyte shape. However, at higher concentrations, once the receptors became saturated excess of memantine molecules (20 μM) would interact with phosphoinositide lipids present in the inner monolayer of the erythrocyte membrane inducing the formation of stomatocytes. However, 40–50 μM memantine was required to interact with isolated phosphatidylcholine bilayers. - Highlights: • The interaction of memantine with human erythrocytes and lipid bilayers were assessed. • Memantine induced morphological changes to human erythrocytes. • Memantine interacted with classes of phospholipids present in the erythrocyte membrane. • Results support the hypothesis that memantine interacts with NMDA receptors.

Familial Alzheimer's disease mutations in presenilin 1 do not alter levels of the secreted amyloid-beta protein precursor generated by beta-secretase cleavage.

Science.gov (United States)

Zhang, Can; Browne, Andrew; Kim, Doo Yeon; Tanzi, Rudolph E

2010-02-01

Alzheimer's disease (AD) is an insidious and progressive disease with a genetically complex and heterogenous etiology. More than 200 fully penetrant mutations in the amyloid beta-protein precursor (APP), presenilin 1 (or PSEN1), and presenilin 2 (PSEN2) have been linked to early-onset familial AD (FAD). 177 PSEN1 FAD mutations have been identified so far and account for more than approximately 80% of all FAD mutations. All PSEN1 FAD mutations can increase the Abeta42:Abeta40 ratio with seemingly different and incompletely understood mechanisms. A recent study has shown that the 286 amino acid N-terminal fragment of APP (N-APP), a proteolytic product of beta-secretase-derived secreted form of APP (sAPPbeta), could bind the death receptor, DR6, and lead to neurodegeneration. Here we asked whether PSEN1 FAD mutations lead to neurodegeneration by modulating sAPPbeta levels. All four different PSEN1 FAD mutations tested (in three mammalian cell lines) did not alter sAPPbeta levels. Therefore PS1 mutations do not appear to contribute to AD pathogenesis via altered production of sAPPbeta.

Beta-amyloid-induced cholinergic denervation correlates with enhanced nitric oxide synthase activity in rat cerebral cortex: Reversal by NMDA receptor blockade : Reversal by NMDA receptor blockade

NARCIS (Netherlands)

O’Mahony, S.; Harkany, T.; Ábrahám, I.; Jong, G.I. de; Varga, J.L.; Zarándi, M.; Penke, B.; Nyakas, C.; Luiten, P.G.M.; Leonard, B.E.

1998-01-01

Ample experimental evidence indicates that acute beta-amyloid infusion into the nucleus basalis of rats elicits abrupt degeneration of the magnocellular cholinergic neurons projecting to the cerebral cortex, In fact, involvement of a permanent Ca2+ overload, partially via N-methyl-D-aspartate (NMDA)

The Effects of Melatonin with Memantin on MPTP-Induced Parkinson Model in Male Mice

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Reza Talebi

2015-09-01

Full Text Available Abstract Background: Oxidative stress and severe neuro-excitation have significant effects on pathogenesis of Parkinson’s disease and agents with antioxidant property can potentially prevent these effects. Herein we examined potential protective effects of melatonin as an antioxidant agent and memantine as an uncompetitive receptor of NMDA, on a model of Parkinson’s disease induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP. Materials and Methods: Male mice were divided into 8 groups with 7 mice in each group: saline, ethanol, melatonin, memantin, MPTP, melatonin+MPTP, memantin+ MPTP, melatonin+ memantin+ MPTP. All of agents were injected intraperitoneally once a day for 14 days before beam traversal test. Dopaminergic neurons of the Substantia Nigra Pars compacta (SNPC were determined by immunohistochemical and were counted. Results: Melatonin improved notably movement dysfunction resulted of MPTP such as the number of errors, paces and the time of movement during behavioral test and also the counting of neurons of Substantia Nigra Pars Compacta. Memantin had a synergic effect on the most of improvements. However, the level of improvement and retrieval of signs was not as in saline and ethanol groups. Conclusion: Melatonin especially together with memantine is able to prevent some of the MPTP-induced dysfunctions. However, the protective effects were not enogh, probably because of the amount of dose and the time of injection.

Memantine reduces stealing behavior and impulsivity in kleptomania: a pilot study.

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Grant, Jon E; Odlaug, Brian L; Schreiber, Liana R N; Chamberlain, Samuel R; Won Kim, Suck

2013-03-01

Kleptomania is characterized by repetitive stealing behavior and has been associated with deleterious unwanted outcomes including forensic contact and increased rates of suicidal behavior. Very few trials have been conducted to investigate pharmacological treatment options for this neglected condition. Memantine is an NMDA-receptor antagonist that has shown promising results in the treatment of other behavioral addictions and substance addictions. Twelve individuals with kleptomania received memantine (10 mg/day, titrated to 30 mg/day maximum depending on clinical response and tolerability) over the course of 8 weeks, in an open-label trial. The effects of treatment were quantified using well-validated measures and select neurocognitive tests (last observation carried forward analyses). Kleptomania disease severity scores decreased across all measures considered, and 11 (91.7%) of the participants met the responder criteria (35% improvement on the primary effectiveness measure plus CGI improved/very much improved; significant improvements were also observed in terms of mood, anxiety, and disability scores along with a significant improvement in stop-signal response inhibition. Memantine was generally well tolerated. This study shows the effectiveness of memantine in reducing urges to shoplift and shoplifting behavior along with improving impulsivity, mood, anxiety, and psychosocial functioning.

Adiponectin is protective against oxidative stress induced cytotoxicity in amyloid-beta neurotoxicity.

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Koon-Ho Chan

Full Text Available Beta-amyloid (Aβ neurotoxicity is important in Alzheimer's disease (AD pathogenesis. Aβ neurotoxicity causes oxidative stress, inflammation and mitochondrial damage resulting in neuronal degeneration and death. Oxidative stress, inflammation and mitochondrial failure are also pathophysiological mechanisms of type 2 diabetes (T(2DM which is characterized by insulin resistance. Interestingly, T(2DM increases risk to develop AD which is associated with reduced neuronal insulin sensitivity (central insulin resistance. We studied the potential protective effect of adiponectin (an adipokine with insulin-sensitizing, anti-inflammatory and anti-oxidant properties against Aβ neurotoxicity in human neuroblastoma cells (SH-SY5Y transfected with the Swedish amyloid precursor protein (Sw-APP mutant, which overproduced Aβ with abnormal intracellular Aβ accumulation. Cytotoxicity was measured by assay for lactate dehydrogenase (LDH released upon cell death and lysis. Our results revealed that Sw-APP transfected SH-SY5Y cells expressed both adiponectin receptor 1 and 2, and had increased AMP-activated protein kinase (AMPK activation and enhanced nuclear factor-kappa B (NF-κB activation compared to control empty-vector transfected SH-SY5Y cells. Importantly, adiponectin at physiological concentration of 10 µg/ml protected Sw-APP transfected SH-SY5Y cells against cytotoxicity under oxidative stress induced by hydrogen peroxide. This neuroprotective action of adiponectin against Aβ neurotoxicity-induced cytotoxicity under oxidative stress involved 1 AMPK activation mediated via the endosomal adaptor protein APPL1 (adaptor protein with phosphotyrosine binding, pleckstrin homology domains and leucine zipper motif and possibly 2 suppression of NF-κB activation. This raises the possibility of novel therapies for AD such as adiponectin receptor agonists.

The effect of the NMDA channel blocker memantine on salicylate-induced tinnitus in rats.

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Ralli, M; Troiani, D; Podda, M V; Paciello, F; Eramo, S L M; de Corso, E; Salvi, R; Paludetti, G; Fetoni, A R

2014-06-01

Short-term tinnitus develops shortly after the administration of a high dose of salicylate. Since salicylate selectively potentiates N-methyl- D-aspartate (NMDA) currents in spiral ganglion neurons, it may play a vital role in tinnitus by amplifying NMDA-mediated neurotransmission. The aim of this study was to determine whether systemic treatment with a NMDA channel blocker, memantine, could prevent salicylate-induced tinnitus in animals. Additional experiments were performed to evaluate the effect of memantine on the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to test for changes in hearing function. Thirty-six rats were divided into 3 groups and treated daily for four consecutive days. One group (n = 12) was injected with salicylate (300 mg/kg/d, IP), the second (n = 12) was treated with memantine (5 mg/kg/d, IP) and the third group (n = 12) was injected with salicylate and memantine. All rats were tested for tinnitus and hearing loss at 2, 24, 48 and 72 h after the first drug administration and 24 h post treatment; tinnituslike behaviour was assessed with gap prepulse inhibition of acoustic startle (GPIAS), and hearing function was measured with DPOAE, ABR and noise burst prepulse inhibition of acoustic startle (NBPIAS). Rats in the salicylate group showed impaired GPIAS indicative of transient tinnitus-like behaviour near 16 kHz that recovered 24 h after the last salicylate treatment. Memantine did not cause a significant change in GPIAS. Combined injection of salicylate and memantine significantly attenuated GPIAS tinnitus-like behaviour at 48 hours after the first injection. None of the treatments induced permanent threshold shifts in the ABR and DPOAE, which recovered completely within one day post treatment. Animals treated with salicylate plus memantine showed results comparable to animals treated with salicylate alone, confirming that there is no effect of memantine on DPOAE which reflects OHC function. The

Green-fluorescent protein+ Astrocytes Attach to beta-Amyloid Plaques in an Alzheimer Mouse Model and GFPare Sensitive for Clasmatodendrosis

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Christian eHumpel

2016-04-01

Full Text Available Alzheimer’s disease (AD is pathologically characterized by beta-amyloid (Aβ plaques and Tau pathology. It is well-established that Aβ plaques are surrounded by reactive astrocytes, highly expressing glial fibrillary acidic protein (GFAP. In order to study the cellular interaction of reactive astrocytes with Aβ plaques, we crossbred mice overexpressing amyloid precursor protein (APP with the Swedish-Dutch-Iowa mutations (APP-SweDI with mice expressing green fluorescent protein (GFP under the GFAP-promotor. Three-dimensional confocal microscopy revealed a tight association and intense sprouting of astrocytic fine branched processes towards Aβ plaques in 12 month old mice. In order to study phagocytosis, 110 µm thick brain slices from 12 month old crossbred mice were cultured overnight, however, we found that the GFP fluorescence faded away, distal processes degenerated and a complete loss of astrocytic morphology was seen (clasmatodendrosis. In summary, our data show that GFP+ reactive astrocytes make intense contact with Aβ plaques but these cells are highly vulnerable for degeneration.

Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis

NARCIS (Netherlands)

Jansen, W.J.; Ossenkoppele, R.; Knol, D.L.; Tijms, B.M.; Scheltens, P.J.; Verhey, F.R.J.; Visser, P.J.; Aalten, P.; Aarsland, D.; Alcolea, D.; Alexander, M.; Almdahl, I.S.; Arnold, S.E.; Baldeiras, I.; Barthel, H.; Berckel, B.N. van; Bibeau, K.; Blennow, K.; Brooks, D.J.; Buchem, M.A. van; Camus, V.; Cavedo, E.; Chen, K.; Chetelat, G.; Cohen, A.D.; Drzezga, A.; Engelborghs, S.; Fagan, A.M.; Fladby, T.; Fleisher, A.S.; Flier, W.M. van der; Ford, L.; Forster, S.; Fortea, J.; Foskett, N.; Frederiksen, K.S.; Freund-Levi, Y.; Frisoni, G.B.; Froelich, L.; Gabryelewicz, T.; Gill, K.D.; Gkatzima, O.; Gomez-Tortosa, E.; Gordon, M.F.; Grimmer, T.; Hampel, H.; Hausner, L.; Hellwig, S.; Herukka, S.K.; Hildebrandt, H.; Ishihara, L.; Ivanoiu, A.; Jagust, W.J.; Johannsen, P.; Kandimalla, R.; Kapaki, E.; Klimkowicz-Mrowiec, A.; Klunk, W.E.; Kohler, S.; Koglin, N.; Kornhuber, J.; Kramberger, M.G.; Laere, K. Van; Landau, S.M.; Lee, D.Y.; Leon, M.; Lisetti, V.; Lleo, A.; Madsen, K.; Maier, W.; Marcusson, J.; Mattsson, N.; Mendonca, A. de; Meulenbroek, O.V.; Meyer, P.T.; Mintun, M.A.; Mok, V.; Molinuevo, J.L.; Mollergard, H.M.; Morris, J.C.; Mroczko, B.; Mussele, S. Van der; Na, D.L.; Newberg, A.; Nordberg, A.; Nordlund, A.; Novak, G.P.; Paraskevas, G.P.; Parnetti, L.; Perera, G.; Peters, O.; Popp, J.; Prabhakar, S.; Rabinovici, G.D.; Ramakers, I.H.; Rami, L.; Oliveira, C.R.; Rinne, J.O.; Rodrigue, K.M.; Rodriguez-Rodriguez, E.; Verbeek, M.M.; et al.,

2015-01-01

IMPORTANCE: Cerebral amyloid-beta aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention

α-Iso-cubebene exerts neuroprotective effects in amyloid beta stimulated microglia activation.

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Park, Sun Young; Park, Se Jin; Park, Nan Jeong; Joo, Woo Hong; Lee, Sang-Joon; Choi, Young-Whan

2013-10-25

Schisandra chinensis is commonly used for food and as a traditional remedy for the treatment of neuronal disorders. However, it is unclear which component of S. chinensis is responsible for its neuropharmacological effects. To answer this question, we isolated α-iso-cubebene, a dibenzocyclooctadiene lignin, from S. chinensis and determined if it has any anti-neuroinflammatory and neuroprotective properties against amyloid β-induced neuroinflammation in microglia. Microglia that are stimulated by amyloid β increased their production of pro-inflammatory cytokines and chemokines, prostaglandin E2 (PGE2), nitric oxide (NO) and reactive oxygen species (ROS) and the enzymatic activity of matrix metalloproteinase 9 (MMP-9). We found this was all inhibited by α-iso-cubebene. Consistent with these results, α-iso-cubebene inhibited the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and MMP-9 in amyloid β-stimulated microglia. Subsequent mechanistic studies revealed that α-iso-cubebene inhibited the phosphorylation and degradation of IκB-α, the phosphorylation and transactivity of NF-κB, and the phosphorylation of MAPK in amyloid β-stimulated microglia. These results suggest that α-iso-cubebene impairs the amyloid β-induced neuroinflammatory response of microglia by inhibiting the NF-κB and MAPK signaling pathways. Importantly, α-iso-cubebene can provide critical neuroprotection for primary cortical neurons against amyloid β-stimulated microglia-mediated neurotoxicity. To the best of our knowledge, this is the first report showing that α-iso-cubebene can provide neuroprotection against, and influence neuroinflammation triggered by, amyloid β activation of microglia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Combined application of tenuigenin and β-asarone improved the efficacy of memantine in treating moderate-to-severe Alzheimer’s disease

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Chang W

2018-03-01

Full Text Available Wenguang Chang,1 Junfang Teng2 1Department of Neurology, Xinxiang Central Hospital, Xinxiang, Henan, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Henan, People’s Republic of China Background: Alzheimer’s disease (AD is a slowly progressive neurodegenerative disease which cannot be cured at present. The aim of this study was to assess whether the combined application of β-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD.Patients and methods: One hundred and fifty-two patients with moderate-to-severe AD were recruited and assigned to two groups. Patients in the experiment group received β-asarone 10 mg/d, tenuigenin 10 mg/d, and memantine 5–20 mg/d. Patients in the control group only received memantine 5–20 mg/d. The Mini Mental State Examination (MMSE, Clinical Dementia Rating Scale (CDR, and Activities of Daily Living (ADL were used to assess the therapeutic effects. The drug-related adverse events were used to assess the safety and acceptability. Treatment was continued for 12 weeks.Results: After 12 weeks of treatment, the average MMSE scores, ADL scores, and CDR scores in the two groups were significantly improved. But, compared to the control group, the experimental group had a significantly higher average MMSE score (p<0.00001, lower average ADL score (p=0.00002, and lower average CDR score (p=0.030. Meanwhile, the rates of adverse events were similar between the two groups. Subgroup analysis indicated that the most likely candidates to benefit from this novel method might be the 60–74-years-old male patients with moderate AD.Conclusion: These results demonstrated that the combined application of β-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD. The clinical applicability of this novel method showed greater promise and should be further explored. Keywords

Intracellular accumulation of amyloid-beta - a predictor for synaptic dysfunction and neuron loss in Alzheimer's disease

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Thomas A Bayer

2010-03-01

Full Text Available Despite of long-standing evidence that beta-amyloid (Aβ peptides have detrimental effects on synaptic function, the relationship between Aβ, synaptic and neuron loss is largely unclear. During the last years there is growing evidence that early intraneuronal accumulation of Aβ peptides is one of the key events leading to synaptic and neuronal dysfunction. Many studies have been carried out using transgenic mouse models of Alzheimer’s disease (AD which have been proven to be valuable model system in modern AD research. The present review discusses the impact of intraneuronal Aβ accumulation on synaptic impairment and neuron loss and provides an overview of currently available AD mouse models showing these pathological alterations.

The pathogenic implication of abnormal interaction between apolipoprotein E isoforms, amyloid-beta peptides, and sulfatides in Alzheimer's disease.

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Han, Xianlin

2010-06-01

Alzheimer's disease (AD) is the most common cause of dementia in the aging population. Prior work has shown that the epsilon4 allele of apolipoprotein E (apoE4) is a major risk factor for "sporadic" AD, which accounts for >99% of AD cases without a defined underlying mechanism. Recently, we have demonstrated that sulfatides are substantially and specifically depleted at the very early stage of AD. To identify the mechanism(s) of sulfatide loss concurrent with AD onset, we have found that: (1) sulfatides are specifically associated with apoE-associated particles in cerebrospinal fluid (CSF); (2) apoE modulates cellular sulfatide levels; and (3) the modulation of sulfatide content is apoE isoform dependent. These findings not only lead to identification of the potential mechanisms underlying sulfatide depletion at the earliest stages of AD but also serve as mechanistic links to explain the genetic association of apoE4 with AD. Moreover, our recent studies further demonstrated that (1) apoE mediates sulfatide depletion in amyloid-beta precursor protein transgenic mice; (2) sulfatides enhance amyloid beta (Abeta) peptides binding to apoE-associated particles; (3) Abeta42 content notably correlates with sulfatide content in CSF; (4) sulfatides markedly enhance the uptake of Abeta peptides; and (5) abnormal sulfatide-facilitated Abeta uptake results in the accumulation of Abeta in lysosomes. Collectively, our studies clearly provide a link between apoE, Abeta, and sulfatides in AD and establish a foundation for the development of effective therapeutic interventions for AD.

Red mold rice ameliorates impairment of memory and learning ability in intracerebroventricular amyloid beta-infused rat by repressing amyloid beta accumulation.

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Lee, Chun-Lin; Kuo, Tzong-Fu; Wang, Jyh-Jye; Pan, Tzu-Ming

2007-11-01

Amyloid beta (Abeta) peptide related to the onset of Alzheimer's disease (AD) damaged neurons and further resulted in dementia. Monascus-fermented red mold rice (RMR), a traditional Chinese medicine as well as health food, includes monacolins (with the same function as statins) and multifunctional metabolites. In this study, ethanol extract of RMR (RE) was used to evaluate neuroprotection against Abeta40 neurotoxicity in PC12 cells. Furthermore, the effects of dietary administration of RMR on memory and learning abilities are confirmed in an animal model of AD rats infused with Abeta40 into the cerebral ventricle. During continuous Abeta40 infusion for 28 days, the rats of test groups were administered RMR or lovastatin. Memory and learning abilities were evaluated in the water maze and passive avoidance tasks. After sacrifice, cerebral cortex and hippocampus were collected for the examination of AD risk factors. The in vitro results clearly indicate that RE provides stronger neuroprotection in rescuing cell viability as well as repressing inflammatory response and oxidative stress. RMR administration potently reverses the memory deficit in the memory task. Abeta40 infusion increases acetylcholinesterase activity, reactive oxygen species, and lipid peroxidation and decreases total antioxidant status and superoxide dismutase activity in brain, but these damages were potently reversed by RMR administration, and the protection was more significant than that with lovastatin administration. The protection provided by RMR is able to prevent Abeta fibrils from being formed and deposited in hippocampus and further decrease Abeta40 accumulation, even though Abeta40 solution was infused into brain continuously. (c) 2007 Wiley-Liss, Inc.

Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor.

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Endo, Hitoshi; Nikaido, Yuri; Nakadate, Mamiko; Ise, Satomi; Konno, Hiroyuki

2014-12-15

Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1-42 mediated cytotoxicity

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Cameron, Ryan T.; Whiteley, Ellanor; Day, Jon P.; Parachikova, Anna I.; Baillie, George S.

2017-01-01

Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4, 5 and 9 could alleviate the cytotoxic effects of amyloid beta 1?42 (A?1?42) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4, 5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the colocalisati...

Classic beta-amyloid deposits cluster around large diameter blood vessels rather than capillaries in sporadic Alzheimer's disease.

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Armstrong, Richard A

2006-11-01

Various hypotheses could explain the relationship between beta-amyloid (Abeta) deposition and the vasculature in Alzheimer's disease (AD). Amyloid deposition may reduce capillary density, affect endothelial cells of blood vessels, result in diffusion from blood vessels, or interfere with the perivascular clearance mechanism. Hence, the spatial pattern of the classic ('cored') type of Abeta deposit was studied in the upper laminae (I,II/III) of the superior frontal gyrus in nine cases of sporadic AD (SAD). Sections were immunostained with antibodies against Abeta and with collagen IV to study the relationships between the spatial distribution of the classic deposits and the blood vessel profiles. Both the classic deposits and blood vessel profiles were distributed in clusters. In all cases, there was a positive spatial correlation between the clusters of the classic deposits and the larger diameter (>10 microm) blood vessel profiles and especially the vertically penetrating arterioles. In only 1 case, was there a significant spatial correlation between the clusters of the classic deposits and the smaller diameter (upper laminae of the frontal cortex. This aggregation could result from diffusion of proteins from blood vessels or from overloading the system of perivascular clearance from the brain.

Amyloid-beta 40 as a biomarker of cognitive impairment in acute ischemic stroke

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Aleksey A. Kulesh

2017-01-01

Full Text Available Aim: to study the role of amyloid-beta 40 (Aβ 40 in the development of cognitive impairment in acute ischemic stroke.Materials and methods. The study included 70 patients aged 33–86 years, 46 men and 24 women. In patients with acute ischemic stroke cognitive status was assessed with Mini-Mental State Examination (MMSE, Montreal Cognitive Assessment Test (MoCA, Frontal Assessment Battery (FAB, Schulte tables, Clock Drawing Test, Test for Semantic Verbal Fluency and Five Words Test. The concentration of Aβ 40 in the cerebrospinal fluid was determined. Morphometric (size of the infarct and leukoaraiosis area, volume of the brain ventricles and hippocampus and diffusion-tensor parameters of MRI (fractional anisotropy of putamen, thalamus, hippocampus, corpus callosum, limbs of the internal capsule, the cingulate, the superior longitudinal and inferior fronto-occipital tracts were studied.Results. The concentration of Aβ 40 in the cerebrospinal fluid was 436,4 (226,0–514,0 pg/ml. The protein level was associated with the result of subtests «Orientation» (MMSE and «Attention» (MoCA, as well as indirect recall with cues in MoCA. Patients with MMSE score of 24–27 points were characterized by a lower concentration of Aβ 40 as compared to patients with a score less than 24 points. Aβ 40 concentration more than 436,4 pg/mL was associated with a more severe somatic co-morbidity of stroke (hypertension, lower hemoglobin and albumin level, higher erythrocyte sedimentation rate, a smaller volume of the brain ventricles, lower fractional anisotropy of the thalamus, cingulate tracts and contralateral hippocampus. Aβ 40 concentration more than 436,4 pg/mL was also associated with a lower global cognitive status (according to the MMSE and MoCA, as well as the reduction in certain cognitive functions, namely, attention, visual-spatial functions and memory.Conclusions. The concentration of Aβ 40 in the cerebrospinal fluid is a biological marker of

Short-term effects of beta-amyloid25-35 peptide aggregates on transmitter release in neuromuscular synapses.

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Garcia, Neus; Santafé, Manel M; Tomàs, Marta; Lanuza, Maria A; Tomàs, Josep

2008-03-01

The beta-amyloid (AB) peptide25-35 contains the functional domain of the AB precursor protein that is both required for neurotrophic effects in normal neural tissues and is involved in the neurotoxic effects in Alzheimer disease. We demonstrated the presence of the amyloid precursor protein/AB peptide in intramuscular axons, presynaptic motor nerve terminals, terminal and myelinating Schwann cells, and the postsynaptic and subsarcolemmal region in the Levator auris longus muscle of adult rats by immunocytochemistry. Using intracellular recording, we investigated possible short-term functional effects of the AB fragment (0.1-10 micromol/L) on acetylcholine release in adult and newborn motor end plates. We found no change in evoked, spontaneous transmitter release or resting membrane potential of the muscle cells. A previous block of the presynaptic muscarinic receptor subtypes and a previous block or stimulation of protein kinase C revealed no masked effect of the peptide on the regulation of transmitter release. The aggregated form of AB peptide25-35, however, interfered acutely with acetylcholine release (quantal content reduction) when synaptic activity was maintained by electric stimulation. The possible relevance of this inhibition of neurotransmission by AB peptide25-35 to the pathogenesis of Alzheimer remains to be determined.

Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent

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Pascale Crissey L

2011-07-01

Full Text Available Abstract Background Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD. There is an accumulation of amyloid-beta peptides (Aβ in both the AD brain and the normal aging brain. Clearance of Aβ from the brain occurs via active transport at the blood-brain barrier (BBB and blood-cerebrospinal fluid barrier (BCSFB. With increasing age, the expression of the Aβ efflux transporters is decreased and the Aβ influx transporter expression is increased at the BBB, adding to the amyloid burden in the brain. Expression of the Aβ transporters at the choroid plexus (CP epithelium as a function of aging was the subject of this study. Methods This project investigated the changes in expression of the Aβ transporters, the low density lipoprotein receptor-related protein-1 (LRP-1, P-glycoprotein (P-gp, LRP-2 (megalin and the receptor for advanced glycation end-products (RAGE at the BCSFB in Brown-Norway/Fischer rats at ages 3, 6, 9, 12, 20, 30 and 36 months, using real time RT-PCR to measure transporter mRNA expression, and immunohistochemistry (IHC to measure transporter protein in isolated rat CP. Results There was an increase in the transcription of the Aβ efflux transporters, LRP-1 and P-gp, no change in RAGE expression and a decrease in LRP-2, the CP epithelium influx transporter, at the BCSFB with aging. Decreased Aβ42 concentration in the CP, as measured by quantitative IHC, was associated with these Aβ transporter alterations. Conclusions Age-dependent alterations in the CP Aβ transporters are associated with a decrease in Aβ42 accumulation in the CP, and are reciprocal to the changes seen in these transporters at the BBB, suggesting a possible compensatory role for the BCSFB in Aβ clearance in aging.

Monomeric Amyloid Beta Peptide in Hexafluoroisopropanol Detected by Small Angle Neutron Scattering.

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Bo Zhang-Haagen

Full Text Available Small proteins like amyloid beta (Aβ monomers are related to neurodegenerative disorders by aggregation to insoluble fibrils. Small angle neutron scattering (SANS is a nondestructive method to observe the aggregation process in solution. We show that SANS is able to resolve monomers of small molecular weight like Aβ for aggregation studies. We examine Aβ monomers after prolonged storing in d-hexafluoroisopropanol (dHFIP by using SANS and dynamic light scattering (DLS. We determined the radius of gyration from SANS as 1.0±0.1 nm for Aβ1-40 and 1.6±0.1 nm for Aβ1-42 in agreement with 3D NMR structures in similar solvents suggesting a solvent surface layer with 5% increased density. After initial dissolution in dHFIP Aβ aggregates sediment with a major component of pure monomers showing a hydrodynamic radius of 1.8±0.3 nm for Aβ1-40 and 3.2±0.4 nm for Aβ1-42 including a surface layer of dHFIP solvent molecules.

PET imaging of brain with the {beta}-amyloid probe, [{sup 11}C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer's disease

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Toyama, Hiroshi [Fujita Health University, Department of Radiology, Aichi (Japan); National Institutes of Health, Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (United States); Ye, Daniel; Cohen, Robert M. [National Institutes of Health, Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland (United States); Ichise, Masanori; Liow, Jeih-San; Cai, Lisheng; Musachio, John L.; Hong, Jinsoo; Crescenzo, Mathew; Tipre, Dnyanesh; Lu, Jian-Qiang; Zoghbi, Sami; Vines, Douglass C.; Pike, Victor W.; Innis, Robert B. [National Institutes of Health, Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (United States); Jacobowitz, David [USUHS, Department of Anatomy, Physiology, and Genetics, Bethesda, Maryland (United States); Seidel, Jurgen; Green, Michael V. [National Institutes of Health, Department of Nuclear Medicine, Warren Grant Magnuson Clinical Center, Bethesda, Maryland (United States); Katada, Kazuhiro [Fujita Health University, Department of Radiology, Aichi (Japan)

2005-04-01

The purpose of this study was to evaluate the capacity of [{sup 11}C]6-OH-BTA-1 and positron emission tomography (PET) to quantify {beta}-amyloid (A{beta}) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0{+-}1.8 months; 23.6{+-}2.6 g) overexpressing a mutated form of human {beta}-amyloid precursor protein (APP) known to result in the production of A{beta} plaques, and in six elderly wild-type litter mates (age 21.8{+-}1.6 months; 29.5{+-}4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [{sup 11}C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. TACs for [{sup 11}C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06{+-}0.04 vs 0.98{+-}0.07, p=0.04; 1.06{+-}0.09 vs 0.93{+-}0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread A{beta} plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild

The NMDA antagonist memantine affects training induced motor cortex plasticity – a study using transcranial magnetic stimulation [ISRCTN65784760

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Schwenkreis Peter

2005-05-01

Full Text Available Abstract Background Training of a repetitive synchronised movement of two limb muscles leads to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS mapping. We used this paradigm to study the effect of memantine, a NDMA antagonist, on short-term motor cortex plasticity in 20 healthy human subjects, and we were especially interested in possible differential effects of different treatment regimens. In a randomised double-blinded cross over study design we therefore administered placebo or memantine either as a single dosage or as an ascending dosage over 8 days. Before and after one hour of motor training, which consisted of a repetitive co-contraction of the abductor pollicis brevis (APB and the deltoid muscle, we assessed the motor output map of the APB muscle by TMS under the different conditions. Results We found a significant medial shift of the APB motor output map after training in the placebo condition, indicating training-induced short-term plastic changes in the motor cortex. A single dosage of memantine had no significant effect on this training-induced plasticity, whereas memantine administered in an ascending dosage over 8 days was able to block the cortical effect of the motor training. The memantine serum levels after 8 days were markedly higher than the serum levels after a single dosage of memantine, but there was no individual correlation between the shift of the motor output map and the memantine serum level. Besides, repeated administration of a low memantine dosage also led to an effective blockade of training-induced cortical plasticity in spite of serum levels comparable to those reached after single dose administration, suggesting that the repeated administration was more important for the blocking effect than the memantine serum levels. Conclusion We conclude that the NMDA-antagonist memantine is able to block training-induced motor cortex plasticity when

A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis.

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de Carvalho, Mamede; Pinto, Susana; Costa, João; Evangelista, Teresinha; Ohana, Bemjamim; Pinto, Anabela

2010-10-01

Our objective is to describe the results of a phase II/III, 12-months, double-blinded, single-centre, randomized, parallel (1:1), clinical trial performed to evaluate the efficacy and safety of memantine in ALS. Patients with probable or definite ALS of less than 36 months disease duration and progression over a one-month lead-in period were randomly assigned to placebo or memantine at 20 mg/day. The primary endpoint was 12-months ALSFRS decline. Forced vital capacity, manual muscle testing, visual analogue scale, quality of life, motor unit number estimation and neurophysiological index were the secondary endpoints. The number of patients included was based on the assumption of a 50% change in the ALSFRS decline. Safety and adverse events were evaluated. Sixty-three patients were included in the trial. Memantine did not show more adverse events or laboratory changes than placebo. Primary and secondary outcomes were not different between groups by intention-to-treat and per-protocol analysis. The most sensitive measurements were neurophysiological, which declined linearly over time. In conclusion, the results of this study show that memantine is well tolerated and safe in ALS patients. We did not observe any evidence of efficacy for memantine but we cannot exclude a positive outcome on survival.

Sphingolipid metabolism correlates with cerebrospinal fluid Beta amyloid levels in Alzheimer's disease.

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Alfred N Fonteh

Full Text Available Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid β42 concentration in CSF from cognitively normal but

Low-dose memantine attenuated morphine addictive behavior through its anti-inflammation and neurotrophic effects in rats.

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Chen, Shiou-Lan; Tao, Pao-Luh; Chu, Chun-Hsien; Chen, Shih-Heng; Wu, Hsiang-En; Tseng, Leon F; Hong, Jau-Shyong; Lu, Ru-Band

2012-06-01

Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer's disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2-1 mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6 days of morphine treatment, cytokine (IL-1β, IL-6) levels had significantly increased in serum; IL-1β and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti-inflammatory and neurotrophic effects.

Effects of Memantine, an NMDA Antagonist, on Metabolic Syndromes in Female NMRI Mice

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Naser Osanloo

2015-10-01

Results: The intraperitoneal administration of memantine increased plasma corticosterone, water intake, fecal weight and eating latency, but had no effect on food intake or weight. The dose and site-dependent intra-accumbens administration of memantine either exacerbated the effects of stress on plasma corticosterone levels and water and food intake, or else had no effect on these parameters. Furthermore, the administration of memantine had no effect on animal’s weight and inhibited the effects of stress on fecal weight and eating latency. Discussion: The inhibition of glutamate NMDA receptors in the nucleus accumbens can inhibit and/or exacerbate the dose and site-dependent effects of chronic stress, with gender playing a significant role in producing this effect.

Synergistic effects of galantamine and memantine in attenuating scopolamine-induced amnesia in mice.

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Busquet, Perrine; Capurro, Valeria; Cavalli, Andrea; Piomelli, Daniele; Reggiani, Angelo; Bertorelli, Rosalia

2012-01-01

We investigated a possible drug efficacy enhancement obtained by combining inactive doses of galantamine and memantine in the scopolamine-induced amnesia model in mice. We evaluated the effects of the two drugs, either alone or in combination, using the spontaneous alternation and object recognition tasks. In both tests, combination of low doses of galantamine (0.1 mg/kg, s.c.) and memantine (0.5 mg/kg, i.p.), which were sub-active per se, rescued the memory impairment induced by scopolamine (1 mg/kg, i.p.). The results suggest that combinations of galantamine and memantine might provide a more effective treatment of memory impairments in cognitive disorders than either drug used alone.

Comparing Efficacy and Side Effects of Memantine vs. Risperidone in the Treatment of Autistic Disorder.

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Nikvarz, Nikvarz; Alaghband-Rad, Javad; Tehrani-Doost, Mehdi; Alimadadi, Abbas; Ghaeli, Padideh

2017-01-01

Introduction: This study was aimed to compare the efficacy and side effects of memantine, an antagonist of the NMDA receptor of glutamate, with risperidone given the fact that glutamate has been noted for its possible effects in the pathogenesis of autism. Risperidone, an atypical antipsychotic, has been approved by FDA for the management of irritability associated with autism. Methods: 30 children, aged 4-17 years, entered an 8-week, randomized trial. Patients were randomly assigned to receive either risperidone or memantine. Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS), Clinical Global Impressions - Improvement (CGI-I) and Clinical Global Impression-Severity (CGI-S) scales were used to assess behavioral symptoms of the patients. Results: Both risperidone and memantine reduced the scores of 4 subscales of ABC as well as the 10-item and the total score of CARS significantly. However, differences between the 2 drugs in the scores of each evaluating scale were not found to be significant. Relatively, larger number of patients on risperidone showed "very much improvement" when assessed by CGI-I scale when compared with those on memantine. Discussion and conclusion: The present study suggests that memantine may have beneficial effects in the treatment of many core symptoms of autism. Therefore, memantine may be considered as a potential medication in the treatment of those autistic children who do not respond or cannot tolerate side effects of risperidone. © Georg Thieme Verlag KG Stuttgart · New York.

Memantine enhances the effect of olanzapine in patients with schizophrenia: A randomized, placebo-controlled study

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Ahmad Fakhri

2016-12-01

Full Text Available Glutamate dysregulation may be involved in the neuropathology of schizophrenia. Memantine, a drug approved by the FDA for the treatment of moderate to severe Alzheimer's disease, acts as a partial uncompetitive NMDA receptor antagonist. The aim of this study was to examine the efficacy of memantine as an adjunctive treatment to olanzapine in patients with schizophrenia. In this double-blind, placebo-controlled studies, patients with schizophrenia according to DSM-IV clinical criteria were selected. Patients were randomly assigned to receive either memantine (week 1:10 mg/day; weeks 2-6:20 mg/day plus olanzapine (15-20 mg/day or olanzapine plus placebo. At baseline, no statistically significant difference regarding the mean total PANSS scores between treatment groups was found. Results showed that memantine significantly improved the positive and negative PANSS score in patients maintained on olanzapine after six weeks compared to olanzapine alone (P<0.001. Furthermore, female patients showed significantly better response than males, especially in positive PANSS score. No significant changes in extrapyramidal symptoms were observed.These findings indicate that olanzapine efficacy might be augmented with memantine. Furthermore, this effect is more remarkable in female patients with schizophrenia.

Beta-structures in fibrous proteins.

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Kajava, Andrey V; Squire, John M; Parry, David A D

2006-01-01

The beta-form of protein folding, one of the earliest protein structures to be defined, was originally observed in studies of silks. It was then seen in early studies of synthetic polypeptides and, of course, is now known to be present in a variety of guises as an essential component of globular protein structures. However, in the last decade or so it has become clear that the beta-conformation of chains is present not only in many of the amyloid structures associated with, for example, Alzheimer's Disease, but also in the prion structures associated with the spongiform encephalopathies. Furthermore, X-ray crystallography studies have revealed the high incidence of the beta-fibrous proteins among virulence factors of pathogenic bacteria and viruses. Here we describe the basic forms of the beta-fold, summarize the many different new forms of beta-structural fibrous arrangements that have been discovered, and review advances in structural studies of amyloid and prion fibrils. These and other issues are described in detail in later chapters.

Bilateral brain reorganization with memantine and constraint-induced aphasia therapy in chronic post-stroke aphasia: An ERP study.

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Barbancho, Miguel A; Berthier, Marcelo L; Navas-Sánchez, Patricia; Dávila, Guadalupe; Green-Heredia, Cristina; García-Alberca, José M; Ruiz-Cruces, Rafael; López-González, Manuel V; Dawid-Milner, Marc S; Pulvermüller, Friedemann; Lara, J Pablo

2015-01-01

Changes in ERP (P100 and N400) and root mean square (RMS) were obtained during a silent reading task in 28 patients with chronic post-stroke aphasia in a randomized, double-blind, placebo-controlled trial of both memantine and constraint-induced aphasia therapy (CIAT). Participants received memantine/placebo alone (weeks 0-16), followed by drug treatment combined with CIAT (weeks 16-18), and then memantine/placebo alone (weeks 18-20). ERP/RMS values (week 16) decreased more in the memantine group than in the placebo group. During CIAT application (weeks 16-18), improvements in aphasia severity and ERP/RMS values were amplified by memantine and changes remained stable thereafter (weeks 18-20). Changes in ERP/RMS occurred in left and right hemispheres and correlated with gains in language performance. No changes in ERP/RMS were found in a healthy group in two separated evaluations. Our results show that aphasia recovery induced by both memantine alone and in combination with CIAT is indexed by bilateral cortical potentials. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic engineering combined with deep UV resonance Raman spectroscopy for structural characterization of amyloid-like fibrils.

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Sikirzhytski, Vitali; Topilina, Natalya I; Higashiya, Seiichiro; Welch, John T; Lednev, Igor K

2008-05-07

Elucidating the structure of the cross-beta core in large amyloid fibrils is a challenging problem in modern structural biology. For the first time, a set of de novo polypeptides was genetically engineered to form amyloid-like fibrils with similar morphology and yet different strand length. Differential ultraviolet Raman spectroscopy allowed for separation of the spectroscopic signatures of the highly ordered beta-sheet strands and turns of the fibril core. The relationship between Raman frequencies and Ramachandran dihedral angles of the polypeptide backbone indicates the nature of the beta-sheet and turn structural elements.

Chronic treatment with amyloid beta(1-42) inhibits non-cholinergic high-affinity choline transport in NG108-15 cells through protein kinase C signaling

Czech Academy of Sciences Publication Activity Database

Nováková, Jana; Mikasová, Lenka; Machová, Eva; Lisá, Věra; Doležal, Vladimír

2005-01-01

Roč. 1062, č. 1-2 (2005), s. 101-110 ISSN 0006-8993 R&D Projects: GA AV ČR(CZ) IAA5011206; GA MŠk(CZ) LC554 Grant - others:Lipidiet(XE) QLK1-CT-2002-00172 Institutional research plan: CEZ:AV0Z50110509 Keywords : choline transporter * beta-amyloid * protein kinase C Subject RIV: ED - Physiology Impact factor: 2.296, year: 2005

Effect of intratympanic dexamethasone, memantine and piracetam on cellular apoptosis due to cisplatin ototoxicity.

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Topdag, M; Iseri, M; Gelenli, E; Yardimoglu, M; Yazir, Y; Ulubil, S A; Topdag, D O; Ustundag, E

2012-11-01

This study aimed to contribute to the literature on the prevention and treatment of ototoxicity due to various drugs and chemicals. This study compared the histological effects of intratympanic dexamethasone, memantine and piracetam on cellular apoptosis due to cisplatin ototoxicity, in 36 rats. Dexamethasone and memantine had significant effects on the stria vascularis, organ of Corti and spiral ganglion (p piracetam decreased the apoptosis rate, this effect was not statistically significant (p > 0.05). Dexamethasone and memantine were found superior to piracetam in reducing apoptosis due to cisplatin ototoxicity. Further studies of this subject are needed, incorporating electron microscopy and auditory brainstem response testing.

Kynurenine pathway and cognitive impairments in schizophrenia: Pharmacogenetics of galantamine and memantine

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Maju Mathew Koola

2016-06-01

Full Text Available The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS project designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia, identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. Galantamine is an acetylcholinesterase inhibitor and a positive allosteric modulator of the α7 nicotinic receptors. Memantine is an N-methyl-D-aspartate (NMDA receptor antagonist. There is evidence to suggest that the combination of galantamine and memantine may be effective in the treatment of cognitive impairments in schizophrenia. There is a growing body of evidence that excess kynurenic acid (KYNA is associated with cognitive impairments in schizophrenia. The α-7 nicotinic and the NMDA receptors may counteract the effects of kynurenic acid (KYNA resulting in cognitive enhancement. Galantamine and memantine through its α-7 nicotinic and NMDA receptors respectively may counteract the effects of KYNA thereby improving cognitive impairments. The Single Nucleotide Polymorphisms in the Cholinergic Receptor, Nicotinic, Alpha 7 gene (CHRNA7, Glutamate (NMDA Receptor, Metabotropic 1 (GRM1 gene, Dystrobrevin Binding Protein 1 (DTNBP1 and kynurenine 3-monooxygenase (KMO gene may predict treatment response to galantamine and memantine combination for cognitive impairments in schizophrenia in the kynurenine pathway.

GMP-compliant automated synthesis of [{sup 18}F]AV-45 (Florbetapir F 18) for imaging {beta}-amyloid plaques in human brain

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Yao, C.-H. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Lin, K.-J. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Department of Medical Imaging and Radiological Sciences, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan (China); Weng, C.-C. [Department of Medical Imaging and Radiological Sciences, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan (China); Hsiao, I.-T. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Department of Medical Imaging and Radiological Sciences, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan (China); Ting, Y.-S. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Yen, T.-C. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Department of Medical Imaging and Radiological Sciences, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan (China); Jan, T.-R. [Department and Graduate Institute of Veterinary Medicine, National Taiwan University, Taipei, Taiwan (China); Skovronsky, Daniel [Avid Radiopharmaceuticals, Inc., Philadelphia, PA 19104 (United States); Kung, M.-P. [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104 (United States); Wey, S.-P., E-mail: spwey@mail.cgu.edu.t [Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taiwan (China); Department of Medical Imaging and Radiological Sciences, Chang Gung University, 259 Wen-Hua 1st Road, Kweishan, Taoyuan 333, Taiwan (China)

2010-12-15

We report herein the Good Manufacturing Practice (GMP)-compliant automated synthesis of {sup 18}F-labeled styrylpyridine, AV-45 (Florbetapir), a novel tracer for positron emission tomography (PET) imaging of {beta}-amyloid (A{beta}) plaques in the brain of Alzheimer's disease patients. [{sup 18}F]AV-45 was prepared in 105 min using a tosylate precursor with Sumitomo modules for radiosynthesis under GMP-compliant conditions. The overall yield was 25.4{+-}7.7% with a final radiochemical purity of 95.3{+-}2.2% (n=19). The specific activity of [{sup 18}F]AV-45 reached as high as 470{+-}135 TBq/mmol (n=19). The present studies show that [{sup 18}F]AV-45 can be manufactured under GMP-compliant conditions and could be widely available for routine clinical use.

Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1{alpha}, suppress amyloid {beta}-induced neurotoxicity

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Raman, Dayanidhi; Milatovic, Snjezana-Zaja [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Milatovic, Dejan [Department of Pediatrics/Pediatric Toxicology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Splittgerber, Ryan [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Fan, Guo-Huang [Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37221 (United States); Richmond, Ann, E-mail: ann.richmond@vanderbilt.edu [VA Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States)

2011-11-15

Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-{beta} (A{beta}). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1{alpha} (SDF-1{alpha}), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress A{beta}-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1{alpha} significantly protected neurons from A{beta}-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1{alpha}. Intra-cerebroventricular (ICV) injection of A{beta} led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The A{beta}-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1{alpha}. Additionally, MIP-2 or SDF-1{alpha} was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against A{beta} neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: Black-Right-Pointing-Pointer Neuroprotective ability of the chemokines MIP2 and CXCL12 against A{beta} toxicity. Black-Right-Pointing-Pointer MIP

Analysis of a compartmental model of amyloid beta production, irreversible loss and exchange in humans.

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Elbert, Donald L; Patterson, Bruce W; Bateman, Randall J

2015-03-01

Amyloid beta (Aβ) peptides, and in particular Aβ42, are found in senile plaques associated with Alzheimer's disease. A compartmental model of Aβ production, exchange and irreversible loss was recently developed to explain the kinetics of isotope-labeling of Aβ peptides collected in cerebrospinal fluid (CSF) following infusion of stable isotope-labeled leucine in humans. The compartmental model allowed calculation of the rates of production, irreversible loss (or turnover) and short-term exchange of Aβ peptides. Exchange of Aβ42 was particularly pronounced in amyloid plaque-bearing participants. In the current work, we describe in much greater detail the characteristics of the compartmental model to two distinct audiences: physician-scientists and biokineticists. For physician-scientists, we describe through examples the types of questions the model can and cannot answer, as well as correct some misunderstandings of previous kinetic analyses applied to this type of isotope labeling data. For biokineticists, we perform a system identifiability analysis and a sensitivity analysis of the kinetic model to explore the global and local properties of the model. Combined, these analyses motivate simplifications from a more comprehensive physiological model to the final model that was previously presented. The analyses clearly demonstrate that the current dataset and compartmental model allow determination with confidence a single 'turnover' parameter, a single 'exchange' parameter and a single 'delay' parameter. When combined with CSF concentration data for the Aβ peptides, production rates may also be obtained. Copyright © 2015 Elsevier Inc. All rights reserved.

Beyond the neurotransmitter-focused approach in treating Alzheimer's disease: drugs targeting beta-amyloid and tau protein.

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Panza, Francesco; Solfrizzi, Vincenzo; Frisardi, Vincenza; Imbimbo, Bruno P; Capurso, Cristiano; D'Introno, Alessia; Colacicco, Anna M; Seripa, Davide; Vendemiale, Gianluigi; Capurso, Antonio; Pilotto, Alberto

2009-12-01

Drugs currently used to treat Alzheimer's Disease (AD) have limited therapeutic value and do not affect the main neuropathological hallmarks of the disease, i.e., senile plaques and neurofibrillar tangles. Senile plaques are mainly formed of beta-amyloid (Abeta), a 42-aminoacid peptide. Neurofibrillar tangles are composed of paired helical filaments of hyperphosphorylated tau protein. New, potentially disease-modifying, therapeutic approaches are targeting Abeta and tau protein. Drugs directed against Abeta include active and passive immunization, that have been found to accelerate Abeta clearance from the brain. The most developmentally advanced monoclonal antibody directly targeting Abeta is bapineuzumab, now being studied in a large Phase III clinical trial. Compounds that interfere with proteases regulating Abeta formation from amyloid precursor protein (APP) are also actively pursued. The discovery of inhibitors of beta-secretase, the enzyme that regulates the first step of the amyloidogenic metabolism of APP, has been revealed to be particularly difficult due to inherent medicinal chemistry problems, and only one compound (CTS-21166) has reached clinical testing. Conversely, several compounds that inhibit gamma-secretase, the pivotal enzyme that generates Abeta, have been identified, the most advanced being LY-450139 (semagacestat), now in Phase III clinical development. Compounds that stimulate alpha-secretase, the enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed, and one of them, EHT-0202, has recently entered Phase II testing. Potent inhibitors of Abeta aggregation have also been identified, and one of such compounds, PBT-2, has provided encouraging neuropsychological results in a recently completed Phase II study. Therapeutic approaches directed against tau protein include inhibitors of glycogen synthase kinase- 3 (GSK-3), the enzyme responsible for tau phosphorylation and tau protein aggregation inhibitors. NP-12

Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons

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Bianca Seifert

2016-01-01

Full Text Available The neurotrophin brain derived neurotrophic factor (BDNF is an important growth factor in the CNS. Deficits in transport of this secretory protein could underlie neurodegenerative diseases. Investigation of disease-related changes in BDNF transport might provide insights into the cellular mechanism underlying, for example, Alzheimer’s disease (AD. To analyze the role of BDNF transport in AD, live cell imaging of fluorescently labeled BDNF was performed in hippocampal neurons of different AD model systems. BDNF and APP colocalized with low incidence in vesicular structures. Anterograde as well as retrograde transport of BDNF vesicles was reduced and these effects were mediated by factors released from hippocampal neurons into the extracellular medium. Transport of BDNF was altered at a very early time point after onset of human APP expression or after acute amyloid-beta(1-42 treatment, while the activity-dependent release of BDNF remained unaffected. Taken together, extracellular cleavage products of APP induced rapid changes in anterograde and retrograde transport of BDNF-containing vesicles while release of BDNF was unaffected by transgenic expression of mutated APP. These early transport deficits might lead to permanently impaired brain functions in the adult brain.

Gold Nanoparticles and Microwave Irradiation Inhibit Beta-Amyloid Amyloidogenesis

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Bastus Neus

2008-01-01

Full Text Available Abstract Peptide-Gold nanoparticles selectively attached to β-amyloid protein (Aβ amyloidogenic aggregates were irradiated with microwave. This treatment produces dramatic effects on the Aβ aggregates, inhibiting both the amyloidogenesis and the restoration of the amyloidogenic potential. This novel approach offers a new strategy to inhibit, locally and remotely, the amyloidogenic process, which could have application in Alzheimer’s disease therapy. We have studied the irradiation effect on the amyloidogenic process in the presence of conjugates peptide-nanoparticle by transmission electronic microscopy observations and by Thioflavine T assays to quantify the amount of fibrils in suspension. The amyloidogenic aggregates rather than the amyloid fibrils seem to be better targets for the treatment of the disease. Our results could contribute to the development of a new therapeutic strategy to inhibit the amyloidogenic process in Alzheimer’s disease.

Chirality and chiroptical properties of amyloid fibrils.

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Dzwolak, Wojciech

2014-09-01

Chirality of amyloid fibrils-linear beta-sheet-rich aggregates of misfolded protein chains-often manifests in morphological traits such as helical twist visible in atomic force microscopy and in chiroptical properties accessible to vibrational circular dichroism (VCD). According to recent studies the relationship between molecular chirality of polypeptide building blocks and superstructural chirality of amyloid fibrils may be more intricate and less deterministic than previously assumed. Several puzzling experimental findings have put into question earlier intuitive ideas on: 1) the bottom-up chirality transfer upon amyloidogenic self-assembly, and 2) the structural origins of chiroptical properties of protein aggregates. For example, removal of a single amino acid residue from an amyloidogenic all-L peptide was shown to reverse handedness of fibrils. On the other hand, certain types of amyloid aggregates revealed surprisingly strong VCD spectra with the sign and shape dependent on the conditions of fibrillation. Hence, microscopic and chiroptical studies have highlighted chirality as one more aspect of polymorphism of amyloid fibrils. This brief review is intended to outline the current state of research on amyloid-like fibrils from the perspective of their structural and superstructural chirality and chiroptical properties. © 2014 Wiley Periodicals, Inc.

Sphingolipid Metabolism Correlates with Cerebrospinal Fluid Beta Amyloid Levels in Alzheimer’s Disease

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Fonteh, Alfred N.; Ormseth, Cora; Chiang, Jiarong; Cipolla, Matthew; Arakaki, Xianghong; Harrington, Michael G.

2015-01-01

Sphingolipids are important in many brain functions but their role in Alzheimer’s disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid β42 concentration in CSF from cognitively normal but not impaired

A study of potential pharmacokinetic and pharmacodynamic interactions between dextromethorphan/quinidine and memantine in healthy volunteers.

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Pope, Laura E; Schoedel, Kerri A; Bartlett, Cynthia; Sellers, Edward M

2012-08-01

Dextromethorphan/quinidine (DMQ) is the first agent indicated for the treatment of pseudobulbar affect. Dextromethorphan, the active ingredient, is a low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. This study evaluated the potential for a drug-drug interaction (DDI) of DMQ with memantine, which is also an NMDA receptor antagonist. This open-label, randomized, parallel-group study enrolled healthy adults who were randomized into one of two treatment groups. Group 1 subjects were administered memantine at a starting dose of 5 mg once daily, which was titrated over a 3-week period to a dose of 10 mg twice daily (every 12 hours) and continued for another 11 days to attain steady state; DMQ 30 mg (dextromethorphan 30 mg/quinidine 30 mg) every 12 hours was then added for a further 8 days. Group 2 subjects received DMQ 30 mg every 12 hours for 8 days to attain steady state; memantine was then added, titrated on the same schedule as in group 1, and continued at 10 mg every 12 hours for an additional 11 days. Pharmacokinetic blood sampling was performed to assess the primary endpoints of the 90% confidence intervals (CIs) for the geometric mean ratios of the areas under the plasma concentration-time curves (AUCs) for memantine, dextromethorphan, dextrorphan - the dextromethorphan metabolite - and quinidine during concomitant therapy versus monotherapy. Safety/tolerability and pharmacodynamic variables were also assessed. A total of 52 subjects were randomized. In both group 1 (n = 23) and group 2 (n = 29), the 90% CIs for the ratios of the AUCs during concomitant therapy versus monotherapy were within the predefined range to indicate similarity (0.8-1.25) for memantine, dextromethorphan and dextrorphan, indicating no pharmacokinetic DDI. The 90% CI for the AUC ratio for quinidine was slightly above the predefined range; however, the mean AUC increased by only 25%. In both groups, incidence of adverse events was similar, and pharmacodynamic

The effects of memantine on recovery, cognitive functions, and pain after propofol anesthesia

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Ulku Emik

Full Text Available Abstract Objectives: Postoperative cognitive dysfunction refers to the problems associated with thought and memory that are often experienced after major surgery. The aim of this study is to evaluate the effects of intraperitoneally administered memantine on recovery, cognitive functions, and pain after propofol anesthesia. Methods: The study was conducted in Gazi University Animal Research Laboratory, Ankara, Turkey in January 2012. Twenty-four adult female Wistar Albino rats weighing 170-270 g were educated for 300 s in the radial arm maze (RAM over three days. Group P was administered 150 mg kg−1 of intraperitoneal (IP propofol; Group M was given 1 mg kg−1 of IP memantine; and Group MP was given 1 mg kg−1 of IP memantine before being administered 150 mg kg−1 of IP propofol. The control group received only IP saline. RAM and hot plate values were obtained after recovery from the groups that received propofol anesthesia and 30 min after the administration of drugs in other two groups. Results: The duration of recovery for Group MP was significantly shorter than Group P (p < 0.001, and the number of entries and exits in the RAM by Group MP was significantly higher during the first hour when compared to Group P (p < 0.0001. Hot plate values, on the other hand, were found to be significantly increased in all groups when compared to the control values, aside from Group C (p < 0.0001. Conclusion: In this study, memantine provided shorter recovery times, better cognitive functions, and reduced postoperative pain. From this study, we find that memantine has beneficial effects on recovery, cognitive functions, and pain after propofol anesthesia.

Memantine prevents cardiomyocytes nuclear size reduction in the left ventricle of rats exposed to cold stress

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Adriano Meneghini

2009-01-01

Full Text Available OBJECTIVES: Memantine is an N-methyl-d-aspartate (NMDA glutamate receptor antagonist used to treat Alzheimer's disease. Previous studies have suggested that receptor blockers act as neuroprotective agents; however, no study has specifically investigated the impact that these drugs have on the heart. We sought to evaluate the effects of memantine on nuclear size reduction in cardiac cells exposed to cold stress. METHOD: We used male EPM-Wistar rats (n=40 divided into 4 groups: 1 Matched control (CON; 2 Memantine-treated rats (MEM; 3 Rats undergoing induced hypothermia (IH and 4 Rats undergoing induced hypothermia that were also treated with memantine (IHM. Animals in the MEM and IHM groups were treated by oral gavage administration of 20 mg/kg/day memantine over an eight-day period. Animals in the IH and IHM groups were submitted to 4 hours of hypothermia in a controlled environment with a temperature of - 8ºC on the last day of the study. RESULTS: The MEM group had the largest cardiomyocyte nuclear size (151 ± 3.5 μm³ vs. CON: 142 ± 2.3 μm³; p<0.05, while the IH group had the smallest mean value of nuclear size. The nuclear size of the IHM group was preserved (125 ± 2.9 μm³ compared to the IH group (108 ± 1.7 μm³; p<0.05. CONCLUSION: Memantine prevented the nuclear size reduction of cardiomyocytes in rats exposed to cold stress.

Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice

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Kittelberger, Kara A.; Piazza, Fabrizio; Tesco, Giuseppina; Reijmers, Leon G.

2012-01-01

Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD). It has been proposed that soluble amyloid-beta (Abeta) oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss. PMID:22238679

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension.

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Aman, Michael G; Findling, Robert L; Hardan, Antonio Y; Hendren, Robert L; Melmed, Raun D; Kehinde-Nelson, Ola; Hsu, Hai-An; Trugman, Joel M; Palmer, Robert H; Graham, Stephen M; Gage, Allyson T; Perhach, James L; Katz, Ephraim

2017-06-01

Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

Efficacy of Memantine, Donepezil, or Their Association in Moderate-Severe Alzheimer’s Disease: A Review of Clinical Trials

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Ivana Molino

2013-01-01

Full Text Available Background. Acetylcholinesterase (AChE/cholinesterase (ChE inhibitors (Is and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer’s disease (AD, respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage. Objectives. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD. Method. Double-blind, placebo-controlled randomized trials (RCTs using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007–2012. Results and Conclusion. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of “adequacy and representativeness.” Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24–52 weeks, and the different cognitive assessment tools used did not allow comparing properly different trials.

The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide.

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Stephanie J Soscia

2010-03-01

Full Text Available The amyloid beta-protein (Abeta is believed to be the key mediator of Alzheimer's disease (AD pathology. Abeta is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Abeta has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities.Here, we provide data supporting an in vivo function for Abeta as an antimicrobial peptide (AMP. Experiments used established in vitro assays to compare antimicrobial activities of Abeta and LL-37, an archetypical human AMP. Findings reveal that Abeta exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue Abeta levels. Consistent with Abeta-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Abeta antibodies.Our findings suggest Abeta is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Abeta-mediated pathology and has important implications for ongoing and future AD treatment strategies.

Aluminum complexing enhances amyloid beta protein penetration of blood-brain barrier.

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Banks, William A; Niehoff, Michael L; Drago, Denise; Zatta, Paolo

2006-10-20

A significant co-morbidity of Alzheimer's disease and cerebrovascular impairment suggests that cerebrovascular dysregulation is an important feature of dementia. Amyloid beta protein (Abeta), a relevant risk factor in Alzheimer's disease, has neurotoxic properties and is thought to play a critical role in the cognitive impairments. Previously, we demonstrated that the 42mer of Abeta (Abeta42) complexed with aluminum (Al-Abeta42) is much more cytotoxic than non-complexed Abeta42. The level of Abeta in the brain is a balance between synthesis, degradation, and fluxes across the blood-brain barrier (BBB). In the present paper, we determined whether complexing with aluminum affected the ability of radioactively iodinated Abeta to cross the in vivo BBB. We found that the rates of uptake of Al-Abeta42 and Abeta42 were similar, but that Al-Abeta42 was sequestered by brain endothelial cells much less than Abeta42 and so more readily entered the parenchymal space of the brain. Al-Abeta42 also had a longer half-life in blood and had increased permeation at the striatum and thalamus. Brain-to-blood transport was similar for Al-Abeta42 and Abeta42. In conclusion, complexing with aluminum affects some aspects of blood-to-brain permeability so that Al-Abeta42 would have more ready access to brain cells than Abeta42.

Clinical and cost implications of amyloid beta detection with amyloid beta positron emission tomography imaging in early Alzheimer's disease - the case of florbetapir.

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Hornberger, John; Bae, Jay; Watson, Ian; Johnston, Joe; Happich, Michael

2017-04-01

Amyloid beta (Aβ) positron emission tomography (PET) imaging helps estimate Aβ neuritic plaque density in patients with cognitive impairment who are under evaluation for Alzheimer's disease (AD). This study aims to evaluate the cost-effectiveness of the Aβ-PET scan as an adjunct to standard diagnostic assessment for diagnosis of AD in France, using florbetapir as an example. A state-transition probability analysis was developed adopting the French Health Technology Assessment (HTA) perspective per guidance. Parameters included test characteristics, rate of cognitive decline, treatment effect, costs, and quality of life. Additional scenarios assessed the validity of the analytical framework, including: (1) earlier evaluation/treatment; (2) cerebrospinal fluid (CSF) as a comparator; and (3) use of other diagnostic procedures. Outputs included differences in quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). All benefits and costs were discounted for time preferences. Sensitivity analyses were performed to assess the robustness of findings and key influencers of outcomes. Aβ-PET used as an adjunct to standard diagnostic assessment increased QALYs by 0.021 years and 10 year costs by €470 per patient. The ICER was €21,888 per QALY gained compared to standard diagnostic assessment alone. When compared with CSF, Aβ-PET costs €24,084 per QALY gained. In other scenarios, Aβ-PET was consistently cost-effective relative to the commonly used affordability threshold (€40,000 per QALY). Over 95% of simulations in the sensitivity analysis were cost-effective. Aβ-PET is projected to affordably increase QALYs from the French HTA perspective per guidance over a range of clinical scenarios, comparators, and input parameters.

A beta2-microglobulin cleavage variant fibrillates at near-physiological pH

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Corlin, Dorthe B; Johnsen, Christina K; Nissen, Mogens H

2009-01-01

Beta2-microglobulin (beta2m) deposits as amyloid in dialysis-related amyloidosis (DRA), predominantly in joints. The molecular mechanisms underlying the amyloidogenicity of beta2m are still largely unknown. In vitro, acidic conditions, pH ... several days. Here, we show that amyloid fibrils are generated in less than an hour when a cleavage variant of beta2m--found in the circulation of many dialysis patients--is exposed to pH levels (pH 6.6) occurring in joints during inflammation. Aggregation and fibrillation, including seeding effects...... with intact, native beta2m were studied by Thioflavin T fluorescence spectroscopy, turbidimetry, capillary electrophoresis, and electron microscopy. We conclude that a biologically relevant variant of beta2m is amyloidogenic at slightly acidic pH. Also, only a very small amount of preformed fibrils...

Complement activation by the amyloid proteins A beta peptide and beta 2-microglobulin

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Nybo, Mads; Nielsen, E H; Svehag, S E

1999-01-01

component nor heparan sulfate did significantly alter the A beta-induced CA. The results indicate that not only fibrillar A beta but also oligomers of, in particular, beta 2M from patients with dialysis-associated amyloidosis are capable of inducing CA at supra-physiological concentrations....

High plasma levels of islet amyloid polypeptide in young with new-onset of type 1 diabetes mellitus.

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Johan F Paulsson

Full Text Available AIMS/HYPOTHESIS: Islet amyloid polypeptide (IAPP is a beta cell hormone secreted together with insulin upon glucose stimulation. IAPP participates in normal glucose regulation, but IAPP is also known for its ability to misfold and form islet amyloid. Amyloid fibrils form through smaller cell toxic intermediates and deposited amyloid disrupts normal islet architecture. Even though IAPP and amyloid formation are much discussed in type 2 diabetes, our aim was to study the significance of IAPP in type 1 diabetes. RESULTS: Plasma IAPP levels in children and adolescents with newly diagnosed type 1 diabetes (n = 224 were analysed and concentrations exceeding 100 pmol/L (127.2-888.7 pmol/L were found in 11% (25/224. The IAPP increase did not correlate with C-peptide levels. CONCLUSIONS/INTERPRETATION: Plasma levels of IAPP and insulin deviate in a subpopulation of young with newly-diagnosed type 1 diabetes. The determined elevated levels of IAPP might increase the risk for IAPP misfolding and formation of cell toxic amyloid in beta cells. This finding add IAPP-aggregation to the list over putative pathological factors causing type 1 diabetes.

Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line

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Ayako Kumagai

2014-12-01

Full Text Available Memantine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds.

Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line

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Kumagai, Ayako; Fujita, Akira; Yokoyama, Tomoki; Nonobe, Yuki; Hasaba, Yasuhiro; Sasaki, Tsutomu; Itoh, Yumi; Koura, Minako; Suzuki, Osamu; Adachi, Shigeki; Ryo, Haruko; Kohara, Arihiro; Tripathi, Lokesh P.; Sanosaka, Masato; Fukushima, Toshiki; Takahashi, Hiroyuki; Kitagawa, Kazuo; Nagaoka, Yasuo; Kawahara, Hidehisa; Mizuguchi, Kenji; Nomura, Taisei; Matsuda, Junichiro; Tabata, Toshihide; Takemori, Hiroshi

2014-01-01

Memantine is a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg) disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR) and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds. PMID:25513882

MEMANTINE ATTENUATES THE OKADAIC ACID INDUCED SHORT-TERM SPATIAL MEMORY IMPAIRMENT AND HIPPOCAMPAL CELL LOSS IN RATS.

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Dashniani, M; Chighladze, M; Burjanadze, M; Beselia, G; Kruashvili, L

2016-03-01

In the present study, the possible beneficial effect of memantine on the Okadaic Acid (OA) induced spatial short-term memory impairment was examined in spatial alternation task, and the neuroprotective potential of memantine on OA-induced structural changes in the hippocampus was evaluated by Nissl staining. OA was dissolved in artificial cerebrospinal fluid (aCSF) and injected intracerebroventriculary (ICV) 200 ng in a volume of 10 μl bilaterally. Vehicle control received aCSF ICV bilaterally. Control and OA injected rats were divided into 2 subgroups injected i.p. with saline or memantine (5 mg/kg). Memantine or saline were given daily for 13 days starting from the day of OA injection. Behavioral study showed that bilateral ICV microinjection of OA induced impairment in spatial short-term memory. Nissl staining in the present study showed that the ICV microinjection of OA significantly decreased the number of surviving pyramidal neurons in the CA1 region of the hippocampus. Chronic administration of memantine effectively attenuated OA induced spatial short-term memory impairment and the OA-induced neuropathological changes in the hippocampus. Therefore, ICV injection of OA can be used as an experimental model to study mechanisms of neurodegeneration and define novel therapeutics targets for AD pathology.

A Stability-Indicating HPLC Method for the Determination of Memantine Hydrochloride in Dosage Forms through Derivatization with 1-Fluoro-2,4-dinitrobenzene

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Jalalizadeh, Hassan; Raei, Mahdi; Tafti, Razieh Fallah; Farsam, Hassan; Kebriaeezadeh, Abbas; Souri, Effat

2014-01-01

Memantine is chemically a tricyclic amine and is used for Parkinson’s disease and movement disorders. Although several HPLC methods with different derivatization reagents have been developed for the determination of memantine in biological fluids, there are some complications which limit the use of these methods in routine analysis of memantine in in vitro tests. We established a simple, sensitive, precise, and accurate HPLC method for the quantification of memantine in dosage forms. Pre-column derivatization of memantine was performed with 1-fluoro-2,4-dinitrobenzene and the reaction product was separated on a Nova-Pak C18 column. A mixture of acetonitrile and sodium dihydrogenphosphate (pH 2.5; 0.05 M) (70: 30, v/v) was used as the mobile phase. UV detection was performed at 360 nm. Forced degradation studies were performed on a powdered tablet sample of memantine hydro-chloride using acidic (0.1 M hydrochloric acid), basic (0.1 M sodium hydroxide), oxidative (10% hydrogen peroxide), thermal (105°C), photolytic, and humidity conditions. Good linearity (r2=0.999) was obtained over the range of 1–12 μg mL−1 of memantine hydrochloride with acceptable within-day and between-day precision values in the range of 0.05–0.95%. The proposed method was used for the assay determination and dissolution rate study of memantine dosage forms with excellent specificity. PMID:24959398

A carrier for non-covalent delivery of functional beta-galactosidase and antibodies against amyloid plaques and IgM to the brain.

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Gobinda Sarkar

Full Text Available BACKGROUND: Therapeutic intervention of numerous brain-associated disorders currently remains unrealized due to serious limitations imposed by the blood-brain-barrier (BBB. The BBB generally allows transport of small molecules, typically <600 daltons with high octanol/water partition coefficients, but denies passage to most larger molecules. However, some receptors present on the BBB allow passage of cognate proteins to the brain. Utilizing such receptor-ligand systems, several investigators have developed methods for delivering proteins to the brain, a critical requirement of which involves covalent linking of the target protein to a carrier entity. Such covalent modifications involve extensive preparative and post-preparative chemistry that poses daunting limitations in the context of delivery to any organ. Here, we report creation of a 36-amino acid peptide transporter, which can transport a protein to the brain after routine intravenous injection of the transporter-protein mixture. No covalent linkage of the protein with the transporter is necessary. APPROACH: A peptide transporter comprising sixteen lysine residues and 20 amino acids corresponding to the LDLR-binding domain of apolipoprotein E (ApoE was synthesized. Transport of beta-galactosidase, IgG, IgM, and antibodies against amyloid plques to the brain upon iv injection of the protein-transporter mixture was evaluated through staining for enzyme activity or micro single photon emission tomography (micro-SPECT or immunostaining. Effect of the transporter on the integrity of the BBB was also investigated. PRINCIPAL FINDINGS: The transporter enabled delivery to the mouse brain of functional beta-galactosidase, human IgG and IgM, and two antibodies that labeled brain-associated amyloid beta plaques in a mouse model of Alzheimer's disease. SIGNIFICANCE: The results suggest the transporter is able to transport most or all proteins to the brain without the need for chemically linking the

Memantine improves attention and episodic memory in Parkinson's disease dementia and dementia with Lewy bodies.

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Wesnes, Keith A; Aarsland, Dag; Ballard, Clive; Londos, Elisabet

2015-01-01

In both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), attentional dysfunction is a core clinical feature together with disrupted episodic memory. This study evaluated the cognitive effects of memantine in DLB and PDD using automated tests of attention and episodic memory. A randomised double-blind, placebo-controlled, 24-week three centre trial of memantine (20 mg/day) was conducted in which tests of attention (simple and choice reaction time) and word recognition (immediate and delayed) from the CDR System were administered prior to dosing and again at 12 and 24 weeks. Although other results from this study have been published, the data from the CDR System tests were not included and are presented here for the first time. Data were available for 51 patients (21 DLB and 30 PDD). In both populations, memantine produced statistically significant medium to large effect sized improvements to choice reaction time, immediate and delayed word recognition. These are the first substantial improvements on cognitive tests of attention and episodic recognition memory identified with memantine in either DLB or PDD. Copyright © 2014 John Wiley & Sons, Ltd.

Effectiveness of Memantine in Improvement of Cognitive Deficits in Specific Learning Disorder

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Elham Ahmadi Zahrani

2016-12-01

Full Text Available Abstract Background: Specific learning disorder is a neurodevelopmental disorder characterized by persistent difficulties in learning academic skills in reading, written expression, or mathematics. This study was performed to investigate the effectiveness of memantine in the relief of cognitive deficits (selective attention, sustained attention, and working memory in specific learning disorder. Materials and Methods: This study is a clinical trial. Of all children 8-12 years referred to Amir Kabir Hospital 94 patients diagnosed with specific learning disorder based on DSMV diagnostic interview referred by specialist and randomly divided by two groups, memantine and placebo. Cognitive deficits before and after treatment were measured with continuous performance test, Stroop test and Wechsler Digit Span forward and reverse and Corsi test. Results: Multivariate analysis of variance showed a significant difference in error when answering, omission answer and corrected answer in continuous performance test, but this difference is not significant in response time. Difference in forward, reverse and collected auditory was significant and not significant in the auditory span. In active visual working memory at corsi cube test, difference was significant (p <0.05. Conclusion: The results showed that memantine in improvement of sustained attention, auditory working memory and visual working memory, is effective, while in selective attention is not effective and according to similarities of learning disorder and Attention deficit / Hyperactivity disorder (ADHD and the effectiveness of memantine in improvement of symptoms of ADHD, we can also use this drug in improvement of cognitive deficits of specific learning disorder.

Nanoparticles and amyloid systems: A fatal encounter?

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Abel, Bernd [Leibniz Institute of Surface Modification, Chemical Department, Permoserstr. 15, D-04318 Leipzig, Germany and Wilhelm-Ostwald-Institute for Physical and Theoretical Chemistry, Linnéstr. 3, D-04103 Leipzig (Germany)

2014-10-06

Nanoparticles (NPs) are used in many products of our daily life, however, there has been concern that they may also be harmful to human health. Recently NPs have been found to accelerate the fibrillation kinetics of amyloid systems. In the past this has been preliminarily attributed to a nucleation effect. Nanoparticle surfaces and interfaces appear to limit the degrees of freedom of amyloid systems (i.e., peptides and proteins) due to a phase space constraint such that rapid cross-beta structures are formed faster than without interface interactions and in turn fibril formation is enhanced significantly. Here we explore if lipid bilayers in the form of liposomes (140nm) also accelerate fibril formation for amyloid systems. We have investigated a fragment NNFGAIL of the Human islet amyloid polypeptide (hIAPP) in contact with 1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) liposomes in aqueous solution. We found that the lipid bilayer vesicles do accelerate fibril formation in time-resolved off-line detected atomic force microscopy experiments. Characteristic Thioflavine-T fluorescence on the same structures verify that the structures consist of aggregated peptides in a typical cross-β-structure arrangement.

The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

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Hongen Wei

Full Text Available Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs from Fmr1 knockout (KO mice, a mouse model for fragile X syndrome (FXS and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.

Comparison of the amyloid pore forming properties of rat and human Alzheimer’s beta-amyloid peptide 1-42: Calcium imaging data

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Coralie Di Scala

2016-03-01

Full Text Available The data here consists of calcium imaging of human neuroblastoma SH-SY5Y cells treated with the calcium-sensitive dye Fluo-4AM and then incubated with nanomolar concentrations of either human or rat Alzheimer’s β-amyloid peptide Aβ1-42. These data are both of a qualitative (fluorescence micrographs and semi-quantitative nature (estimation of intracellular calcium concentrations of cells probed by Aβ1-42 peptides vs. control untreated cells. Since rat Aβ1-42 differs from its human counterpart at only three amino acid positions, this comparative study is a good assessment of the specificity of the amyloid pore forming assay. The interpretation of this dataset is presented in the accompanying study “Broad neutralization of calcium-permeable amyloid pore channels with a chimeric Alzheimer/Parkinson peptide targeting brain gangliosides” [1].

Soluble beta-amyloid precursor protein is related to disease progression in amyotrophic lateral sclerosis.

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Petra Steinacker

Full Text Available BACKGROUND: Biomarkers of disease progression in amyotrophic lateral sclerosis (ALS could support the identification of beneficial drugs in clinical trials. We aimed to test whether soluble fragments of beta-amyloid precursor protein (sAPPα and sAPPß correlated with clinical subtypes of ALS and were of prognostic value. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-sectional study including patients with ALS (N = 68 with clinical follow-up data over 6 months, Parkinson's disease (PD, N = 20, and age-matched controls (N = 40, cerebrospinal fluid (CSF levels of sAPPα a, sAPPß and neurofilaments (NfH(SMI35 were measured by multiplex assay, Progranulin by ELISA. CSF sAPPα and sAPPß levels were lower in ALS with a rapidly-progressive disease course (p = 0.03, and p = 0.02 and with longer disease duration (p = 0.01 and p = 0.01, respectively. CSF NfH(SMI35 was elevated in ALS compared to PD and controls, with highest concentrations found in patients with rapid disease progression (p<0.01. High CSF NfH(SMI3 was linked to low CSF sAPPα and sAPPß (p = 0.001, and p = 0.007, respectively. The ratios CSF NfH(SMI35/CSF sAPPα,-ß were elevated in patients with fast progression of disease (p = 0.002 each. CSF Progranulin decreased with ongoing disease (p = 0.04. CONCLUSIONS: This study provides new CSF candidate markers associated with progression of disease in ALS. The data suggest that a deficiency of cellular neuroprotective mechanisms (decrease of sAPP is linked to progressive neuro-axonal damage (increase of NfH(SMI35 and to progression of disease.

Changes in cerebral glucose metabolism in patients with posttraumatic cognitive impairment after memantine therapy. A preliminary study

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Kim, Yong-Wook; Shin, Ji-Cheol; An, Young-Sil

2010-01-01

The objective of this study was to investigate the changes in cerebral glucose metabolism in patients with posttraumatic cognitive impairment after memantine therapy. We performed serial F-18 fluorodeoxyglucose positron emission tomography studies before and after memantine therapy (20 mg per day) on 17 patients with posttraumatic cognitive impairment using statistical parametric mapping analysis. In addition, covariance analysis was performed to identify regions, where changes in regional cerebral glucose metabolism correlated significantly with increased Mini-Mental Status Examination scores. Statistical parametric mapping analysis demonstrated that, compared with baseline, significantly increased cerebral glucose metabolism occurred in both inferior, middle and superior frontal gyri, both angular gyri, both precuneus, the right middle cingulum, the left inferior parietal lobule, the left fusiform gyrus, the left precentral gyrus, the left paracentral lobule, and the left lingual gyrus after memantine therapy (P uncorrected uncorrected corrected <0.0001). Our findings indicate that the prefrontal and the parietal association cortices may be the relevant structures for the pharmacological response to memantine therapy in patients with posttraumatic cognitive impairment. (author)

Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters.

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Toneff, Thomas; Funkelstein, Lydiane; Mosier, Charles; Abagyan, Armen; Ziegler, Michael; Hook, Vivian

2013-08-01

Beta-amyloid (Aβ) peptides are secreted from neurons, resulting in extracellular accumulation of Aβ and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that Aβ undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of Aβ(1-40) and Aβ(1-42) with peptide neurotransmitters (galanin, enkephalin, and NPY) and catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Regulated secretion from chromaffin cells was stimulated by KCl depolarization and nicotine. Forskolin, stimulating cAMP, also induced co-secretion of Aβ peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of Aβ with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, Aβ was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, β- and γ-secretases, that are necessary for production of Aβ. Thus, Aβ can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of Aβ(1-40) and Aβ(1-42) with the galanin neurotransmitter. These findings illustrate that Aβ peptides are present in neurotransmitter-containing DCSV, and undergo co-secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions. Copyright © 2013 Elsevier Inc. All rights reserved.

Bioassay-Guided Isolation of Neuroprotective Compounds from Uncaria rhynchophylla against Beta-Amyloid-Induced Neurotoxicity.

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Xian, Yan-Fang; Lin, Zhi-Xiu; Mao, Qing-Qiu; Hu, Zhen; Zhao, Ming; Che, Chun-Tao; Ip, Siu-Po

2012-01-01

Uncaria rhynchophylla is a component herb of many Chinese herbal formulae for the treatment of neurodegenerative diseases. Previous study in our laboratory has demonstrated that an ethanol extract of Uncaria rhynchophylla ameliorated cognitive deficits in a mouse model of Alzheimer's disease induced by D-galactose. However, the active ingredients of Uncaria rhynchophylla responsible for the anti-Alzheimer's disease activity have not been identified. This study aims to identify the active ingredients of Uncaria rhynchophylla by a bioassay-guided fractionation approach and explore the acting mechanism of these active ingredients by using a well-established cellular model of Alzheimer's disease, beta-amyloid- (Aβ-) induced neurotoxicity in PC12 cells. The results showed that six alkaloids, namely, corynoxine, corynoxine B, corynoxeine, isorhynchophylline, isocorynoxeine, and rhynchophylline were isolated from the extract of Uncaria rhynchophylla. Among them, rhynchophylline and isorhynchophylline significantly decreased Aβ-induced cell death, intracellular calcium overloading, and tau protein hyperphosphorylation in PC12 cells. These results suggest that rhynchophylline and isorhynchophylline are the major active ingredients responsible for the protective action of Uncaria rhynchophylla against Aβ-induced neuronal toxicity, and their neuroprotective effect may be mediated, at least in part, by inhibiting intracellular calcium overloading and tau protein hyperphosphorylation.

Memantine as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial.

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Ghaleiha, Ali; Asadabadi, Mahtab; Mohammadi, Mohammad-Reza; Shahei, Maryam; Tabrizi, Mina; Hajiaghaee, Reza; Hassanzadeh, Elmira; Akhondzadeh, Shahin

2013-05-01

Autism is a neurodevelopmental disorder that causes significant impairment in socialization and communication. It is also associated with ritualistic and stereotypical behaviour. Recent studies propose both hyper-and hypoglutamatergic ideologies for autism. The objective of this study was to assess the effects of memantine plus risperidone in the treatment of children with autism. Children with autism were randomly allocated to risperidone plus memantine or placebo plus risperidone for a 10-wk, double-blind, placebo-controlled study. The dose of risperidone was titrated up to 3 mg/d and memantine was titrated to 20 mg/d. Children were assessed at baseline and after 2, 4, 6, 8 and 10 wk of starting medication protocol. The primary outcome measure was the irritability subscale of Aberrant Behavior Checklist-Community (ABC-C). Difference between the two treatment arms was significant as the group that received memantine had greater reduction in ABC-C subscale scores for irritability, stereotypic behaviour and hyperactivity. Eight side-effects were observed over the trial, out of the 25 side-effects that the checklist included. The difference between the two groups in the frequency of side-effects was not significant. The present study suggests that memantine may be a potential adjunctive treatment strategy for autism and it was generally well tolerated. This trial is registered with the Iranian Clinical Trials Registry (IRCT1138901151556N10; www.irct.ir).

The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by beta-amyloid peptide.

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Kurz, C; Ungerer, I; Lipka, U; Kirr, S; Schütt, T; Eckert, A; Leuner, K; Müller, W E

2010-05-01

beta-Amyloid peptide (Abeta) is implicated in the pathogenesis of Alzheimer's disease by initiating a cascade of events from mitochondrial dysfunction to neuronal death. The metabolic enhancer piracetam has been shown to improve mitochondrial dysfunction following brain aging and experimentally induced oxidative stress. We used cell lines (PC12 and HEK cells) and murine dissociated brain cells. The protective effects of piracetam in vitro and ex vivo on Abeta-induced impairment of mitochondrial function (as mitochondrial membrane potential and ATP production), on secretion of soluble Abeta and on neurite outgrowth in PC12 cells were investigated. Piracetam improves mitochondrial function of PC12 cells and acutely dissociated brain cells from young NMRI mice following exposure to extracellular Abeta(1-42). Similar protective effects against Abeta(1-42) were observed in dissociated brain cells from aged NMRI mice, or mice transgenic for mutant human amyloid precursor protein (APP) treated with piracetam for 14 days. Soluble Abeta load was markedly diminished in the brain of those animals after treatment with piracetam. Abeta production by HEK cells stably transfected with mutant human APP was elevated by oxidative stress and this was reduced by piracetam. Impairment of neuritogenesis is an important consequence of Abeta-induced mitochondrial dysfunction and Abeta-induced reduction of neurite growth in PC12 cells was substantially improved by piracetam. Our findings strongly support the concept of improving mitochondrial function as an approach to ameliorate the detrimental effects of Abeta on brain function.

Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat.

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Villette, Vincent; Poindessous-Jazat, Frédérique; Simon, Axelle; Léna, Clément; Roullot, Elodie; Bellessort, Brice; Epelbaum, Jacques; Dutar, Patrick; Stéphan, Aline

2010-08-18

The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.

Spatial patterns of brain amyloid-beta burden and atrophy rate associations in mild cognitive impairment

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Tosun, Duygu; Schuff, Norbert; Mathis, Chester A.; Jagust, William; Weiner, Michael W.; Saradha, A.; Abdi, Herve; Abdulkadir, Ahmed; Abeliovich, Asa; Abellan van Kan, Gabor; Abner, Erin; Acharya, Deepa; Agrusti, Antonella; Agyemang, Alex; Ahdidan, Jamila; Ahmed, Shiek; Ahn, Jae Eun; Aisen, Paul; Aksu, Yaman; Al-Akhras, Mousa; Alarcon, Marcelo; Alberca, Roman; Alexander, Gene; Alexander, Daniel; Alin, Aylin; Almeida, Fabio; Amlien, Inge; Anand, Shyam; Anderson, Dallas; Andrew, Marilee; Angersbach, Steve; Anjum, Ayesha; Aoyama, Eiji; Arfanakis, Konstantinos; Armor, Tom; Arnold, Steven; Arunagiri, Vidhya; Asatryan, Albert; Ashe-McNalley, Cody; Ashiga, Hirokazu; Assareh, Arezoo; Le Page, Aurelie; Avants, Brian; Avinash, Gopal; Aviv, Richard; Awasthi, Sukrati; Ayan-Oshodi, Mosun; Babic, Tomislav; Baek, Young; Bagci, Ulas; Bai, Shuyang; Baird, Geoffrey; Baker, John; Banks, Sarah; Bard, Jonathan; Barnes, Josephine; Bartlett, Jonathan; Bartzokis, George; Barua, Neil; Bauer, Corinna; Bayley, Peter; Beck, Irene; Becker, James; Becker, J. Alex; Beckett, Laurel; Bednar, Martin; Beg, Mirza Faisal; Bek, Stephan; Belaroussi, Boubakeur; Belmokhtar, Nabil; Bernard, Charlotte; Bertram, Lars; Bhaskar, Uday; Biffi, Alessandro; Bigler, Erin; Bilgic, Basar; Bishop, Courtney; Bittner, Daniel; Black, Ronald; Bogorodzki, Piotr; Bokde, Arun; Bonner-Jackson, Aaron; Boppana, Madhu; Bourgeat, Pierrick; Bowes, Mike; Bowman, DuBois; Bowman, Gene; Braskie, Meredith; Braunewell, Karl; Breitner, Joihn; Bresell, Anders; Brewer, James; Brickman, Adam; Britschgi, Markus; Broadbent, Steve; Brogren, Jacob; Brooks, David; Browndyke, Jeffrey; Brunton, Simon; Buchert, Ralph; Buchsbaum, Monte; Buckley, Chris; Buerger, Katharina; Burger, Cyrill; Burnham, Samantha; Burns, Jeffrey; Burton, David; Butman, John; Cabeza, Rafael; Cairns, Nigel; Callhoff, Johanna; Calvini, Piero; Cantillon, Marc; Capella, Heraldo; Carbotti, Angela; Cardona-Sanclemente, Luis Eduardo; Carle, Adam; Carmasin, Jeremy; Carranza-Ath, Fredy; Casabianca, Jodi; Casanova, Ramon; Cash, David; Cedarbaum, Jesse; Cella, Massimo; Celsis, Pierre; Chanu, Pascal; Chao, Linda; Charil, Arnaud; Chemali, Zeina; Chen, Rong; Chen, Jake; Chen, Gennan; Chen, Wei; Chen, Kewei; Chen, Shuzhong; Chen, Minhua; Cheng, Wei-Chen; Cherkas, Yauheniya; Chertkow, Howard; Cheung, Charlton; Cheung, Vinci; Chiang, Gloria; Chiba, Koji; Chin, Simon; Chisholm, Jane; Cho, Youngsang; Choe, John; Choubey, Suresh; Chowbina, Sudhir; Christensen, Anette Luther; Clark, David; Clark, Chris; Clarkson, Matt; Clayton, David; Clunie, David; Coen, Michael; Coimbra, Alexandre; Compton, David; Coppola, Giovanni; Coulin, Samuel; Cover, Keith S.; Crane, Paul; Crans, Gerald; Croop, Robert; Crowther, Daniel; Crum, William; Cui, Yue; Curry, Charles; Curtis, Steven; Cutter, Gary; Daiello, Lori; Dake, Michael; Dale, Anders; Daliri, Mohammad Reza; Damato, Vito Domenico; Darby, Eveleen; Darkner, Sune; Davatzikos, Christos; Dave, Jay; David, Renaud; DavidPrakash, Bhaskaran; Davidson, Julie; de Bruijne, Marleen; de Meyer, Geert; de Nunzio, Giorgio; Decarli, Charles; Dechairo, Bryan; DeDuck, Kristina; Dehghan, Hossein; Dejkam, Arsalan; Delfino, Manuel; Della Rosa, Pasquale Anthony; Dellavedova, Luca; Delpassand, Ebrahim; Delrieu, Julien; DeOrchis, Vincent; Depy Carron, Delphine; deToledo-Morrell, Leyla; Devanand, Davangere; Devanarayan, Viswanath; DeVous, Michael; Diaz-Arrastia, Ramon; Bradford, Dickerson; Ding, Xiaobo; Dinov, Ivo; Dobson, Howard; Dodge, Hiroko; Donohue, Michael; Dore, Vincent; Dorflinger, Ernest; Dowling, Maritza; Duan, Xujun; Dubal, Dena; Duchesne, Simon; Duff, Kevin; Dukart, Jrgen; Durazzo, Timothy; Dykstra, Kevin; Earl, Nancy; Edula, Goutham; Ekin, Ahmet; Elcoroaristizabal, Xabier; Emahazion, Tesfai; Engelman, Corinne; Epstein, Noam; Erten-Lyons, Deniz; Eskildsen, Simon; Falcone, Guido; Fan, Lingzhong; Fan, Yong; Farahibozorg, Seyedehrezvan; Farb, Norman; Farnum, Michael; Farrer, Lindsay; Farzan, Ali; Faux, Noel; Feldman, Betsy; Feldman, Howard; Feldman, Susan; Fennema-Notestine, Christine; Fernandes, Michel; Fernandez, Elsa; Ferrarini, Luca; Ferreira, Manuel Joao; Ferrer, Eugene; Figurski, Michal; Filipovych, Roman; Fillit, Howard; Finch, Stephen; Finlay, Daniel; Fiot, Jean-Baptiste; Flenniken, Derek; Fletcher, P. Thomas; Fletcher, Evan; Flynn Longmire, Crystal; Focke, Niels; Forman, Mark; Forsythe, Alan; Fox, Steven; Fox-Bosetti, Sabrina; Francis, Alexander L.; Franco-Villalobos, Conrado; Franko, Edit; Freeman, Stefanie; Friedrich, Christoph M.; Friesenhahn, Michel; Frings, Lars; Frisoni, Giovanni; Fritzsche, Klaus; Fujimoto, Yoko; Fujiwara, Ken; Fullerton, Terence; Furney, Simon; Gallins, Paul; Galvin, Ben; Gamst, Anthony; Gan, Ke; Garcia, Maria Teresa; Garg, Gaurav; Gaser, Christian; Gastineau, Edward; Gauthier, Serge; Gavett, Brandon; Gavidia, Giovana; Gazdzinski, Stefan; Ge, Qi; Ge, Tian; Gemme, Gianluca; Geraci, Joseph; Ghassabi, Zeinab; Gieschke, Ronald; Gil, Juan E.; Gill, Ryan; Gitelman, Darren; Gleason, Carey; Glymour, M. Maria; Godbey, Michael; Goghari, Vina; Gold, Michael; Goldberg, Terry; Goldman, Jennifer; Gomeni, Roberto; Gong, Shangwenyan; Gonzales, Celedon; Goodro, Robert; Gordon, Brian; Gore, Chris; Gorriz, Juan Manuel; Grachev, Igor; Grandey, Emily; Grasela, Thaddeus; Gratt, Jeremy; Gray, Katherine; Greenberg, Barry; Gregg, Keith; Gregory, Erik; Greicius, Michael; Greve, Douglas; Grill, Joshua; Gross, Alden; Gross, Alan; Guignot, Isabelle; Guo, Jeffrey; Guo, Qimiao; Guo, Hongbin; Guo, Lianghao; Habeck, Christian; Hai, Yizhen; Haight, Thaddeus; Hammarstrom, Per; Hampel, Harald; Han, Duke; Han, Jian; Han, Tony; Hanif, Muhammad; Hanna, Yousef; Hardy, Peter; Harvey, Danielle; Hasan, Md Kamrul; Hayashi, Toshihiro; Hazart, Aurelien; He, Huiguang; He, Yong; Head, Denise; Heckemann, Rolf; Heidebrink, Judith; Henderson, David; Henrard, Sebastien; Herholz, Karl; Hernandez, Monica; Herskovits, A. Zara; Hess, Christopher; Hildenbrand, Maike; Hobart, Jeremy; Hoffman, John; Holder, Daniel; Hollingworth, Paul; Holmes, Robin; Honigberg, Lee; Hoppin, Jack; Hou, Yangyang; Hsu, Ailing; Hsu, Wei-Wen; Hu, Xiaolan; Hu, Zhiwei; Hu, William; Huang, Juebin; Huang, Chien-Chih; Huang, Chingwen; Huang, Shuai; Huang, Yifan; Huang, Fude; Huang, Chun-Jung; Huang, Shu-Pang; Hubbard, Rebecca; Huentelman, Matthew; Hui, Shen; Huppertz, Hans-Jürgen; Hurko, Orest; Hurt, Stephen; Huyck, Susan; Hwang, Scott; Hyun, JungMoon; Ifeachor, Emmanuel; Iglesias, Martina; Ikari, Yasuhiko; Ikonomidou, Vasiliki; Imani, Farzin; Immermann, Fred; Inlow, Mark; Inoue, Lurdes; Insel, Philip; Irizarry, Michael; Irungu, Benson mwangi; Ishibashi, Taro; Ishii, Kenji; Ismail, Sara; Ismail, Shahina; Ito, Kaori; Iturria-Medina, Yasser; Iwatsubo, Takeshi; Jacobson, Mark; Jacqmin, Philippe; Jafari, Aria; Jafari-Khouzani, Kourosh; Jaffe, Carl; Jara, Hernan; Jasperse, Bas; Jedynak, Bruno; Jefferson, Angela; Jennings, J. Richard; Jessen, Walter; Jia, Fucang; Jiang, Tianzi; Jing, Huang; Johnson, Julene; Johnson, Sterling; Johnson, David K.; Jones, Richard; Juengling, Freimut; Juh, Rahyeong; Julin, Per; Kadish, Bill; Kahle-Wrobleski, Kristin; Kallam, Hanimi Reddy; Kamboh, M. Ilyas; Kaneko, Tomoki; Kaneta, Tomohiro; Kang, Ju Hee; Karageorgiou, Elissaios; Karantzoulis, Stella; Karlawish, Jason; Katz, Elyse; Kaushik, Sandeep S.; Kauwe, John; Kawakami, Hirofumi; Kazimipoor, Borhan; Kelleher, Thomas; Kennedy, Richard; Kerchner, Geoffrey; Kerrouche, Nacer; Khalil, Iya; Khalil, Andre; Killeen, Neil; Killiany, Ron; Kim, Jong Hun; Kim, Heeyoung; Kim, Ana; Kim, Yeonhee; Kim, Hyoungkyu; Kim, Seongkyun; Kim, Hyewon; Kimberg, Daniel; Kimura, Tokunori; King, Richard; Kirby, Justin; Kirsch, Wolff; Klimas, Michael; Kline, Richard; Kling, Mitchel; Klopfenstein, Erin; Koikkalainen, Juha; Kokomoor, Anders; Kolasny, Anthony; Koppel, Jeremy; Korolev, Igor; Kotran, Nickolas; Kouassi, Alex; Kowalczyk, Adam; Kozma, Lynn; Krams, Michael; Kratzer, Martina; Kuceyeski, Amy; Kuhn, Felix Pierre; Kumar, Sreedhar; Kuo, Hsun Ting; Kuo, Julie; Kurosawa, Ken; Kwon, Oh Hun; Labrish, Catherine; Laforet, Genevieve; Lai, Song; Lakatos, Anita; Lam, On Ki; Lampron, Antoine; Landau, Susan; Landen, Jaren; Lane, Richard; Langbaum, Jessica; Langford, Dianne; Lanius, Vivian; Laxamana, Joel; Le, Trung; Leahy, Richard; Lee, Jong-Min; Lee, Vita; Lee, Joseph H.; Lee, Grace; Lee, Dongsoo; Lee, Noah; Lefkimmiatis, Stamatis; Lemaitre, Herve; Lenfant, Pierre; Lenz, Robert; Leoutsakos, Jeannie-Marie; Lester, Gayle; Levey, Allan; Li, Shi-jiang; Li, Shanshan; Li, Wenjun; Li, Chin-Shang; Li, Xiaodong; Li, Rui; Li, Ming; Li, Lexin; Li, Jinhe; Li, Yi; Li, Quanzheng; Li, Gang; Liang, Kuchang; Liang, Peipeng; Liang, Lichen; Liao, Yuan-Lin; Lin, Ling-chih; Lin, Lan; Lin, Mingkuan; Lin, Ai-Ling; Liu, Songling; Liu, Yuan; Liu, Tianming; Liu, Meijie; Liu, Xiuwen; Liu, Li; Liu, Honggang; Liu, Pu; Liu, Tao; Liu, Sophia; Liu, Dazhong; Lo, Raymond; Lobanov, Victor; Loewenstein, David; Logovinsky, Veronika; Long, Xiaojing; Long, Ziyi; Looi, Jeffrey; Lu, Po-Haong; Lukic, Ana; Lull, Juan J.; Luo, Xiongjian; Lynch, John; Ma, Lei; Mackin, Scott; Mada, Marius; Magda, Sebastian; Maglio, Silvio; Maikusa, Norihide; Mak, Henry Ka-Fung; Malave, Vicente; Maldjian, Joseph; Mandal, Pravat; Mangin, Jean-Francois; Manjon, Jose; Mantri, Ninad; Manzour, Amir; Marambaud, Philippe; Marchewka, Artur; Marek, Kenneth; Markind, Samuel; Marshall, Gad; Martinez Torteya, Antonio; Mather, Mara; Mathis, Chester; Matoug, Sofia; Matsuo, Yoshiyuki; Mattei, Peter; Matthews, Dawn; McArdle, John; McCarroll, Steven; McEvoy, Linda; McGeown, William; McGonigle, John; McIntyre, John; McLaren, Donald; McQuail, Joseph; Meadowcroft, Mark; Meda, Shashwath; Mehta, Nirav; Melie-Garcia, Lester; Melrose, Rebecca; Mendonca, Brian; Menendez, Manuel; Meredith, Jere; Merrill, David; Mesulam, Marek-Marsel; Metti, Andrea; Meyer, Carsten; Mez, Jesse; Mickael, Guedj; Miftahof, Roustem; Mikhno, Arthur; Miller, David; Millikin, Colleen; Min, Ye; Mirza, Mubeena; Mistridis, Panagiota; Mitchell, Meghan; Mitsis, Effie; Mohan, Ananth; Moore, Dana; Moradi Birgani, Parmida; Moratal, David; Morimoto, Bruce; Mormino, Elizabeth; Mortamet, Benedicte; Moscato, Pablo; Mueller, Kathyrne; Mueller, Susanne; Mueller, Notger; Mukherjee, Shubhabrata; Mulder, Emma; Murayama, Shigeo; Murphy, Michael; Murray, Brian; Musiek, Erik; Myers, Amanda; Najafi, Shahla; Nazarparvar, Babak; Nazeri, Arash; Nettiksimmons, Jasmine; Neu, Scott; Ng, Yen-Bee; Nguyen, Nghi; Nguyen Xuan, Tuong; Nichols, Thomas; Nicodemus, Kristin; Niecko, Timothy; Nielsen, Casper; Notomi, Keiji; Nutakki, Gopi Chand; O'Bryant, Sid; O'Neil, Alison; Obisesan, Thomas; Oh, Dong Hoon; Oh, Joonmi; Okonkwo, Ozioma; Olde Rikkert, Marcel; Olmos, Salvador; Ortner, Marion; Ostrowitzki, Susanne; Oswald, Annahita; Ott, Brian; Ourselin, Sebastien; Ouyang, Gaoxiang; Paiva, Renata; Pan, Zhifang; Pande, Yogesh; Pardo, Jose; Pardoe, Heath; Park, Hyunjin; Park, Lovingly; Park, Moon Ho; Park, Sang hyun; Park, Kee Hyung; Park, Sujin; Parsey, Ramin; Parveen, Riswana; Paskavitz, James; Patel, Yogen; Patil, Manasi; Pawlak, Mikolaj; Payoux, Pierre; Pearson, Jim; Peavy, Guerry; Pell, Gaby; Peng, Yahong; Pennec, Xavier; Pepin, Jean louis; Perea, Rodrigo; Perneczky, Robert; Petitti, Diana; Petrella, Jeffrey; Peyrat, Jean-Marc; Pezoa, Jorge; Pham, Chi-Tuan; Phillips, Justin; Phillips, Nicole; Pierson, Ronald; Piovezan, Mauro; Podhorski, Adam; Pollari, Mika; Pontecorvo, Michael; Poppenk, Jordan; Posner, Holly; Potkin, Steven; Potter, Guy; Potter, Elizabeth; Poulin, Stephane; Prasad, Gautam; Prenger, Kurt; Prince, Jerry; Priya, Anandh; Puchakayala, Shashidhar Reddy; Qiu, Ruolun; Qiu, Anqi; Qiu, Wendy; Qualls, Constance Dean; Rabie, Huwaida; Rajeesh, Rajeesh; Rallabandi, V. P. Subramanyam; Ramage, Amy; Randolph, Christopher; Rao, Anil; Rao, Divya; Raubertas, Richard; Ray, Debashis; Razak, Hana; Redolfi, Alberto; Reed, Bruce; Reid, Andrew; Reilhac, Anthonin; Reinsberger, Claus; Restrepo, Lucas; Retico, Alessandra; Richards, John; Riddle, William; Ries, Michele; Rincon, Mariano; Rischall, Matt; Rizk-Jackson, Angela; Robieson, Weining; Rocha-Rego, Vanessa; Rogalski, Emily; Rogers, Elizabeth; Rojas, Ignacio; Rojas Balderrama, Javier; Romero, Klaus; Rorden, Chris; Rosand, Jonathan; Rosen, Allyson; Rosen, Ori; Rosenberg, Paul; Ross, David; Roubini, Eli; Rousseau, François; Rowe, Christopher; Rubin, Daniel; Rubright, Jonathan; Ruiz, Agustin; Rusinek, Henry; Ryan, Laurie; Saad, Ahmed; Sabbagh, Marway; Sabuncu, Mert; Sachs, Michael; Sadeghi, Ali; Said, Yasmine; Saint-Aubert, Laure; Sakata, Muneyuki; Salat, David; Salmon, David; Salter, Hugh; Samwald, Matthias; Sanchez, Luciano; Sanders, Elizabeth; Sanjo, Nobuo; Sarnel, Haldun; Sato, Hajime; Sato, Shinji; Saumier, Daniel; Savio, Alexandre; Sawada, Ikuhisa; Saykin, Andrew; Schaffer, J. David; Scharre, Douglas; Schegerin, Marc; Schlosser, Gretchen; Schmand, Ben; Schmansky, Nick; Schmidt, Mark; Schmidt-Wilcke, Tobias; Schneider, Lon; Schramm, Hauke; Schuerch, Markus; Schwartz, Eben; Schwartz, Craig; Schwarz, Adam; Seethamraju, Ravi; Seixas, Flavio; Selnes, Per; Senjem, Matthew; Senlin, Wang; Seo, Sang Won; Sethuraman, Gopalan; Sevigny, Jeffrey; Sfikas, Giorgos; Sghedoni, Roberto; Shah, Said Khalid; Shahbaba, Babak; Shams, Soheil; Shattuck, David; Shaw, Leslie; Sheela, Jaba; Shen, Weijia; Shen, Qian; Shera, David; Sherman, John; Sherva, Richard; Shi, Feng; Shukla, Vinay; Shuler, Catherine; Shulman, Joshua; Siegel, Rene; Siemers, Eric; Silveira, Margarida; Silver, Michael; Silverman, Daniel; Sim, Ida; Simmons, Andy; Simoes, Rita; Simon, Melvin; Simpson, Ivor; Singh, Simer Preet; Singh, Nikhil; Siuciak, Judy; Sjogren, Niclas; Skinner, Jeannine; Skup, Martha; Small, Gary; Smith, Michael; Smith, Benjamin; Smith, Charles; Smyth, Timothy; Snow, Sarah; Soares, Holly; Soldea, Octavian; Solomon, Paul; Solomon, Alan; Som, Subhojit; Song, Changhong; Song, Mingli; Sosova, Iveta; Soudah, Eduardo; Soydemir, Melih; Spampinato, Maria Vittoria; Spenger, Christian; Sperling, Reisa; Spiegel, Rene; Spies, Lothar; Squarcia, Sandro; Squire, Larry; Staff, Roger; Stern, Yaakov; Straw, Jack; Stricker, Nikki; Strittmatter, Stephen; Stühler, Elisabeth; Styren, Scot; Subramanian, Vijayalakshmi; Sugishita, Morihiro; Sukkar, Rafid; Sun, Jia; Sun, Ying; Sun, Yu; Sundell, Karen; Suri, Muhammad; Suzuki, Akiyuki; Svetnik, Vladimir; Swan, Melanie; Takahasi, Tetsuhiko; Takeuchi, Tomoko; Tanaka, Shoji; Tanchi, Chaturaphat; Tancredi, Daniel; Tao, Wenwen; Tao, Dacheng; Taylor-Reinwald, Lisa; Teng, Edmond; Terlizzi, Rita; Thames, April; Thiele, Frank; Thomas, Benjamin; Thomas, Ronald; Thompson, Paul; Thompson, Wesley; Thornton-Wells, Tricia; Thorvaldsson, Valgeir; Thurfjell, Lennart; Titeux, Laurence; Tokuda, Takahiko; Toledo, Juan B.; Tolli, Tuomas; Toma, Ahmed; Tomita, Naoki; Toro, Roberto; Torrealdea, Patxi; Tousian, Mona; Toussaint, Paule; Toyoshiba, Hiroyoshi; Tractenberg, Rochelle E.; Trittschuh, Emily; Trojanowski, John; Truran, Diana; Tsechpenakis, Gavriil; Tucker-Drob, Elliot; Tufail, Ahsan; Tung, Joyce; Turken, And; Ueda, Yoji; Ullrich, Lauren; Umadevi Venkataraju, Kannan; Umar, Nisser; Uzunbas, Gokhan; van de Nes, Joseph; van der Brug, Marcel; van Horn, John; van Leemput, Koen; van Train, Kenneth; van Zeeland, Ashley; Vasanawala, Minal; Vemuri, Prashanthi; Verwaerde, Philippe; Videbaek, Charlotte; Vidoni, Eric; Villanueva-Meyer, Javier; Visser, Pieter Jelle; Vitolo, Ottavio; Vounou, Maria; Wade, Sara; Walhovd, Kristine B.; Wan, Hong; Wang, Huanli; Wang, Yongmei Michelle; Wang, Yalin; Wang, Angela; Wang, Lei; Wang, Yue; Wang, Xu; Wang, Ze; Wang, Yaping; Wang, Tiger; Wang, Alex; Wang, Huali; Wang, Li-San; Wang, Wei; Wang, Li; Ward, Michael; Warfield, Simon; Waring, Stephen; Watanabe, Toshiyuki; Webb, David; Wei, Lili; Weiner, Michael; Wen, Shu-Hui; Wenjing, Li; Wenzel, Fabian; Westlye, Lars T.; Whitcher, Brandon; Whitlow, Christopher; Whitwell, Jennifer; Wilhelmsen, Kirk; Williams, David; Wilmot, Beth; Wimsatt, Matt; Wingo, Thomas; Wiste, Heather; Wolfson, Tanya; Wolke, Ira; Wolz, Robin; Woo, Jongwook; Woo, Ellen; Woods, Lynn; Worth, Andrew; Worth, Eric; Wouters, Hans; Wu, Teresa; Wu, Yi-Gen; Wu, Liang; Wu, Xiaoling; Wyman, Bradley; Wyss-Coray, Tony; Xiao, Guanghua; Xiao, Liu; Xie, Sharon; Xu, Shunbin; Xu, Ye; Xu, Yi-Zheng; Xu, Guofan; Xu, Jun; Yamane, Tomohiko; Yamashita, Fumio; Yan, Yunyi; Yan, Pingkun; Yang, Eric; Yang, Jinzhong; Yang, Qing X.; Yang, Zijiang; Yang, Guang; Yang, Zhitong; Yang, Wenlu; Ye, Liang; Ye, Byoung Seok; Ye, Jieping; Ye, Jong; Yee, Laura; Yesavage, Jerome; Ying, Song; Yoo, Bongin; Young, Jonathan; Yu, Shiwei; Yu, Dongchuan; Yuan, Guihong; Yuan, Kai; Yushkevich, Paul; Zaborszky, Laszlo; Zagorodnov, Vitali; Zagorski, Michael; Zawadzki, Rezi; Zeitzer, Jamie; Zelinski, Elizabeth; Zhang, Kurt; Zhang, Huixiong; Zhang, Tianhao; Zhang, Xin; Zhang, Ping; Zhang, Bin; Zhang, Jing; Zhang, Linda; Zhang, Lijun; Zhang, Zhiguo; Zhao, Qinying; Zhao, Jim; Zhao, Peng; Zhen, Xiantong; Zheng, Yuanjie; Zhijun, Yao; Zhou, Bin; Zhou, Sheng; Zhu, Wen; Zhu, Hongtu; Zhu, Wanlin; Zilka, Samantha; Zito, Giancarlo; Zou, Heng

2011-01-01

Amyloid-β accumulation in the brain is thought to be one of the earliest events in Alzheimer's disease, possibly leading to synaptic dysfunction, neurodegeneration and cognitive/functional decline. The earliest detectable changes seen with neuroimaging appear to be amyloid-β accumulation detected by

An Open-Label Trial of Memantine for Cognitive Impairment in Patients with Posttraumatic Stress Disorder

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Sriram Ramaswamy

2015-01-01

Full Text Available Background. Studies using standard neuropsychological instruments have demonstrated memory deficits in patients with PTSD. We evaluated the efficacy and safety of the N-methyl-D-aspartate antagonist memantine in veterans with PTSD and cognitive impairment. Methods. Twenty-six veterans with PTSD and cognitive impairment received 16 weeks of memantine in an open-label fashion. Cognition was assessed using the Spatial Span, Logical Memory I, and Letter-Number Sequencing subtests of the Wechsler Memory Scale III and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS. RBANS measures attention, language, visuospatial skills, and immediate and delayed memories. The Clinician Administered PTSD Scale (CAPS, Hamilton Depression Scale (HAM-D, Hamilton Anxiety Scale (HAM-A, Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q, and Sheehan Disability Scale (SDS were secondary outcome measures. Results. There was a significant improvement in RBANS, both total and subscale scores (P<0.05, over time. There was a reduction in total CAPS scores, avoidance/numbing symptoms (CAPS-C and hyperarousal symptoms (CAPS-D, HAM-D, Q-LES-Q, and SDS scores. However, there was no reduction in reexperiencing (CAPS-B and HAM-A scores. Memantine was well tolerated. Conclusions. Memantine improved cognitive symptoms, PTSD symptoms, and mood in veterans with PTSD. Randomized double-blind studies are needed to validate these preliminary observations.

Amyloid beta inhibits olfactory bulb activity and the ability to smell.

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Reynaldo Alvarado-Martínez

Full Text Available Early olfactory dysfunction has been consistently reported in both Alzheimer's disease (AD and in transgenic mice that reproduce some features of this disease. In AD transgenic mice, alteration in olfaction has been associated with increased levels of soluble amyloid beta protein (Aβ as well as with alterations in the oscillatory network activity recorded in the olfactory bulb (OB and in the piriform cortex. However, since AD is a multifactorial disease and transgenic mice suffer a variety of adaptive changes, it is still unknown if soluble Aβ, by itself, is responsible for OB dysfunction both at electrophysiological and behavioral levels. Thus, here we tested whether or not Aβ directly affects OB network activity in vitro in slices obtained from mice and rats and if it affects olfactory ability in these rodents. Our results show that Aβ decreases, in a concentration- and time-dependent manner, the network activity of OB slices at clinically relevant concentrations (low nM and in a reversible manner. Moreover, we found that intrabulbar injection of Aβ decreases the olfactory ability of rodents two weeks after application, an effect that is not related to alterations in motor performance or motivation to seek food and that correlates with the presence of Aβ deposits. Our results indicate that Aβ disrupts, at clinically relevant concentrations, the network activity of the OB in vitro and can trigger a disruption in olfaction. These findings open the possibility of exploring the cellular mechanisms involved in early pathological AD as an approach to reduce or halt its progress.

Effect of co-administration of memantine and sertraline on the antidepressant-like activity and brain-derived neurotrophic factor (BDNF) levels in the rat brain.

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Amidfar, Meysam; Réus, Gislaine Z; Quevedo, João; Kim, Yong-Ku; Arbabi, Mohammad

2017-01-01

A developing body of data has drawn attention to the N-methyl-d-aspartate (NMDA) receptor antagonists as potential drugs for the treatment of major depressive disorder (MDD). We investigated the possibility of synergistic interactions between the antidepressant sertraline with the uncompetitive NMDA receptor antagonist, memantine. The present study was aimed to evaluate behavioural and molecular effects of the chronic treatment with memantine and sertraline alone or in combination in rats. To this aim, rats were chronically treated with memantine (2.5 and 5mg/kg) and sertraline (5mg/kg) for 14days once a day, and then exposed to the forced swimming test. The brain-derived neurotrophic factor (BDNF) levels were assessed in the hippocampus and prefrontal cortex in all groups by ELISA sandwich assay. Sertraline and memantine (2.5mg/kg) alone did not have effect on the immobility time; however, the effect of sertraline was enhanced by both doses of memantine. Combined treatment with memantine and sertraline produced stronger increases in the BDNF protein levels in the hippocampus and prefrontal cortex. Our results indicate that co-administration of antidepressant memantine with sertraline may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. Antidepressant properties using the combination of memantine and sertraline could be attributed to increased levels of BDNF. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whereas limiting side effects. Copyright © 2016 Elsevier Inc. All rights reserved.

Potential Natural Products for Alzheimer’s Disease: Targeted Search Using the Internal Ribosome Entry Site of Tau and Amyloid-β Precursor Protein

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Yun-Chieh Tasi

2015-04-01

Full Text Available Overexpression of the amyloid precursor protein (APP and the hyperphosphorylation of the tau protein are vital in the understanding of the cause of Alzheimer’s disease (AD. As a consequence, regulation of the expression of both APP and tau proteins is one important approach in combating AD. The APP and tau proteins can be targeted at the levels of transcription, translation and protein structural integrity. This paper reports the utilization of a bi-cistronic vector containing either APP or tau internal ribosome entry site (IRES elements flanked by β-galactosidase gene (cap-dependent and secreted alkaline phosphatase (SEAP (cap-independent to discern the mechanism of action of memantine, an N-methyl-d-aspartate (NMDA receptor antagonist. Results indicate that memantine could reduce the activity of both the APP and tau IRES at a concentration of ~10 μM (monitored by SEAP activity without interfering with the cap-dependent translation as monitored by the β-galactosidase assay. Western blot analysis of the tau protein in neuroblastoma (N2A and rat hippocampal cells confirmed the halting of the expression of the tau proteins. We also employed this approach to identify a preparation named NB34, extracts of Boussingaultia baselloides (madeira-vine fermented with Lactobacillus spp., which can function similarly to memantine in both IRES of APP and Tau. The water maze test demonstrated that NB34 could improve the spatial memory of a high fat diet induced neurodegeneration in apolipoprotein E-knockout (ApoE−/− mice. These results revealed that the bi-cistronic vector provided a simple, and effective platform in screening and establishing the mechanistic action of potential compounds for the treatment and management of AD.

Thermodynamically stable amyloid-β monomers have much lower membrane affinity than the small oligomers

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Bidyut eSarkar

2013-04-01

Full Text Available Amyloid beta (Aβ is an extracellular 39-43 residue long peptide present in the mammalian cerebrospinal fluid, whose aggregation is associated with Alzheimer’s disease. Small oligomers of Aβ are currently thought to be the key to toxicity. However, it is not clear why the monomers of Aβ are non-toxic, and at what stage of aggregation toxicity emerges. Interactions of Aβ with cell membranes is thought to be the initiator of toxicity, but membrane-binding studies with different preparations of monomers and oligomers have not settled this issue. We have earlier found that thermodynamically stable Aβ monomers emerge spontaneously from oligomeric mixtures upon long term incubation in physiological solutions (Nag et al, JBC, 2011. Here we show that the membrane-affinity of these stable Aβ monomers is much lower than that of a mixture of small oligomers (containing dimers to decamers, providing a clue to the emergence of toxicity. Fluorescently labeled Aβ40 monomers show negligible binding to cell membranes of a neuronal cell line (RN46A at physiological concentrations (250 nM, while oligomers at the same concentrations show strong binding within 30 minutes of incubation. The increased affinity most likely does not require any specific neuronal receptor, since this difference in membrane-affinity was also observed in a somatic cell-line (HEK 293T. Similar results are also obtained for Aβ42 monomers and oligomers. Minimal amount of cell death is observed at these concentrations even after 36 hours of incubation. It is likely that membrane binding precedes subsequent slower toxic events induced by Aβ. Our results a provide an explanation for the non-toxic nature of Aβ monomers, b suggest that Aβ toxicity emerges at the initial oligomeric phase, and c provide a quick assay for monitoring the benign-to-toxic transformation of Aβ.

Toxic β-Amyloid (Aβ) Alzheimer's Ion Channels: From Structure to Function and Design

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Nussinov, Ruth

2012-02-01

Full-length amyloid beta peptides (Aβ1-40/42) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. Recent biophysical and cell biological studies suggest a direct mechanism of amyloid beta toxicity -- ion channel mediated loss of calcium homeostasis. Truncated amyloid beta fragments (Aβ11-42 and Aβ17-42), commonly termed as non-amyloidogenic are also found in amyloid plaques of Alzheimer's disease (AD) and in the preamyloid lesions of Down's syndrome (DS), a model system for early onset AD study. Very little is known about the structure and activity of these smaller peptides although they could be key AD and DS pathological agents. Using complementary techniques of explicit solvent molecular dynamics (MD) simulations, atomic force microscopy (AFM), channel conductance measurements, cell calcium uptake assays, neurite degeneration and cell death assays, we have shown that non-amyloidogenic Aβ9-42 and Aβ17-42 peptides form ion channels with loosely attached subunits and elicit single channel conductances. The subunits appear mobile suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in APP-deficient cells and cause neurite degeneration in human cortical neurons. Channel conductance, calcium uptake and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus truncated Aβ fragments could account for undefined roles played by full length Aβs and provide a novel mechanism of AD and DS pathology. The emerging picture from our large-scale simulations is that toxic ion channels formed by β-sheets are highly polymorphic, and spontaneously break into loosely interacting dynamic units (though still maintaining ion channel structures as imaged with AFM), that associate and dissociate leading to toxic ion flux. This sharply contrasts intact conventional gated ion channels that consist of tightly

The effects of lower than conventional doses of oral nadolol on relative beta 1/beta 2-adrenoceptor blockade.

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Wheeldon, N M; McDevitt, D G; Lipworth, B J

1994-08-01

1. The aim of the present study was to evaluate the relative beta 1/beta 2 antagonist selectivity of the beta-adrenoceptor blocker nadolol, in lower than conventional clinical doses. 2. Eight normal volunteers received single oral doses of either placebo (PL), nadolol 5 mg (N5), 20 mg (N20) or 80 mg (N80) in a single-blind, randomised crossover design. beta 1-adrenoceptor antagonism was assessed by attenuation of exercise tachycardia, and beta 2-adrenoceptor blockade by effects on salbutamol-induced chronotropic, hypokalaemic and finger tremor responses. The relative percentage attenuation of beta 2 and beta 1-mediated responses was calculated and expressed as beta 2:beta 1 selectivity ratios. 3. Nadolol produced dose-related reductions in exercise tachycardia in keeping with increasing beta 1-adrenoceptor blockade; mean % reduction (95% CI) compared with placebo: N5 10.7 (6.6 to 14.8), N20 21.4 (17.3 to 25.4), N80 38.9 (34.8 to 42.9). However, even the lowest dose of nadolol (5 mg) produced almost complete blunting of beta 2-mediated effects and significantly increase exercise hyperkalaemia; peak exercise hyperkalaemia (mmol l-1) (means and 95% CI): PL 4.88 (4.68 to 5.07), N5 5.36 (5.17 to 5.55), N20 5.48 (5.28 to 5.67), N80 5.42 (5.22 to 5.61). beta 2:beta 1 selectivity ratios significantly increased as the dose of nadolol was reduced. 4. These data suggest that whereas in the clinical dose range nadolol behaves as a non-selective beta-adrenoceptor antagonist, as the dose is reduced this drug demonstrates an increasing degree of selectivity for the beta 2-adrenoceptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Methods for labeling .beta.-amyloid plaques and neurofibrillary tangles

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Barrio, Jorge R.; Petric, Andrej; Satyamurthy, Nagichettiar; Small, Gary W.; Cole, Gregory M.; Huang, Sung-Cheng

2001-01-01

A method for labeling .beta.-amyloid plaques and neurofibrillary tangles in vivo and in vitro, comprises contacting a compound of formula (I): ##STR1## with mammalian tissue. In formula (I), R.sub.1 is selected from the group consisting of --C(O)-alkyl, --C(O)-alkylenyl-R.sub.4, --C(O)O-alkyl, --C(O)O-alkylenyl-R.sub.4, --C.dbd.C(CN).sub.2 -alkyl, --C.dbd.C(CN).sub.2 -alkylenyl-R.sub.4 , ##STR2## R.sub.4 is a radical selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl; R.sub.5, is a radical selected from the group consisting of --NH.sub.2, --OH, --SH, --NH-alkyl, --NHR.sub.4, --NH-alkylenyl-R.sub.4, --O-alkyl, --O-alkylenyl-R.sub.4, --S-alkyl, and --S-alkylenyl-R.sub.4 ; R.sub.6 is a radical selected from the group consisting of --CN, --COOH, --C(O)O-alkyl, --C(O)O-alkylenyl-R.sub.4, --C(O)-alkyl, --C(O)-alkylenyl-R.sub.4, --C(O)-halogen, --C(O)NH , --C(O)NH-alkyl, --C(O)NH-alkylenyl-R.sub.4 ; R.sub.7 is a radical selected from the group consisting of O, NH, and S; and R.sub.8 is N, O or S. R.sub.2 and R.sub.3 are each independently selected from the group consisting of alkyl and alkylenyl-R.sub.10, wherein R.sub.10 is selected from the group consisting of --OH, --OTs, halogen, spiperone, spiperone ketal and spiperone-3-yl. Alternatively, R.sub.2 and R.sub.3 together form a heterocyclic ring, optionally substituted with at least one radical selected from the group consisting of alkyl, alkoxy, OH, OTs, halogen, alkylenyl-R.sub.10, carbonyl, spiperone, spiperone ketal and spiperone-3-yl. In the compounds of formula (I), one or more of the hydrogen, halogen or carbon atoms can, optionally, be replaced with a radiolabel.

Compositions for labeling .beta.-amyloid plaques and neurofibrillary tangles

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Barrio, Jorge R [Agoura Hills, CA; Petric, Andrej [Ljubljana, SI; Satyamurthy, Nagichettiar [Los Angeles, CA; Small, Gary W [Los Angeles, CA; Cole, Gregory M [Santa Monica, CA; Huang, Sung-Cheng [Sherman Oaks, CA

2008-03-11

Compositions useful for labeling .beta.-amyloid plaques and neurofibrillary tangles are provided. The compositions comprises compounds of formula (I): ##STR00001## wherein R.sub.1 is selected from the group consisting of --C(O)-alkyl, --C(O)-alkylenyl-R.sub.4, --C(O)O-alkyl, --C(O)O-alkylenyl-R.sub.4, --C.dbd.C(CN).sub.2-alkyl, --C.dbd.C(CN).sub.2-alkylenyl-R.sub.4, ##STR00002## wherein R.sub.4 is a radical selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl; R.sub.5 is a radical selected from the group consisting of --NH.sub.2, --OH, --SH, --NH-alkyl, --NHR.sub.4, --NH-alkylenyl-R.sub.4, --O-alkyl, --O-alkylenyl-R.sub.4, --S-alkyl, and --S-alkylenyl-R.sub.4; R.sub.6 is a radical selected from the group consisting of --CN, --COOH, --C(O)O-alkyl, --C(O)O-alkylenyl-R.sub.4, --C(O)-alkyl, --C(O)-alkylenyl-R.sub.4, --C(O)-halogen, --C(O)NH-alkyl, --C(O)NH-alkylenyl-R.sub.4 and --C(O)NH.sub.2; R.sub.7 is a radical selected from the group consisting of O, NH, and S; and R.sub.8 is N, O or S; and R.sub.2 is selected from the group consisting of alkyl and alkylenyl-R.sub.10 and R.sub.3 is alkylenyl-R.sub.10, wherein R.sub.10 is selected from the group consisting of --OH, --OTs, halogen, spiperone, spiperone ketal, and spiperone-3-yl, or R.sub.2 and R.sub.3 together form a heterocyclic ring, optionally substituted with at least one radical selected from the group consisting of alkyl, alkoxy, OH, OTs, halogen, alkyl-R.sub.10, carbonyl, spiperone, spiperone ketal and spiperone-3-yl, and further wherein one or more of the hydrogen, halogen or carbon atoms are optionally replaced with a radiolabel.

Pleomorphic copper coordination by Alzheimer's disease amyloid-beta peptide.

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Drew, Simon C; Noble, Christopher J; Masters, Colin L; Hanson, Graeme R; Barnham, Kevin J

2009-01-28

Numerous conflicting models have been proposed regarding the nature of the Cu(2+) coordination environment of the amyloid beta (Abeta) peptide, the causative agent of Alzheimer's disease. This study used multifrequency CW-EPR spectroscopy to directly resolve the superhyperfine interactions between Cu(2+) and the ligand nuclei of Abeta, thereby avoiding ambiguities associated with introducing point mutations. Using a library of Abeta16 analogues with site-specific (15)N-labeling at Asp1, His6, His13, and His14, numerical simulations of the superhyperfine resonances delineated two independent 3N1O Cu(2+) coordination modes, {N(a)(D1), O, N(epsilon)(H6), N(epsilon)(H13)} (component Ia) and {N(a)(D1), O, N(epsilon)(H6), N(epsilon)(H14)} (component Ib), between pH 6-7. A third coordination mode (component II) was identified at pH 8.0, and simulation of the superhyperfine resonances indicated a 3N1O coordination sphere involving nitrogen ligation by His6, His13, and His14. No differences were observed upon (17)O-labeling of the phenolic oxygen of Tyr10, confirming it is not a key oxygen ligand in the physiological pH range. Hyperfine sublevel correlation (HYSCORE) spectroscopy, in conjunction with site-specific (15)N-labeling, provided additional support for the common role of His6 in components Ia and Ib, and for the assignment of a {O, N(epsilon)(H6), N(epsilon)(H13), N(epsilon)(H14)} coordination sphere to component II. HYSCORE studies of a peptide analogue with selective (13)C-labeling of Asp1 revealed (13)C cross-peaks characteristic of equatorial coordination by the carboxylate oxygen of Asp1 in component Ia/b coordination. The direct resolution of Cu(2+) ligand interactions, together with the key finding that component I is composed of two distinct coordination modes, provides valuable insight into a range of conflicting ligand assignments and highlights the complexity of Cu(2+)/Abeta interactions.

Amyloid- and FDG-PET imaging in amyotrophic lateral sclerosis

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Matias-Guiu, Jordi A.; Pytel, Vanesa; Galan, Lucia; Valles-Salgado, Maria; Guerrero, Antonio; Moreno-Ramos, Teresa; Matias-Guiu, Jorge [Hospital Clinico San Carlos, San Carlos Institute for Health Research (IdISSC), Universidad Complutense de Madrid, Department of Neurology, Madrid (Spain); Cabrera-Martin, Maria Nieves; Carreras, Jose Luis [Hospital Clinico San Carlos, San Carlos Institute for Health Research (IdISSC), Universidad Complutense de Madrid, Department of Nuclear Medicine, Madrid (Spain)

2016-10-15

We aimed to study brain metabolism and presence of beta-amyloid deposits using positron emission tomography (PET) in patients with amyotrophic lateral sclerosis (ALS). This prospective cross-sectional study included 18 patients with definite or probable ALS according to the revised El Escorial diagnostic criteria, and 24 healthy controls. Patients underwent neurological and neuropsychological assessments, PET with {sup 18}F-fluorodeoxyglucose (FDG), and amyloid-PET with {sup 18}F-florbetaben. Patients with ALS showed hypometabolism in the frontal area and hypermetabolism in the cerebellum compared to healthy controls. Four patients (22 %) displayed cognitive impairment and decreased metabolism in the frontal area extending bilaterally to the parietal regions, and increased metabolism in the posterior area of the cerebellum. In patients with no cognitive impairment, metabolism was lower in the left superior frontal gyrus and higher in the anterior and posterior lobes of the cerebellum. In the individual analysis, six patients (35 %) displayed more anterior involvement with hypometabolism affecting the superior frontal, medial, and inferior gyri; six patients (35 %) exhibited a more posterior pattern with hypometabolism in the precentral and postcentral gyri and in the superior and inferior parietal lobules; two patients (11 %) showed a mixed pattern; and three patients (17 %) showed no alterations in brain metabolism. Three (16 %) showed increased {sup 18}F-florbetaben uptake compared to controls. We have identified two main patterns of brain metabolism with an association to cognitive status. Only a subgroup of patients showed an increased uptake of the amyloid tracer. Our results suggest that ALS is heterogeneous from a clinical, metabolic, and molecular standpoint. (orig.)

Amyloid- and FDG-PET imaging in amyotrophic lateral sclerosis

International Nuclear Information System (INIS)

Matias-Guiu, Jordi A.; Pytel, Vanesa; Galan, Lucia; Valles-Salgado, Maria; Guerrero, Antonio; Moreno-Ramos, Teresa; Matias-Guiu, Jorge; Cabrera-Martin, Maria Nieves; Carreras, Jose Luis

2016-01-01

We aimed to study brain metabolism and presence of beta-amyloid deposits using positron emission tomography (PET) in patients with amyotrophic lateral sclerosis (ALS). This prospective cross-sectional study included 18 patients with definite or probable ALS according to the revised El Escorial diagnostic criteria, and 24 healthy controls. Patients underwent neurological and neuropsychological assessments, PET with 18 F-fluorodeoxyglucose (FDG), and amyloid-PET with 18 F-florbetaben. Patients with ALS showed hypometabolism in the frontal area and hypermetabolism in the cerebellum compared to healthy controls. Four patients (22 %) displayed cognitive impairment and decreased metabolism in the frontal area extending bilaterally to the parietal regions, and increased metabolism in the posterior area of the cerebellum. In patients with no cognitive impairment, metabolism was lower in the left superior frontal gyrus and higher in the anterior and posterior lobes of the cerebellum. In the individual analysis, six patients (35 %) displayed more anterior involvement with hypometabolism affecting the superior frontal, medial, and inferior gyri; six patients (35 %) exhibited a more posterior pattern with hypometabolism in the precentral and postcentral gyri and in the superior and inferior parietal lobules; two patients (11 %) showed a mixed pattern; and three patients (17 %) showed no alterations in brain metabolism. Three (16 %) showed increased 18 F-florbetaben uptake compared to controls. We have identified two main patterns of brain metabolism with an association to cognitive status. Only a subgroup of patients showed an increased uptake of the amyloid tracer. Our results suggest that ALS is heterogeneous from a clinical, metabolic, and molecular standpoint. (orig.)

Accumulation of Exogenous Amyloid-Beta Peptide in Hippocampal Mitochondria Causes Their Dysfunction: A Protective Role for Melatonin

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Sergio Rosales-Corral

2012-01-01

Full Text Available Amyloid-beta (Aβ pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS. Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer’s disease (AD brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance.

Impaired memory is more closely associated with brain beta-amyloid than leukoaraiosis in hypertensive patients with cognitive symptoms.

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Eric E Smith

Full Text Available Hypertension is the strongest modifiable risk factor for subcortical ischemic changes and is also a risk factor for Alzheimer's dementia. We used neuroimaging to investigate the pathological basis of early cognitive symptoms in patients with hypertension.In this cross-sectional cohort study 67 patients age >60 years with hypertension and Clinical Dementia Rating scale score of 0.5 without dementia, and without history of symptomatic stroke, underwent MRI for measurement of subcortical vascular changes and positron emission tomography (PET scan with Pittsburgh Compound B (PiB-PET to detect beta-amyloid deposition. These imaging measures were related to neuropsychological tests of memory, executive function and processing speed.Mean age was 75.0 (standard deviation, SD, 7.3. Mean neuropsychological Z scores were: episodic memory -0.63 (SD 1.23, executive function -0.40 (SD 1.10, processing speed -0.24 (SD 0.88; 22 of the 67 subjects met criteria for mild cognitive impairment (MCI and the remaining 45 subjects had subjective cognitive concerns only. In multivariable models adjusting for age and years of education, each 0.1 unit increase in mean cortical PiB-PET binding was associated with 0.14 lower mean Z score for episodic memory (95% CI -0.28 to -0.01. This means that for every 0.1 unit increase in mean cortical PiB-PET, episodic memory was 0.14 standard deviations lower. White matter hyperintensity volume, silent brain infarcts and microbleeds were not associated with neuropsychological test scores.Episodic memory was prominently affected in hypertensive participants with MCI or subjective cognitive concerns, and was associated with PiB-PET binding. This suggests a prominent role for Alzheimer pathology in cognitive impairment even in hypertensive participants at elevated risk for vascular cognitive impairment.

A sensitive and selective electrochemical biosensor for the determination of beta-amyloid oligomer by inhibiting the peptide-triggered in situ assembly of silver nanoparticles

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Xing Y

2017-04-01

Full Text Available Yun Xing,1,2 Xiao-Zhen Feng,2 Lipeng Zhang,1 Jiating Hou,2 Guo-Cheng Han,2 Zhencheng Chen2 1Henan Province of Key Laboratory of New Optoelectronic Functional Materials, College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang, 2School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, Guangxi, People’s Republic of China Abstract: Soluble beta-amyloid (Aβ oligomer is believed to be the most important toxic species in the brain of Alzheimer’s disease (AD patients. Thus, it is critical to develop a simple method for the selective detection of Aβ oligomer with low cost and high sensitivity. In this paper, we report an electrochemical method for the detection of Aβ oligomer with a peptide as the bioreceptor and silver nanoparticle (AgNP aggregates as the redox reporters. This strategy is based on the conversion of AgNP-based colorimetric assay into electrochemical analysis. Specifically, the peptide immobilized on the electrode surface and presented in solution triggered together the in situ formation of AgNP aggregates, which produced a well-defined electrochemical signal. However, the specific binding of Aβ oligomer to the immobilized peptide prevented the in situ assembly of AgNPs. As a result, a poor electrochemical signal was observed. The detection limit of the method was found to be 6 pM. Furthermore, the amenability of this method for the analysis of Aβ oligomer in serum and artificial cerebrospinal fluid (aCSF samples was demonstrated. Keywords: electrochemical biosensors, Alzheimer’s disease, beta-amyloid oligomer, peptide, silver nanoparticles

Effect of Gabapentin/Memantine on the Infantile Nystagmus Syndrome in the Zebrafish Model: Implications for the Therapy of Ocular Motor Diseases.

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Bögli, Stefan Yu; Afthinos, Maresa; Huang, Melody Ying-Yu

2017-06-01

Infantile nystagmus syndrome (INS) is a disorder characterized by typical horizontal eye oscillations. Due to the uncertain etiology of INS, developing specific treatments remains difficult. Single reports demonstrated, on limited measures, alleviating effects of gabapentin and memantine. In the current study, we employed the zebrafish INS model belladonna (bel) to conduct an in-depth study of how gabapentin and memantine interventions alleviate INS signs, which may further restore visual conditions in affected subjects. Moreover, we described the influence of both medications on ocular motor functions in healthy zebrafish, evaluating possible iatrogenic effects. Ocular motor function and INS characteristics were assessed by eliciting optokinetic response, spontaneous nystagmus, and spontaneous saccades in light and in dark, in 5- to 6-day postfertilization bel larvae and heterozygous siblings. Single larvae were recorded before and after a 1-hour drug treatment (200 mM gabapentin/0.2 mM memantine). Both interventions significantly reduced nystagmus intensity (gabapentin: 59.98%, memantine: 39.59%). However, while the application of gabapentin affected all tested ocular motor functions, memantine specifically reduced nystagmus amplitude and intensity, and thus left controls completely unaffected. Finally, both drug treatments resulted in specific changes in nystagmus waveform and velocity. Our study provides deeper insight into gabapentin and memantine treatment effect in the zebrafish INS model. Moreover, this study should establish zebrafish as a pharmacologic animal model for treating nystagmus and ocular motor disease, serving as a basis for future large-scale drug screenings.

Memantine reduces stealing behavior and impulsivity in kleptomania

DEFF Research Database (Denmark)

Grant, Jon E; Odlaug, Brian Lawrence; Schreiber, Liana R N

2013-01-01

Kleptomania is characterized by repetitive stealing behavior and has been associated with deleterious unwanted outcomes including forensic contact and increased rates of suicidal behavior. Very few trials have been conducted to investigate pharmacological treatment options for this neglected...... was generally well tolerated. This study shows the effectiveness of memantine in reducing urges to shoplift and shoplifting behavior along with improving impulsivity, mood, anxiety, and psychosocial functioning....

Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1.

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Rizvi, Syed Mohd Danish; Shaikh, Sibhghatulla; Khan, Mahiuddin; Biswas, Deboshree; Hameed, Nida; Shakil, Shazi

2014-01-01

Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters (SERT) to increase the synaptic concentrations of serotonin. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) is responsible for amyloid β plaque formation. Hence it is an interesting target for Alzheimer's disease (AD) therapy. This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named 'Fetzima' with BACE-1 and SERT. Fetzima is chemically known as levomilnacipran. The study has explored a possible link between the treatment of Depression and AD. 'Autodock 4.2' was used for docking study. The free energy of binding (ΔG) values for 'levomilnacipran-SERT' interaction and 'levomilnacipran-BACE1' interaction were found to be -7.47 and -8.25 kcal/mol, respectively. Levomilnacipran was found to interact with S438, known to be the most important amino acid residue of serotonin binding site of SERT during 'levomilnacipran-SERT' interaction. In the case of 'levomilnacipran-BACE1' interaction, levomilnacipran interacted with two very crucial aspartic acid residues of BACE-1, namely, D32 and D228. These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain. Hence, Fetzima (levomilnacipran) might act as a potent dual inhibitor of SERT and BACE-1 and expected to form the basis of a future dual therapy against depression and AD. It is an established fact that development of AD is associated with Major Depressive Disorder. Therefore, the design of new BACE-1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial.

Ellagic acid promotes A{beta}42 fibrillization and inhibits A{beta}42-induced neurotoxicity

Energy Technology Data Exchange (ETDEWEB)

Feng, Ying [Department of Histology and Embryology, College of Basic Medical Science, China Medical University, Shenyang 110001 (China); Tsinghua University School of Medicine, Haidian District, Beijing 100084 (China); Yang, Shi-gao; Du, Xue-ting; Zhang, Xi; Sun, Xiao-xia; Zhao, Min [Tsinghua University School of Medicine, Haidian District, Beijing 100084 (China); Sun, Gui-yuan, E-mail: sungy2004@sohu.com [Department of Histology and Embryology, College of Basic Medical Science, China Medical University, Shenyang 110001 (China); Liu, Rui-tian, E-mail: rtliu@tsinghua.edu.cn [Tsinghua University School of Medicine, Haidian District, Beijing 100084 (China)

2009-12-25

Smaller, soluble oligomers of {beta}-amyloid (A{beta}) play a critical role in the pathogenesis of Alzheimer's disease (AD). Selective inhibition of A{beta} oligomer formation provides an optimum target for AD therapy. Some polyphenols have potent anti-amyloidogenic activities and protect against A{beta} neurotoxicity. Here, we tested the effects of ellagic acid (EA), a polyphenolic compound, on A{beta}42 aggregation and neurotoxicity in vitro. EA promoted A{beta} fibril formation and significant oligomer loss, contrary to previous results that polyphenols inhibited A{beta} aggregation. The results of transmission electron microscopy (TEM) and Western blot displayed more fibrils in A{beta}42 samples co-incubated with EA in earlier phases of aggregation. Consistent with the hypothesis that plaque formation may represent a protective mechanism in which the body sequesters toxic A{beta} aggregates to render them harmless, our MTT results showed that EA could significantly reduce A{beta}42-induced neurotoxicity toward SH-SY5Y cells. Taken together, our results suggest that EA, an active ingredient in many fruits and nuts, may have therapeutic potential in AD.

Modification of hippocampal markers of synaptic plasticity by memantine in animal models of acute and repeated restraint stress: implications for memory and behavior.

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Amin, Shaimaa Nasr; El-Aidi, Ahmed Amro; Ali, Mohamed Mostafa; Attia, Yasser Mahmoud; Rashed, Laila Ahmed

2015-06-01

Stress is any condition that impairs the balance of the organism physiologically or psychologically. The response to stress involves several neurohormonal consequences. Glutamate is the primary excitatory neurotransmitter in the central nervous system, and its release is increased by stress that predisposes to excitotoxicity in the brain. Memantine is an uncompetitive N-methyl D-aspartate glutamatergic receptors antagonist and has shown beneficial effect on cognitive function especially in Alzheimer's disease. The aim of the work was to investigate memantine effect on memory and behavior in animal models of acute and repeated restraint stress with the evaluation of serum markers of stress and the expression of hippocampal markers of synaptic plasticity. Forty-two male rats were divided into seven groups (six rats/group): control, acute restraint stress, acute restraint stress with Memantine, repeated restraint stress, repeated restraint stress with Memantine and Memantine groups (two subgroups as positive control). Spatial working memory and behavior were assessed by performance in Y-maze. We evaluated serum cortisol, tumor necrotic factor, interleukin-6 and hippocampal expression of brain-derived neurotrophic factor, synaptophysin and calcium-/calmodulin-dependent protein kinase II. Our results revealed that Memantine improved spatial working memory in repeated stress, decreased serum level of stress markers and modified the hippocampal synaptic plasticity markers in both patterns of stress exposure; in ARS, Memantine upregulated the expression of synaptophysin and brain-derived neurotrophic factor and downregulated the expression of calcium-/calmodulin-dependent protein kinase II, and in repeated restraint stress, it upregulated the expression of synaptophysin and downregulated calcium-/calmodulin-dependent protein kinase II expression.

Cerebral amyloid-beta protein accumulation with aging in cotton-top tamarins: a model of early Alzheimer's disease?

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Lemere, Cynthia A; Oh, Jiwon; Stanish, Heather A; Peng, Ying; Pepivani, Imelda; Fagan, Anne M; Yamaguchi, Haruyasu; Westmoreland, Susan V; Mansfield, Keith G

2008-04-01

Alzheimer's disease (AD) is the most common progressive form of dementia in the elderly. Two major neuropathological hallmarks of AD include cerebral deposition of amyloid-beta protein (Abeta) into plaques and blood vessels, and the presence of neurofibrillary tangles in brain. In addition, activated microglia and reactive astrocytes are often associated with plaques and tangles. Numerous other proteins are associated with plaques in human AD brain, including Apo E and ubiquitin. The amyloid precursor protein and its shorter fragment, Abeta, are homologous between humans and non-human primates. Cerebral Abeta deposition has been reported previously for rhesus monkeys, vervets, squirrel monkeys, marmosets, lemurs, cynomologous monkeys, chimpanzees, and orangutans. Here we report, for the first time, age-related neuropathological changes in cotton-top tamarins (CTT, Saguinus oedipus), an endangered non-human primate native to the rainforests of Colombia and Costa Rica. Typical lifespan is 13-14 years of age in the wild and 15-20+ years in captivity. We performed detailed immunohistochemical analyses of Abeta deposition and associated pathogenesis in archived brain sections from 36 tamarins ranging in age from 6-21 years. Abeta plaque deposition was observed in 16 of the 20 oldest tamarins (>12 years). Plaques contained mainly Abeta42, and in the oldest animals, were associated with reactive astrocytes, activated microglia, Apo E, and ubiquitin-positive dystrophic neurites, similar to human plaques. Vascular Abeta was detected in 14 of the 20 aged tamarins; Abeta42 preceded Abeta40 deposition. Phospho-tau labeled dystrophic neurites and tangles, typically present in human AD, were absent in the tamarins. In conclusion, tamarins may represent a model of early AD pathology.

An Open-Label, Multicenter Observational Study for Patients with Alzheimer’s Disease Treated with Memantine in the Clinical Practice

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S.S. Stamouli

2011-01-01

Full Text Available Background/Aims: In this post-marketing observational study, the safety and effectiveness of memantine were evaluated in patients with Alzheimer’s disease (AD. Methods: In a 6-month, observational, open-label study at 202 specialist sites in Greece, the effectiveness of memantine was evaluated using the Mini-Mental State Examination (MMSE and the Instrumental Activities of Daily Living (IADL scale at baseline, and after 3 and 6 months. Discontinuation rates and adverse drug reactions (ADRs were also recorded to evaluate the safety profile of memantine. Results: 2,570 patients participated in the study. Three and 6 months after baseline, MMSE and IADL scores were significantly improved compared to baseline. At the end of the study, 67% of the patients had improved their MMSE score; 7.1% of the patients reported ≧1 ADRs, and treatment was discontinued due to ADR in 0.7%. Conclusion: Memantine was well tolerated and had a positive effect on the patient’s cognitive and functional ability in real-life clinical practice, in agreement with randomized, controlled trials.

Rationale and design of a multicenter randomized clinical trial with memantine and dextromethorphan in ketamine-responder patients.

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Pickering, Gisèle; Pereira, Bruno; Morel, Véronique; Tiberghien, Florence; Martin, Elodie; Marcaillou, Fabienne; Picard, Pascale; Delage, Noémie; de Montgazon, Géraldine; Sorel, Marc; Roux, Delphine; Dubray, Claude

2014-07-01

The N-methyl-D-aspartate receptor plays an important role in central sensitization of neuropathic pain and N-methyl-D-aspartate receptor antagonists, such as ketamine, memantine and dextromethorphan may be used for persistent pain. However, ketamine cannot be repeated too often because of its adverse events. A drug relay would be helpful in the outpatient to postpone or even cancel the next ketamine infusion. This clinical trial evaluates if memantine and/or dextromethorphan given as a relay to ketamine responders may maintain or induce a decrease of pain intensity and have a beneficial impact on cognition and quality of life. This trial is a multi-center, randomized, controlled and single-blind clinical study (NCT01602185). It includes 60 ketamine responder patients suffering from neuropathic pain. They are randomly allocated to memantine, dextromethorphan or placebo. After ketamine infusion, 60 patients received either memantine (maximal dose 20 mg/day), or dextromethorphan (maximal dose 90 mg/day), or placebo for 12 weeks. The primary endpoint is pain measured on a (0-10) Numeric Rating Scale 1 month after inclusion. Secondary outcomes include assessment of neuropathic pain, sleep, quality of life, anxiety/depression and cognitive function at 2 and 3 months. Data analysis is performed using mixed models and the tests are two-sided, with a type I error set at α=0.05. This study will explore if oral memantine and/or dextromethorphan may be a beneficial relay in ketamine responders and may diminish ketamine infusion frequency. Preservation of cognitive function and quality of life is also a central issue that will be analyzed in these vulnerable patients. Copyright © 2014. Published by Elsevier Inc.

Protein kinase C involvement in the acetylcholine release reduction induced by amyloid-beta(25-35) aggregates on neuromuscular synapses.

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Tomàs, Marta; Garcia, Neus; Santafé, Manuel M; Lanuza, Maria; Tomàs, Josep

2009-01-01

Using intracellular recording of the diaphragm muscle of adult rats, we have investigated the short-term functional effects of amyloid-beta (Abeta(25-35) peptide aggregates on the modulation of acetylcholine (ACh) release and the involvement of protein kinase C (PKC). The non-aggregated form of this peptide does not change the evoked and spontaneous transmitter release parameters on the neuromuscular synapse. However, the aggregated form of Abeta(25-35) acutely interferes with evoked quantal ACh release (approximately 40% reduction) when synaptic activity in the ex vivo neuromuscular preparation is maintained by low frequency (1 Hz) electrical stimulation. This effect is partially dependent on the activity of PKC that may have a permissive action. The end result of Abeta(25-35) is in opposition to the PKC-dependent maintenance effect on ACh release manifested in active synapses.

Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease.

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Cohen, Mark; Appleby, Brian; Safar, Jiri G

2016-01-01

Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrP(Sc)). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (Aβ) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only ∼30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct Aβ particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.

Bioassay-Guided Isolation of Neuroprotective Compounds from Uncaria rhynchophylla against Beta-Amyloid-Induced Neurotoxicity

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Yan-Fang Xian

2012-01-01

Full Text Available Uncaria rhynchophylla is a component herb of many Chinese herbal formulae for the treatment of neurodegenerative diseases. Previous study in our laboratory has demonstrated that an ethanol extract of Uncaria rhynchophylla ameliorated cognitive deficits in a mouse model of Alzheimer’s disease induced by D-galactose. However, the active ingredients of Uncaria rhynchophylla responsible for the anti-Alzheimer’s disease activity have not been identified. This study aims to identify the active ingredients of Uncaria rhynchophylla by a bioassay-guided fractionation approach and explore the acting mechanism of these active ingredients by using a well-established cellular model of Alzheimer’s disease, beta-amyloid- (Aβ- induced neurotoxicity in PC12 cells. The results showed that six alkaloids, namely, corynoxine, corynoxine B, corynoxeine, isorhynchophylline, isocorynoxeine, and rhynchophylline were isolated from the extract of Uncaria rhynchophylla. Among them, rhynchophylline and isorhynchophylline significantly decreased Aβ-induced cell death, intracellular calcium overloading, and tau protein hyperphosphorylation in PC12 cells. These results suggest that rhynchophylline and isorhynchophylline are the major active ingredients responsible for the protective action of Uncaria rhynchophylla against Aβ-induced neuronal toxicity, and their neuroprotective effect may be mediated, at least in part, by inhibiting intracellular calcium overloading and tau protein hyperphosphorylation.

Transdermal therapeutic systems for memantine delivery. Comparison of passive and iontophoretic transport.

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Del Río-Sancho, S; Serna-Jiménez, C E; Sebastián-Morelló, M; Calatayud-Pascual, M A; Balaguer-Fernández, C; Femenía-Font, A; Kalia, Y N; Merino, V; López-Castellano, A

2017-01-30

Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist used in the treatment of moderate to severe dementia including the symptoms of Alzheimer's disease (AD). It is administered orally but compliance, swallowing problems and the routine use of multiple medications in elderly AD patients means that an alternative route of administration would be of interest. The aim of the present study was to develop memantine hydrochloride occlusive transdermal therapeutic systems (TTS) for passive and iontophoretic delivery across the skin. Polyvinyl pyrrolidone (PVP) and a mixture with polyvinyl alcohol (PVA) were employed as polymeric matrices. The study involved the TTS characterization in addition to quantification of the memantine transport across porcine skin in vitro. The evaluation of the TTS physical properties suggested that systems were made more mechanically resistant by including PVA (6%) or high concentrations of PVP (24%). Moreover, a linear correlation was observed between the concentration of PVP and the bioadhesion of the systems. Drug delivery experiments showed that the highest transdermal flux provided by a passive TTS (PVP 24% w/w limonene) was 8.89±0.81μgcm -2 h -1 whereas the highest iontophoretic transport was 46.4±3.6μgcm -2 h -1 . These innovative TTS would enable two dosage regimens that could lead to therapeutic plasma concentrations. Copyright © 2016 Elsevier B.V. All rights reserved.

Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line

OpenAIRE

Kumagai, Ayako; Fujita, Akira; Yokoyama, Tomoki; Nonobe, Yuki; Hasaba, Yasuhiro; Sasaki, Tsutomu; Itoh, Yumi; Koura, Minako; Suzuki, Osamu; Adachi, Shigeki; Ryo, Haruko; Kohara, Arihiro; Tripathi, Lokesh; Sanosaka, Masato; Fukushima, Toshiki

2014-01-01

Memantine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer’s disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype-modulating drugs and found that memantine (10 mg/kg) disrupted the sense of balance in the mutants. Moreover, the mu...

Characterization of the beta amyloid precursor protein-like gene in the central nervous system of the crab Chasmagnathus. Expression during memory consolidation.

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Fustiñana, Maria Sol; Ariel, Pablo; Federman, Noel; Freudenthal, Ramiro; Romano, Arturo

2010-09-01

Human β-amyloid, the main component in the neuritic plaques found in patients with Alzheimer's disease, is generated by cleavage of the β-amyloid precursor protein. Beyond the role in pathology, members of this protein family are synaptic proteins and have been associated with synaptogenesis, neuronal plasticity and memory, both in vertebrates and in invertebrates. Consolidation is necessary to convert a short-term labile memory to a long-term and stable form. During consolidation, gene expression and de novo protein synthesis are regulated in order to produce key proteins for the maintenance of plastic changes produced during the acquisition of new information. Here we partially cloned and sequenced the beta-amyloid precursor protein like gene homologue in the crab Chasmagnathus (cappl), showing a 37% of identity with the fruit fly Drosophila melanogaster homologue and 23% with Homo sapiens but with much higher degree of sequence similarity in certain regions. We observed a wide distribution of cappl mRNA in the nervous system as well as in muscle and gills. The protein localized in all tissues analyzed with the exception of muscle. Immunofluorescence revealed localization of cAPPL in associative and sensory brain areas. We studied gene and protein expression during long-term memory consolidation using a well characterized memory model: the context-signal associative memory in this crab species. mRNA levels varied at different time points during long-term memory consolidation and correlated with cAPPL protein levels cAPPL mRNA and protein is widely distributed in the central nervous system of the crab and the time course of expression suggests a role of cAPPL during long-term memory formation.

Effect of four medicinal plants on Amyloid-β induced neurotoxicity in ...

African Journals Online (AJOL)

Amyloid-beta peptide (Aâ) is implicated in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder. This study was designed to determine the effect of four medicinal plants used to treat neurodegenerative diseases on Aâ-induced cell death. Cytotoxicity of the ethanol extracts of the plants was ...

Cerebral amyloid angiopathy: diagnosis and potential therapies.

Science.gov (United States)

Weber, Stewart A; Patel, Ranish K; Lutsep, Helmi L

2018-06-01

Cerebral amyloid angiopathy (CAA) is characterized by the pathologic deposition of amyloid-beta within cortical and leptomeningeal arteries, arterioles, capillaries and, in rare cases, the venules of the brain. It is often associated with the development of lobar intracerebral hemorrhages (ICHs) but may cause other neurologic symptoms or be asymptomatic. Magnetic resonance imaging characteristics, such as lobar microbleeds, support a diagnosis of CAA and assist with hemorrhage risk assessments. Immunosuppressants are used to treat rarer inflammatory forms of CAA. For the more common forms of CAA, the use of antihypertensive medications can prevent ICH recurrence while the use of antithrombotics may increase hemorrhage risk. Anti-amyloid approaches to treatment have not yet been investigated in phase 3 trials. Areas covered: A literature search was conducted using MEDLINE on the topics of imaging, biomarkers, ICH prevention and treatment trials in CAA, focusing on its current diagnosis and management and opportunities for future therapeutic approaches. Expert commentary: There is likely a significant unrecognized burden of CAA in the elderly population. Continued research efforts to discover biomarkers that allow the early diagnosis of CAA will enhance the opportunity to develop treatment interventions.

Data supporting beta-amyloid dimer structural transitions and protein–lipid interactions on asymmetric lipid bilayer surfaces using MD simulations on experimentally derived NMR protein structures

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Sara Y. Cheng

2016-06-01

Full Text Available This data article supports the research article entitled “Maximally Asymmetric Transbilayer Distribution of Anionic Lipids Alters the Structure and interaction with Lipids of an Amyloidogenic Protein Dimer Bound to the Membrane Surface” [1]. We describe supporting data on the binding kinetics, time evolution of secondary structure, and residue-contact maps of a surface-absorbed beta-amyloid dimer protein on different membrane surfaces. We further demonstrate the sorting of annular and non-annular regions of the protein/lipid bilayer simulation systems, and the correlation of lipid-number mismatch and surface area per lipid mismatch of asymmetric lipid membranes.

APP processing and the APP-KPI domain involvement in the amyloid cascade.

Science.gov (United States)

Menéndez-González, M; Pérez-Pinera, P; Martínez-Rivera, M; Calatayud, M T; Blázquez Menes, B

2005-01-01

Alternative APP mRNA splicing can generate isoforms of APP containing a Kunitz protease inhibitor (KPI) domain. KPI is one of the main serine protease inhibitors. Protein and mRNA KPI(+)APP levels are elevated in Alzheimer's disease (AD) brain and are associated with increased amyloid beta deposition. In the last years increasing evidence on multiple points in the amyloid cascade where KPI(+)APP is involved has been accumulated, admitting an outstanding position in the pathogenesis of AD to the KPI domain. This review focuses on the APP processing, the molecular activity of KPI and its physiological and pathological roles and the KPI involvement in the amyloid cascade through the nerve growth factor, the lipoprotein receptor-related protein, the tumor necrosis factor-alpha converting enzyme and the Notch1 protein.

The Golgi-Localized γ-Ear-Containing ARF-Binding (GGA Proteins Alter Amyloid-β Precursor Protein (APP Processing through Interaction of Their GAE Domain with the Beta-Site APP Cleaving Enzyme 1 (BACE1.

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Bjoern von Einem

Full Text Available Proteolytic processing of amyloid-β precursor protein (APP by beta-site APP cleaving enzyme 1 (BACE1 is the initial step in the production of amyloid beta (Aβ, which accumulates in senile plaques in Alzheimer's disease (AD. Essential for this cleavage is the transport and sorting of both proteins through endosomal/Golgi compartments. Golgi-localized γ-ear-containing ARF-binding (GGA proteins have striking cargo-sorting functions in these pathways. Recently, GGA1 and GGA3 were shown to interact with BACE1, to be expressed in neurons, and to be decreased in AD brain, whereas little is known about GGA2. Since GGA1 impacts Aβ generation by confining APP to the Golgi and perinuclear compartments, we tested whether all GGAs modulate BACE1 and APP transport and processing. We observed decreased levels of secreted APP alpha (sAPPα, sAPPβ, and Aβ upon GGA overexpression, which could be reverted by knockdown. GGA-BACE1 co-immunoprecipitation was impaired upon GGA-GAE but not VHS domain deletion. Autoinhibition of the GGA1-VHS domain was irrelevant for BACE1 interaction. Our data suggest that all three GGAs affect APP processing via the GGA-GAE domain.

Destruction of α-synuclein based amyloid fibrils by a low temperature plasma jet

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Karakas, Erdinc; Munyanyi, Agatha; Greene, Lesley; Laroussi, Mounir

2010-10-01

Amyloid fibrils are ordered beta-sheet aggregates that are associated with a number of neurodegenerative diseases such as Alzheimer and Parkinson. At present, there is no cure for these progressive and debilitating diseases. Here we report initial studies that indicate that low temperature atmospheric pressure plasma can break amyloid fibrils into smaller units in vitro. The plasma was generated by the "plasma pencil," a device capable of emitting a long, low temperature plasma plume/jet. This avenue of research may facilitate the development of a plasma-based medical treatment.

Destruction of α-synuclein based amyloid fibrils by a low temperature plasma jet

International Nuclear Information System (INIS)

Karakas, Erdinc; Laroussi, Mounir; Munyanyi, Agatha; Greene, Lesley

2010-01-01

Amyloid fibrils are ordered beta-sheet aggregates that are associated with a number of neurodegenerative diseases such as Alzheimer and Parkinson. At present, there is no cure for these progressive and debilitating diseases. Here we report initial studies that indicate that low temperature atmospheric pressure plasma can break amyloid fibrils into smaller units in vitro. The plasma was generated by the 'plasma pencil', a device capable of emitting a long, low temperature plasma plume/jet. This avenue of research may facilitate the development of a plasma-based medical treatment.

Feasibility and acceptance of simultaneous amyloid PET/MRI

International Nuclear Information System (INIS)

Schuetz, Lisa; Tiepolt, Solveig; Werner, Peter; Jochimsen, Thies; Rullmann, Michael; Sattler, Bernhard; Patt, Marianne; Barthel, Henryk; Lobsien, Donald; Fritzsch, Dominik; Hoffmann, Karl-Titus; Schroeter, Matthias L.; Villringer, Arno; Berrouschot, Joerg; Saur, Dorothee; Classen, Joseph; Hesse, Swen; Sabri, Osama; Gertz, Hermann-Josef

2016-01-01

Established Alzheimer's disease (AD) biomarker concepts classify into amyloid pathology and neuronal injury biomarkers, while recent alternative concepts classify into diagnostic and progression AD biomarkers. However, combined amyloid positron emission tomography/magnetic resonance imaging (PET/MRI) offers the chance to obtain both biomarker category read-outs within one imaging session, with increased patient as well as referrer convenience. The aim of this pilot study was to investigate this matter for the first time. 100 subjects (age 70 ± 10 yrs, 46 female), n = 51 with clinically defined mild cognitive impairment (MCI), n = 44 with possible/probable AD dementia, and n = 5 with frontotemporal lobe degeneration, underwent simultaneous [ 18 F]florbetaben or [ 11 C]PIB PET/MRI (3 Tesla Siemens mMR). Brain amyloid load, mesial temporal lobe atrophy (MTLA) by means of the Scheltens scale, and other morphological brain pathologies were scored by respective experts. The patients/caregivers as well as the referrers were asked to assess on a five-point scale the convenience related to the one-stop-shop PET and MRI approach. In three subjects, MRI revealed temporal lobe abnormalities other than MTLA. According to the National Institute on Aging-Alzheimer's Association classification, the combined amyloid-beta PET/MRI evaluation resulted in 31 %, 45 %, and 24 % of the MCI subjects being categorized as ''MCI-unlikely due to AD'', ''MCI due to AD-intermediate likelihood'', and ''MCI due to AD-high likelihood'', respectively. 50 % of the probable AD dementia patients were categorized as ''High level of evidence of AD pathophysiological process'', and 56 % of the possible AD dementia patients as ''Possible AD dementia - with evidence of AD pathophysiological process''. With regard to the International Working Group 2 classification, 36 subjects had both positive

Feasibility and acceptance of simultaneous amyloid PET/MRI

Energy Technology Data Exchange (ETDEWEB)

Schuetz, Lisa; Tiepolt, Solveig; Werner, Peter; Jochimsen, Thies; Rullmann, Michael; Sattler, Bernhard; Patt, Marianne; Barthel, Henryk [Leipzig University Hospital, Department of Nuclear Medicine, Leipzig (Germany); Lobsien, Donald; Fritzsch, Dominik; Hoffmann, Karl-Titus [Leipzig University Hospital, Department of Neuroradiology, Leipzig (Germany); Schroeter, Matthias L.; Villringer, Arno [Leipzig University Hospital and Max Planck Institute for Human Cognitive and Brain Sciences, Day Clinic for Cognitive Neurology, Leipzig (Germany); Leipzig University Hospital, IFB Adiposity Diseases, Leipzig (Germany); Berrouschot, Joerg [Clinical Centre Altenburger Land, Altenburg (Germany); Saur, Dorothee; Classen, Joseph [Leipzig University Hospital, Department of Neurology, Leipzig (Germany); Hesse, Swen; Sabri, Osama [Leipzig University Hospital, Department of Nuclear Medicine, Leipzig (Germany); Leipzig University Hospital, IFB Adiposity Diseases, Leipzig (Germany); Gertz, Hermann-Josef [Leipzig University Hospital, Department of Psychiatry, Leipzig (Germany)

2016-11-15

Established Alzheimer's disease (AD) biomarker concepts classify into amyloid pathology and neuronal injury biomarkers, while recent alternative concepts classify into diagnostic and progression AD biomarkers. However, combined amyloid positron emission tomography/magnetic resonance imaging (PET/MRI) offers the chance to obtain both biomarker category read-outs within one imaging session, with increased patient as well as referrer convenience. The aim of this pilot study was to investigate this matter for the first time. 100 subjects (age 70 ± 10 yrs, 46 female), n = 51 with clinically defined mild cognitive impairment (MCI), n = 44 with possible/probable AD dementia, and n = 5 with frontotemporal lobe degeneration, underwent simultaneous [{sup 18}F]florbetaben or [{sup 11}C]PIB PET/MRI (3 Tesla Siemens mMR). Brain amyloid load, mesial temporal lobe atrophy (MTLA) by means of the Scheltens scale, and other morphological brain pathologies were scored by respective experts. The patients/caregivers as well as the referrers were asked to assess on a five-point scale the convenience related to the one-stop-shop PET and MRI approach. In three subjects, MRI revealed temporal lobe abnormalities other than MTLA. According to the National Institute on Aging-Alzheimer's Association classification, the combined amyloid-beta PET/MRI evaluation resulted in 31 %, 45 %, and 24 % of the MCI subjects being categorized as ''MCI-unlikely due to AD'', ''MCI due to AD-intermediate likelihood'', and ''MCI due to AD-high likelihood'', respectively. 50 % of the probable AD dementia patients were categorized as ''High level of evidence of AD pathophysiological process'', and 56 % of the possible AD dementia patients as ''Possible AD dementia - with evidence of AD pathophysiological process''. With regard to the International Working Group 2 classification, 36 subjects had both

GM1 Ganglioside Inhibits β-Amyloid Oligomerization Induced by Sphingomyelin

Czech Academy of Sciences Publication Activity Database

Amaro, Mariana; Šachl, Radek; Aydogan, Gokcan; Mikhalyov, I.; Vácha, R.; Hof, Martin

2016-01-01

Roč. 55, č. 32 (2016), s. 9411-9415 ISSN 1433-7851 R&D Projects: GA ČR(CZ) GBP208/12/G016 Grant - others:GA MŠk(CZ) LM2010005 Institutional support: RVO:61388955 Keywords : amyloid beta-peptides * Alzheimer's disease * diffusion coefficients Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 11.994, year: 2016

Study of the effect of memantine therapy on the treatment of dyslexia in children

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Mojgan Karahmadi

2017-01-01

Full Text Available Background: Reading disorder (RD is one of the important complaints in children with learning disorders (LD that is prevalent in 4% of children in the United States. Treating this disorder includes education of reading practices and treating psychological disorders, and there are no exact medications prescribed in these children. Memantine has been effective in treating memory problems in Alzheimer Dementia, obsessive–compulsive disorder, autism disorder, and other psychological diseases. The aim of this study is to evaluate the effect of memantine in improving RD in children. Materials and Methods: In this randomized clinical trial, 62 children, with RD in Pediatric Psychiatry Clinics of Noor and Ali-Asghar Hospital in Isfahan from 2015 to 2016, were participated. They were randomly assigned to two groups of equal number, one receiving education plus memantine and the other education plus placebo. RD was evaluated at the beginning, 1 and 3 months after intervention by Iranian standard reading and dyslexia test (Nama. Results: Mean (standard deviation age of participants was 7.55 (0.60 years. Most of the participants were boy (55%, most having parents in 36–45-year-old age group (52% and 48% for fathers and mothers, respectively, and also most parents in diploma and bachelor educational group (61% and 60% for fathers and mothers, respectively. There were statistical significant difference in trend of total score (P = 0.034, word chain (P < 0.001, rhyming (P < 0.001, text comprehension (P < 0.001, and letter fluency (P = 0.002, subscale between two groups. However, the difference of time trend between two groups was not significant in word reading (P = 0.14, word comprehension (P = 0.06, phoneme deletion (P = 0.12, reading nonwords (P = 0.32, and category fluency (P = 0.06. Conclusion: Adding memantine to educational practices is effective in improving RD in school-age children with LD.

Elucidation of amyloid beta-protein oligomerization mechanisms: discrete molecular dynamics study.

Science.gov (United States)

Urbanc, B; Betnel, M; Cruz, L; Bitan, G; Teplow, D B

2010-03-31

Oligomers of amyloid beta-protein (Abeta) play a central role in the pathology of Alzheimer's disease. Of the two predominant Abeta alloforms, Abeta(1-40) and Abeta(1-42), Abeta(1-42) is more strongly implicated in the disease. We elucidated the structural characteristics of oligomers of Abeta(1-40) and Abeta(1-42) and their Arctic mutants, [E22G]Abeta(1-40) and [E22G]Abeta(1-42). We simulated oligomer formation using discrete molecular dynamics (DMD) with a four-bead protein model, backbone hydrogen bonding, and residue-specific interactions due to effective hydropathy and charge. For all four peptides under study, we derived the characteristic oligomer size distributions that were in agreement with prior experimental findings. Unlike Abeta(1-40), Abeta(1-42) had a high propensity to form paranuclei (pentameric or hexameric) structures that could self-associate into higher-order oligomers. Neither of the Arctic mutants formed higher-order oligomers, but [E22G]Abeta(1-40) formed paranuclei with a similar propensity to that of Abeta(1-42). Whereas the best agreement with the experimental data was obtained when the charged residues were modeled as solely hydrophilic, further assembly from spherical oligomers into elongated protofibrils was induced by nonzero electrostatic interactions among the charged residues. Structural analysis revealed that the C-terminal region played a dominant role in Abeta(1-42) oligomer formation whereas Abeta(1-40) oligomerization was primarily driven by intermolecular interactions among the central hydrophobic regions. The N-terminal region A2-F4 played a prominent role in Abeta(1-40) oligomerization but did not contribute to the oligomerization of Abeta(1-42) or the Arctic mutants. The oligomer structure of both Arctic peptides resembled Abeta(1-42) more than Abeta(1-40), consistent with their potentially more toxic nature.

Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease.

Science.gov (United States)

Barage, Sagar H; Sonawane, Kailas D

2015-08-01

Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. Various therapeutic approaches are being used to improve the cholinergic neurotransmission, but their role in AD pathogenesis is still unknown. Although, an increase in tau protein concentration in CSF has been described in AD, but several issues remains unclear. Extensive and accurate analysis of CSF could be helpful to define presence of tau proteins in physiological conditions, or released during the progression of neurodegenerative disease. The amyloid cascade hypothesis postulates that the neurodegeneration in AD caused by abnormal accumulation of amyloid beta (Aβ) plaques in various areas of the brain. The amyloid hypothesis has continued to gain support over the last two decades, particularly from genetic studies. Therefore, current research progress in several areas of therapies shall provide an effective treatment to cure this devastating disease. This review critically evaluates general biochemical and physiological functions of Aβ directed therapeutics and their relevance. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Behavioural problems and personality change related to cerebral amyloid angiopathy].

Science.gov (United States)

Gahr, Maximilian; Connemann, Bernhard J; Schönfeldt-Lecuona, Carlos

2012-11-01

Cerebral amyloid angiopathy (CAA) belongs to the group of amyloidoses that are characterized by the deposition of insoluble and tissue-damaging amyloid proteins. Spontaneous intracerebral hemorrhage is the common clinical presentation of CAA resulting from the degenerative effect of beta amyloid on the cerebral vascular system. Though CAA is rather a neurological disease psychiatric symptoms can occur and even dominate the clinical picture. A case report is presented in order to illustrate the association between CAA and psychiatric symptoms. We report the case of a 54-year-old female patient with radiologic references to a probable CAA and mild cognitive impairment who developed behavioural difficulties and personality change that necessitated a psychiatric treatment. Psychiatric symptoms were most likely due to CAA. CAA can be associated with psychiatric symptoms and hence should be considered in the treatment of elderly patients with behavioural problems or personality changes. Diagnostic neuroimaging and examination of cerebrospinal fluid is recommended. © Georg Thieme Verlag KG Stuttgart · New York.

Characterization of the beta amyloid precursor protein-like gene in the central nervous system of the crab Chasmagnathus. Expression during memory consolidation

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Fustiñana Maria

2010-09-01

Full Text Available Abstract Background Human β-amyloid, the main component in the neuritic plaques found in patients with Alzheimer's disease, is generated by cleavage of the β-amyloid precursor protein. Beyond the role in pathology, members of this protein family are synaptic proteins and have been associated with synaptogenesis, neuronal plasticity and memory, both in vertebrates and in invertebrates. Consolidation is necessary to convert a short-term labile memory to a long-term and stable form. During consolidation, gene expression and de novo protein synthesis are regulated in order to produce key proteins for the maintenance of plastic changes produced during the acquisition of new information. Results Here we partially cloned and sequenced the beta-amyloid precursor protein like gene homologue in the crab Chasmagnathus (cappl, showing a 37% of identity with the fruit fly Drosophila melanogaster homologue and 23% with Homo sapiens but with much higher degree of sequence similarity in certain regions. We observed a wide distribution of cappl mRNA in the nervous system as well as in muscle and gills. The protein localized in all tissues analyzed with the exception of muscle. Immunofluorescence revealed localization of cAPPL in associative and sensory brain areas. We studied gene and protein expression during long-term memory consolidation using a well characterized memory model: the context-signal associative memory in this crab species. mRNA levels varied at different time points during long-term memory consolidation and correlated with cAPPL protein levels Conclusions cAPPL mRNA and protein is widely distributed in the central nervous system of the crab and the time course of expression suggests a role of cAPPL during long-term memory formation.

IMPY, a potential {beta}-amyloid imaging probe for detection of prion deposits in scrapie-infected mice

Energy Technology Data Exchange (ETDEWEB)

Song, P.-J. [INSERM, U619, F-37000 Tours (France); Universite Francois-Rabelais, F-37000 Tours (France); IFR135, F-37000 Tours (France); Bernard, Serge [IFR135, F-37000 Tours (France); INRA, UR1282, IASP, 37380 Nouzilly (France)], E-mail: bernard@tours.inra.fr; Sarradin, Pierre [INRA, UR1282, IASP, 37380 Nouzilly (France); Vergote, Jackie [INSERM, U619, F-37000 Tours (France); Universite Francois-Rabelais, F-37000 Tours (France); IFR135, F-37000 Tours (France); Barc, Celine [INRA, UR1282, IASP, 37380 Nouzilly (France); Chalon, Sylvie [INSERM, U619, F-37000 Tours (France); Universite Francois-Rabelais, F-37000 Tours (France); IFR135, F-37000 Tours (France); Kung, M.-P.; Kung, Hank F. [Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104 (United States); Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 (United States); Guilloteau, Denis [INSERM, U619, F-37000 Tours (France); Universite Francois-Rabelais, F-37000 Tours (France); IFR135, F-37000 Tours (France)

2008-02-15

Introduction: A potential single-photon emission computed tomography imaging agent for labeling of A{beta} plaques of Alzheimer's disease, IMPY (2-(4'-dimethylaminophenyl)-6-iodo-imidazo[1,2-a]pyridine), would be effective in detection of prion amyloid deposits in transmissible spongiform encephalopathies (TSEs). Methods: In vitro autoradiographic studies were carried out with [{sup 125}I]IMPY on brain sections from scrapie-infected mice and age-matched controls. Competition study was performed to evaluate the prion deposit binding specificity with nonradioactive IMPY. Results: Binding of [{sup 125}I]IMPY was observed in infected brain sections, while on age-matched control brain sections, there was no or very low labeling. Prion deposit binding was confirmed by histoblots with prion protein-specific monoclonal antibody 2D6. In the presence of nonradioactive IMPY, the binding of [{sup 125}I]IMPY was significantly inhibited in all regions studied. Conclusions: These findings indicate that IMPY can detect the prion deposits in vitro in scrapie-infected mice. Labeled with {sup 123}I, this ligand may be useful to quantitate prion deposit burdens in TSEs by in vivo imaging.

Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer's beta-amyloid proteins.

Science.gov (United States)

Fujiwara, Hironori; Iwasaki, Koh; Furukawa, Katsutoshi; Seki, Takashi; He, Mei; Maruyama, Masahiro; Tomita, Naoki; Kudo, Yukitsuka; Higuchi, Makoto; Saido, Takaomi C; Maeda, Sumihiro; Takashima, Akihiko; Hara, Masahiko; Ohizumi, Yasushi; Arai, Hiroyuki

2006-08-01

Because the deposition of beta-amyloid protein (Abeta) is a consistent pathological hallmark of Alzheimer's disease (AD) brains, inhibition of Abeta generation, prevention of Abeta fibril formation, or destabilization of preformed Abeta fibrils would be attractive therapeutic strategies for the treatment of AD. We examined the effects of several medicinal herbs used in traditional Chinese medical formulae on the formation and destabilization of Abeta fibrils by using the thioflavin T binding assay, atomic force microscopic imaging, and electrophoresis. Our study demonstrates that several of these herbs have potent inhibitory effects on fibril formation of both Abeta(1-40) and Abeta(1-42) in concentration-dependent manners; in particular, Uncaria rhynchophylla inhibited Abeta aggregation most intensively. Significant destabilization of preformed Abeta(1-40) and Abeta(1-42) fibrils was also induced by Uncaria rhynchophylla as well as some other herb extracts. Three-dimensional HPLC analysis indicated that the water extract of this herb contains several different chemical compounds, including oxindole and indol alkaloids, which have been regarded as neuroprotective. Our results suggest that Uncaria rhynchophylla has remarkably inhibitory effects on the regulation of Abeta fibrils, and we conclude that this medicinal herb could have the potency to be a novel therapeutic agent to prevent and/or cure AD.

Is Verbal Episodic Memory in Elderly with Amyloid Deposits Preserved Through Altered Neuronal Function?

NARCIS (Netherlands)

Ossenkoppele, R.; Madison, C.; Oh, H.; Wirth, M.; van Berckel, B.N.M.; Jagust, W.J.

2014-01-01

A potential mechanism that enables intellectual preservation in cognitively normal elderly that harbor beta-amyloid (Aβ) pathology is heightened cerebral glucose metabolism. To investigate cross-sectional inter-relationships between Aβ, glucose metabolism, and cognition, 81 subjects (mean age: 75±7

AFM-based force spectroscopy measurements of mature amyloid fibrils of the peptide glucagon

DEFF Research Database (Denmark)

Dong, M. D.; Hovgaard, M. B.; Mamdouh, W.

2008-01-01

We report on the mechanical characterization of individual mature amyloid fibrils by atomic force microscopy (AFM) and AFM-based single-molecule force spectroscopy (SMFS). These self-assembling materials, formed from the 29-residue amphiphatic peptide hormone glucagon, were found to display...... a reversible elastic behaviour. Based on AFM morphology and SMFS studies, we suggest that the observed elasticity is due to a force-induced conformational transition which is reversible due to the beta-helical conformation of protofibrils, allowing a high degree of extension. The elastic properties...... of such mature fibrils contribute to their high stability, suggesting that the internal hydrophobic interactions of amyloid fibrils are likely to be of fundamental importance in the assembly of amyloid fibrils and therefore for the understanding of the progression of their associated pathogenic disorders...

Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and microglia in vitro

NARCIS (Netherlands)

Mulder, S.D.; Nielsen, H.M.; Blankenstein, M.A.; Eikelenboom, P.; Veerhuis, R.

2014-01-01

Defective clearance of the amyloid-β peptide (Aβ) from the brain is considered a strong promoter in Alzheimer's disease (AD) pathogenesis. Astrocytes and microglia are important mediators of Aβ clearance and Aβ aggregation state and the presence of amyloid associated proteins (AAPs), such as

Natural Modulators of Amyloid-Beta Precursor Protein Processing

Science.gov (United States)

Zhang, Can; Tanzi, Rudolph E.

2013-01-01

Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the primary cause of dementia, with no cure currently available. The pathogenesis of AD is believed to be primarily driven by Aβ, the principal component of senile plaques. Aβ is an ~4 kDa peptide generated from the amyloid-β precursor protein (APP) through proteolytic secretases. Natural products, particularly those utilized in traditional Chinese medicine (TCM), have a long history alleviating common clinical disorders, including dementia. However, the cell/molecular pathways mediated by these natural products are largely unknown until recently when the underlying molecular mechanisms of the disorders begin to be elucidated. Here, the mechanisms with which natural products modulate the pathogenesis of AD are discussed, in particular, by focusing on their roles in the processing of APP. PMID:22998566

Surface Mediated Self-Assembly of Amyloid Peptides

Science.gov (United States)

Fakhraai, Zahra

2015-03-01

Amyloid fibrils have been considered as causative agents in many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes and amyloidosis. Amyloid fibrils form when proteins or peptides misfold into one dimensional crystals of stacked beta-sheets. In solution, amyloid fibrils form through a nucleation and growth mechanism. The rate limiting nucleation step requires a critical concentration much larger than those measured in physiological conditions. As such the exact origins of the seeds or oligomers that result in the formation of fully mature fibrils in the body remain topic intense studies. It has been suggested that surfaces and interfaces can enhance the fibrillization rate. However, studies of the mechanism and kinetics of the surface-mediated fibrillization are technologically challenging due to the small size of the oligomer and protofibril species. Using smart sample preparation technique to dry the samples after various incubation times we are able to study the kinetics of fibril formation both in solution and in the vicinity of various surfaces using high-resolution atomic force microscopy. These studies elucidate the role of surfaces in catalyzing amyloid peptide formation through a nucleation-free process. The nucleation free self-assembly is rapid and requires much smaller concentrations of peptides or proteins. We show that this process resembles diffusion limited aggregation and is governed by the peptide adhesion rate, two -dimensional diffusion of the peptides on the surface, and preferential interactions between the peptides. These studies suggest an alternative pathway for amyloid formation may exist, which could lead to new criteria for disease prevention and alternative therapies. Research was partially supported by a seed grant from the National Institute of Aging of the National Institutes of Health (NIH) under Award Number P30AG010124 (PI: John Trojanowski) and the University of Pennsylvania.

Transthyretin protects against A-beta peptide toxicity by proteolytic cleavage of the peptide: a mechanism sensitive to the Kunitz protease inhibitor.

Directory of Open Access Journals (Sweden)

Rita Costa

Full Text Available Alzheimer's disease (AD is a neurodegenerative disorder characterized by the deposition of amyloid beta-peptide (A-Beta in the brain. Transthyretin (TTR is a tetrameric protein of about 55 kDa mainly produced in the liver and choroid plexus of the brain. The known physiological functions of TTR are the transport of thyroid hormone T(4 and retinol, through binding to the retinol binding protein. TTR has also been established as a cryptic protease able to cleave ApoA-I in vitro. It has been described that TTR is involved in preventing A-Beta fibrilization, both by inhibiting and disrupting A-Beta fibrils, with consequent abrogation of toxicity. We further characterized the nature of the TTR/A-Beta interaction and found that TTR, both recombinant or isolated from human sera, was able to proteolytically process A-Beta, cleaving the peptide after aminoacid residues 1, 2, 3, 10, 13, 14,16, 19 and 27, as determined by mass spectrometry, and reversed phase chromatography followed by N-terminal sequencing. A-Beta peptides (1-14 and (15-42 showed lower amyloidogenic potential than the full length counterpart, as assessed by thioflavin binding assay and ultrastructural analysis by transmission electron microscopy. A-Beta cleavage by TTR was inhibited in the presence of an alphaAPP peptide containing the Kunitz Protease Inhibitor (KPI domain but not in the presence of the secreted alphaAPP derived from the APP isoform 695 without the KPI domain. TTR was also able to degrade aggregated forms of A-Beta peptide. Our results confirmed TTR as a protective molecule in AD, and prompted A-Beta proteolysis by TTR as a protective mechanism in this disease. TTR may prove to be a useful therapeutic agent for preventing or retarding the cerebral amyloid plaque formation implicated in AD pathology.

Drug Product Life-Cycle Management as Anticompetitive Behavior: The Case of Memantine.

Science.gov (United States)

Capati, Vincent C; Kesselheim, Aaron S

2016-04-01

A "product hop" involves the substitution of a new formulation of a prescription drug by a pharmaceutical manufacturer for an old version to forestall generic competition. In 2015, for example, Forest Laboratories, the brand-name drug manufacturer of memantine, an Alzheimer's disease treatment, introduced an extended-release version and tried to restrict patient access to the previous version. Product hops can lead to useful incremental innovation but can also have major public health implications by disrupting patients on stable treatment regimens and increasing costs for patients and payers. This commentary reviews alleged anticompetitive product hopping in the case of memantine, which involved proposed conduct that would have left Alzheimer's disease patients with no effective choice but to transition to memantine XR. Policy solutions that can limit anticompetitive product hops include raising the bar for obtaining patents on new drug product formulations and changing automatic generic substitution laws. No outside funding supported this research. To support his work at PORTAL in the summer of 2015, Capati was the recipient of the University of New Hampshire School of Law Rudman Center Public Service Fellowship. Kesselheim's research was supported by Greenwall Faculty Scholars program, the Laura and John Arnold Foundation, and the Harvard Program in Therapeutic Science. In 2013, Kesselheim served as an expert on behalf of a class of individual plaintiffs against Warner Chilcott regarding potential antitrust violations Kesselheim was responsible for concept and design of this commentary. Capati took the lead in data collection and analysis, along with Kesselheim. Capati wrote the manuscript, which was revised by primarily by Kesselheim, along with Capati.

Calcium binding to beta-2-microglobulin at physiological pH drives the occurrence of conformational changes which cause the protein to precipitate into amorphous forms that subsequently transform into amyloid aggregates.

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Sukhdeep Kumar

Full Text Available Using spectroscopic, calorimetric and microscopic methods, we demonstrate that calcium binds to beta-2-microglobulin (β2m under physiological conditions of pH and ionic strength, in biological buffers, causing a conformational change associated with the binding of up to four calcium atoms per β2m molecule, with a marked transformation of some random coil structure into beta sheet structure, and culminating in the aggregation of the protein at physiological (serum concentrations of calcium and β2m. We draw attention to the fact that the sequence of β2m contains several potential calcium-binding motifs of the DXD and DXDXD (or DXEXD varieties. We establish (a that the microscopic aggregation seen at physiological concentrations of β2m and calcium turns into actual turbidity and visible precipitation at higher concentrations of protein and β2m, (b that this initial aggregation/precipitation leads to the formation of amorphous aggregates, (c that the formation of the amorphous aggregates can be partially reversed through the addition of the divalent ion chelating agent, EDTA, and (d that upon incubation for a few weeks, the amorphous aggregates appear to support the formation of amyloid aggregates that bind to the dye, thioflavin T (ThT, resulting in increase in the dye's fluorescence. We speculate that β2m exists in the form of microscopic aggregates in vivo and that these don't progress to form larger amyloid aggregates because protein concentrations remain low under normal conditions of kidney function and β2m degradation. However, when kidney function is compromised and especially when dialysis is performed, β2m concentrations probably transiently rise to yield large aggregates that deposit in bone joints and transform into amyloids during dialysis related amyloidosis.

FKBP12 regulates the localization and processing of amyloid ...

Indian Academy of Sciences (India)

2014-01-27

Jan 27, 2014 ... One of the pathological hallmarks of Alzheimer's disease is the presence of insoluble extracellular amyloid plaques. These plaques ... The proteolytic cleavage of amyloid precursor protein (APP) ..... lower sAPPα/sAPPs ratio, which may lead to an increase in ..... spine density in healthy adult mouse brain.

Cerebral Amyloid Angiopathy-Related Inflammation: Report of a Case with Very Difficult Therapeutic Management

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Francesca Crosta

2015-01-01

Full Text Available Background. Cerebral amyloid angiopathy-related inflammation (CAA-ri results from autoimmune response to beta-amyloid deposits in cerebral vessels. Its clinical course and complications have seldom been described in literature. Case Report. In a patient presenting with delirium and left hemiparesis the diagnosis of CAA-ri was supported by the finding of elevated anti-amyloid autoantibodies in the cerebrospinal fluid (CSF. Steroid therapy produced significant improvements in clinical and investigational assessments, but after two months, it caused Acute Respiratory Distress Syndrome. After steroid therapy discontinuation the patient presented a rapidly progressive dementia, Guillain-Barré syndrome, new cerebral ischemic lesions, and thrombosis of the right cephalic and subclavian veins that were treated with subcutaneous heparin. After a week the patient died because of brain hemorrhage. Conclusion. This case suggests caution in steroid therapy discontinuation and antithrombotic therapy administration in patients with CAA-ri. The CSF search of anti-amyloid autoantibodies could be helpful to support the diagnosis.

Evaluation of the amyloid beta-GFP fusion protein as a model of amyloid beta peptides-mediated aggregation: A study of DNAJB6 chaperone

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Rasha Mohamed Hussein

2015-07-01

Full Text Available Alzheimer’s disease is a progressive neurodegenerative disease characterized by the accumulation and aggregation of extracellular amyloid β (Aβ peptides and intracellular aggregation of hyper-phosphorylated tau protein. Recent evidence indicates that accumulation and aggregation of intracellular amyloid β peptides may also play a role in disease pathogenesis. This would suggest that intracellular Heat Shock Proteins (HSP that maintain cellular protein homeostasis might be candidates for disease amelioration. We recently found that DNAJB6, a member of DNAJ family of heat shock proteins, effectively prevented the aggregation of short aggregation-prone peptides containing large poly glutamines (associated with CAG repeat diseases both in vitro and in cells. Moreover, recent in vitro data showed that DNAJB6 can delay the aggregation of Aβ42 peptides. In this study, we investigated the ability of DNAJB6 to prevent the aggregation of extracellular and intracellular Aβ peptides using transfection of HEK293 cells with Aβ-GFP fusion construct and performing western blotting and immunofluorescence techniques. We found that DNAJB6 indeed suppresses Aβ-GFP aggregation, but not seeded aggregation initiated by extracellular Aβ peptides. Unexpectedly and unlike what we found for peptide-mediated aggregation, DNAJB6 required interaction with HSP70 to prevent the aggregation of the Aβ-GFP fusion protein and its J-domain was crucial for its anti-aggregation effect. In addition, other DNAJ proteins as well as HSPA1a overexpression also suppressed Aβ-GFP aggregation efficiently. Our findings suggest that Aβ aggregation differs from poly Q peptide induced aggregation in terms of chaperone handling and sheds doubt on the usage of Aβ-GFP fusion construct for studying Aβ peptide aggregation in cells.

Methyl Salicylate Lactoside Protects Neurons Ameliorating Cognitive Disorder Through Inhibiting Amyloid Beta-Induced Neuroinflammatory Response in Alzheimer's Disease.

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Li, Jinze; Ma, Xiaowei; Wang, Yu; Chen, Chengjuan; Hu, Min; Wang, Linlin; Fu, Junmin; Shi, Gaona; Zhang, Dongming; Zhang, Tiantai

2018-01-01

Neuroinflammatory reactions mediated by microglia and astrocytes have been shown to play a key role in early progression of Alzheimer's disease (AD). Increased evidences have demonstrated that neurons exacerbate local inflammatory reactions by producing inflammatory mediators and act as an important participant in the pathogenesis of AD. Methyl salicylate lactoside (MSL) is an isolated natural product that is part of a class of novel non-steroidal anti-inflammatory drugs (NSAID). In our previous studies, we demonstrated that MSL exhibited therapeutic effects on arthritis-induced mice and suppressed the activation of glial cells. In the current study, we investigated the effects of MSL on cognitive function and neuronal protection induced by amyloid-beta peptides (Aβ) and explored potential underlying mechanisms involved. Amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice were used to evaluate the effects of MSL through behavioral testing and neuronal degenerative changes. In addition, copper-injured APP Swedish mutation overexpressing SH-SY5Y cells were used to determine the transduction of cyclooxygenase (COX) and mitogen-activated protein kinase (MAPK) pathways. Our results indicated that at an early stage, MSL treatment ameliorated cognitive impairment and neurodegeneration in APP/PS1 mice. Moreover, in an in vitro AD model, MSL treatment protected injured cells by increasing cell viability, improving mitochondrial dysfunction, and decreasing oxidative damage. In addition, MSL inhibited the phosphorylated level of c-Jun N-terminal kinase (JNK) and p38 MAPK, and suppressed the expression of COX-1/2. As a novel NSAIDs and used for the treatment in early stage of AD, MSL clearly demonstrated cognitive preservation by protecting neurons via a pleiotropic anti-inflammatory effect in the context of AD-associated deficits. Therefore, early treatment of anti-inflammatory therapy may be an effective strategy for treating AD.

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis.

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Luo, Jinghui; Wärmländer, Sebastian K T S; Gräslund, Astrid; Abrahams, Jan Pieter

2016-08-05

Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-β (Aβ) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between Aβ and other amyloid proteins. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Blood-brain barrier dysfunction and amyloid precursor protein accumulation in microvascular compartment following ischemia-reperfusion brain injury with 1-year survival.

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Pluta, R

2003-01-01

This study examined the late microvascular consequences of brain ischemia due to cardiac arrest in rats. In reacted vibratome sections scattered foci of extravasated horseradish peroxidase were noted throughout the brain and did not appear to be restricted to any specific area of brain. Ultrastructural investigation of leaky sites frequently presented platelets adhering to the endothelium of venules and capillaries. Endothelial cells demonstrated pathological changes with evidence of perivascular astrocytic swelling. At the same time, we noted C-terminal of amyloid precursor protein/beta-amyloid peptide (CAPP/betaA) deposits in cerebral blood vessels, with a halo of CAPP/betaA immunoreactivity in the surrounding parenchyma suggested diffusion of CAPP/betaA out of the vascular compartment. Changes predominated in the hippocampus, cerebral and entorhinal cortex, corpus callosum, thalamus, basal ganglia and around the lateral ventricles. These data implicate delayed abnormal endothelial function of vessels following ischemia-reperfusion brain injury as a primary event in the pathogenesis of the recurrent cerebral infarction.

Emerging role of amyloid beta in stress response: Implication for depression and diabetes.

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Morgese, Maria Grazia; Schiavone, Stefania; Trabace, Luigia

2017-12-15

Chronic stress is considered a widely accepted risk factor for the development of neuropsychiatric and neurological disorders. Indeed, high cortisol levels, and, thus, hypothalamic pituitary adrenal (HPA)-axis dysregulation, have been indicated as the most frequent alteration in patients affected by depression, as well as by Alzheimer's disease (AD). Furthermore, depressive state has been pointed as an early manifestation of AD, advocating an overlap between these neuropathological events. We have previously demonstrated that central soluble beta amyloid 1-42 (Aβ) administration peptide induces a depressive like-behavior in rats, with altered HPA axis activation, reduced cortical serotonin and neurotrophin levels. The crucial role of Aβ in stress response is becoming more and more evident, indeed many reports indicate that its release is increased in stressful conditions and stress-based paradigm. Furthermore, it has been reported that stress controls Aβ production and/or clearance. Chronic stress is responsible of inducing neuroinflammation processes and reduced serotoninergic tone, both pathophysiological mechanisms proposed in the association of depression with another chronic disease, such as diabetes. Likewise, AD has also been indicated as type 3 diabetes, considering the large body of literature that suggests common biological bases. Thus, the main aim of the present review is to evaluate the most recent literature findings in humans and animal models in regard to the role of Aβ in stress response and in relation to the biological substrates and pathological pathways common to AD and comorbid diseases, such as depression and diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

Novel neuroprotective function of apical-basal polarity gene crumbs in amyloid beta 42 (aβ42 mediated neurodegeneration.

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Andrew M Steffensmeier

Full Text Available Alzheimer's disease (AD, OMIM: 104300, a progressive neurodegenerative disorder with no cure to date, is caused by the generation of amyloid-beta-42 (Aβ42 aggregates that trigger neuronal cell death by unknown mechanism(s. We have developed a transgenic Drosophila eye model where misexpression of human Aβ42 results in AD-like neuropathology in the neural retina. We have identified an apical-basal polarity gene crumbs (crb as a genetic modifier of Aβ42-mediated-neuropathology. Misexpression of Aβ42 caused upregulation of Crb expression, whereas downregulation of Crb either by RNAi or null allele approach rescued the Aβ42-mediated-neurodegeneration. Co-expression of full length Crb with Aβ42 increased severity of Aβ42-mediated-neurodegeneration, due to three fold induction of cell death in comparison to the wild type. Higher Crb levels affect axonal targeting from the retina to the brain. The structure function analysis identified intracellular domain of Crb to be required for Aβ42-mediated-neurodegeneration. We demonstrate a novel neuroprotective role of Crb in Aβ42-mediated-neurodegeneration.

Amyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer's parents

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Mosconi, Lisa; Rinne, Juha O; Tsui, Wai H

2013-01-01

This study examines the relationship between fibrillar beta-amyloid (Aβ) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimer's disease (AD). Forty-seven 40-80-year-old NL received positr...

High-Performance Liquid Chromatographic Ultraviolet Determination of Memantine Hydrochloride after In Vitro Transdermal Diffusion Studies

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Sergio del Rio-Sancho

2013-01-01

Full Text Available The purpose of the present work was to validate an accurate and precise high-performance liquid chromatography (HPLC method involving ultraviolet detection for the quantitative analysis of memantine hydrochloride. In order to analyze a molecule with no chromophoric groups that could be detected by a UV/visible detector, it was necessary to extract the drug and to perform a dansylation reaction that enabled the UV/visible detection of the derivatized molecule. Separation was carried out with a 150 mm Kromasil C18 column at room temperature. The detection response, at 218 nm, was found to be linear in the concentration range from 0.5 to 50 μg/mL. The method was validated for specificity, linearity, precision, accuracy, limit of detection, limit of quantification, and robustness. The limit of detection (LOD was 0.144 μg/mL, and the limit of quantification (LOQ was 0.437 μg/mL. The dansylated memantine complex was stable for at least five days in all the conditions evaluated. The potential use of this method has been demonstrated by the quantification of memantine hydrochloride contained in samples from the study of its in vitro transdermal permeation.

Protective effects of some medicinal plants from Lamiaceae family against beta-amyloid induced toxicity in PC12 cell

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Balali P

2012-10-01

Full Text Available Background: Excessive accumulation of beta-amyliod peptide (Aβ, the major component of senile plaques in Alzheimer's disease (AD, causes neuronal cell death through induction of oxidative stress. Therefore, antioxidants may be of use in the treatment of AD. The medicinal plants from the Lamiaceae family have been widely used in Iranian traditional medicine. These plants contain compounds with antioxidant activity and some species in this family have been reported to have neuroprotective properties. In the present study, methanolic extract of seven plants from salvia and satureja species were evaluated for their protective effects against beta-amyloid induced neurotoxicity.Methods: Aerial parts of the plants were extracted with ethyl acetate and methanol, respectively, by percolation at room temperature and subsequently, methanolic extracts of the plants were prepared. PC12 cells were incubated with different concentrations of the extracts in culture medium 1h prior to incubation with Aβ. Cell toxicity was assessed 24h after addition of Aβ by MTT assay.Results: Satureja bachtiarica, Salvia officinalis and Salvia macrosiphon methanolic extracts exhibited high protective effects against Aβ induced toxicity (P<0.001. Protective effects of Satureja bachtiarica and Salvia officinalis were dose-dependent.Conclusion: The main constituents of these extracts are polyphenolic and flavonoid compounds such as rosmarinic acid, naringenin, apigenin and luteolin which have antioxidant properties and may have a role in neuroprotection. Based on neuroprotective effect of these plants against Aβ induced toxicity, we recommend greater attention to their use in the treatment of Alzheimer disease.

Caspase activation increases beta-amyloid generation independently of caspase cleavage of the beta-amyloid precursor protein (APP).

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Tesco, Giuseppina; Koh, Young Ho; Tanzi, Rudolph E

2003-11-14

The amyloid precursor protein (APP) undergoes "alternative" proteolysis mediated by caspases. Three major caspase recognition sites have been identified in the APP, i.e. one at the C terminus (Asp720) and two at the N terminus (Asp197 and Asp219). Caspase cleavage at Asp720 has been suggested as leading to increased production of Abeta. Thus, we set out to determine which putative caspase sites in APP, if any, are cleaved in Chinese hamster ovary cell lines concurrently with the increased Abeta production that occurs during apoptosis. We found that cleavage at Asp720 occurred concurrently with caspase 3 activation and the increased production of total secreted Abeta and Abeta1-42 in association with staurosporine- and etoposide-induced apoptosis. To investigate the contribution of caspase cleavage of APP to Abeta generation, we expressed an APP mutant truncated at Asp720 that mimics APP caspase cleavage at the C-terminal site. This did not increase Abeta generation but, in contrast, dramatically decreased Abeta production in Chinese hamster ovary cells. Furthermore, the ablation of caspase-dependent cleavage at Asp720, Asp197, and Asp219 (by site-directed mutagenesis) did not prevent enhanced Abeta production following etoposide-induced apoptosis. These findings indicate that the enhanced Abeta generation associated with apoptosis does not require cleavage of APP at its C-terminal (Asp720) and/or N-terminal caspase sites.

Proactive Semantic Interference is Associated with Total and Regional Abnormal Amyloid Load in Non-Demented Community-Dwelling Elders: A Preliminary Study.

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Loewenstein, David A; Greig, Maria T; Curiel, Rosie; Rodriguez, Rosemarie; Wicklund, Meredith; Barker, Warren W; Hidalgo, Jacqueline; Rosado, Marian; Duara, Ranjan

2015-12-01

To evaluate the relationship between susceptibility to proactive semantic interference (PSI) and retroactive semantic interference (RSI) and brain amyloid load in non-demented elders. 27 participants (11 cognitively normal [CN] with subjective memory complaints, 8 CN without memory complaints, and 8 with mild cognitive impairment [MCI]) underwent complete neurological and neuropsychological evaluations. Participants also received the Semantic Interference Test (SIT) and AV-45 amyloid PET imaging. High levels of association were present between total amyloid load, regional amyloid levels, and the PSI measure (in the entire sample and a subsample excluding MCI subjects). RSI and other memory measures showed much weaker associations or no associations with total and regional amyloid load. No associations between amyloid levels and non-memory performance were observed. In non-demented individuals, vulnerability to PSI was highly associated with total and regional beta-amyloid load and may be an early cognitive marker of brain pathology. Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Detection of Alzheimer’s disease amyloid-beta plaque deposition by deep brain impedance profiling

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Béduer, Amélie; Joris, Pierre; Mosser, Sébastien; Fraering, Patrick C.; Renaud, Philippe

2015-04-01

Objective. Alzheimer disease (AD) is the most common form of neurodegenerative disease in elderly people. Toxic brain amyloid-beta (Aß) aggregates and ensuing cell death are believed to play a central role in the pathogenesis of the disease. In this study, we investigated if we could monitor the presence of these aggregates by performing in situ electrical impedance spectroscopy measurements in AD model mice brains. Approach. In this study, electrical impedance spectroscopy measurements were performed post-mortem in APPPS1 transgenic mice brains. This transgenic model is commonly used to study amyloidogenesis, a pathological hallmark of AD. We used flexible probes with embedded micrometric electrodes array to demonstrate the feasibility of detecting senile plaques composed of Aß peptides by localized impedance measurements. Main results. We particularly focused on deep brain structures, such as the hippocampus. Ex vivo experiments using brains from young and old APPPS1 mice lead us to show that impedance measurements clearly correlate with the percentage of Aβ plaque load in the brain tissues. We could monitor the effects of aging in the AD APPPS1 mice model. Significance. We demonstrated that a localized electrical impedance measurement constitutes a valuable technique to monitor the presence of Aβ-plaques, which is complementary with existing imaging techniques. This method does not require prior Aβ staining, precluding the risk of variations in tissue uptake of dyes or tracers, and consequently ensuring reproducible data collection.

Icariin Prevents Amyloid Beta-Induced Apoptosis via the PI3K/Akt Pathway in PC-12 Cells

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Dongdong Zhang

2015-01-01

Full Text Available Icariin is a prenylated flavonol glycoside derived from the Chinese herb Epimedium sagittatum that exerts a variety of pharmacological activities and shows promise in the treatment and prevention of Alzheimer’s disease. In this study, we investigated the neuroprotective effects of icariin against amyloid beta protein fragment 25–35 (Aβ25–35 induced neurotoxicity in cultured rat pheochromocytoma PC12 cells and explored potential underlying mechanisms. Our results showed that icariin dose-dependently increased cell viability and decreased Aβ25–35-induced apoptosis, as assessed by MTT assay and Annexin V/propidium iodide staining, respectively. Results of western blot analysis revealed that the selective phosphatidylinositol 3-kinase (PI3K inhibitor LY294002 suppressed icariin-induced Akt phosphorylation, suggesting that the protective effects of icariin are associated with activation of the PI3K/Akt signaling pathway. LY294002 also blocked the icariin-induced downregulation of proapoptotic factors Bax and caspase-3 and upregulation of antiapoptotic factor Bcl-2 in Aβ25–35-treated PC12 cells. These findings provide further evidence for the clinical efficacy of icariin in the treatment of Alzheimer’s disease.

An Open-Label Exploratory Study with Memantine: Correlation between Proton Magnetic Resonance Spectroscopy and Cognition in Patients with Mild to Moderate Alzheimer’s Disease

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Marc L. Gordon

2012-08-01

Full Text Available Aim: To characterize progression of Alzheimer’s disease (AD using proton magnetic resonance spectroscopy (1H MRS. Methods: Eleven subjects with mild to moderate AD underwent neurocognitive testing and single-voxel 1H MRS from the precuneus and posterior cingulate region at baseline, after 24 weeks of monotherapy with a cholinesterase inhibitor, and after another 24 weeks of combination therapy with open-label memantine and a cholinesterase inhibitor. Baseline metabolites [N-acetylaspartate (NAA, myo-inositol (mI, choline (Cho, and creatine (Cr] and their ratios in AD subjects were compared with those of an age-matched control group of 28 cognitively normal subjects. Results: AD subjects had significantly higher mI/Cr and lower NAA, NAA/Cr, NAA/Cho, and NAA/mI. Baseline Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL scores significantly correlated with NAA/Cr, mI/Cr, and NAA/mI. There was an increase in mI and a decrease in NAA/mI, but no significant change in other metabolites or ratios, or neurocognitive measures, when memantine was added to a cholinesterase inhibitor. Conclusion: Metabolite ratios significantly differed between AD and control subjects. Baseline metabolite ratios correlated with function (ADCS-ADL. There was an increase in mI and a decrease in NAA/mI, but no changes in other metabolites, ratios, or cognitive measures, when memantine was added to a cholinesterase inhibitor.

Use of amyloid PET across the spectrum of Alzheimer's disease: clinical utility and associated ethical issues.

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Leuzy, Antoine; Zimmer, Eduardo Rigon; Heurling, Kerstin; Rosa-Neto, Pedro; Gauthier, Serge

2014-09-01

Abstract Recent advances have made possible the in vivo detection of beta-amyloid (Aβ) pathology using positron emission tomography. While the gold standard for amyloid imaging, carbon-11 labeled Pittsburgh compound B is increasingly being replaced by fluorine-18 labeled radiopharmaceuticals, with three already approved for clinical use by US and European regulatory bodies. Appropriate use criteria proposed by an amyloid imaging taskforce convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging recommend restricting use of this technology to the evaluation of patients with mild cognitive impairment or atypical dementia syndromes. While use among asymptomatic individuals is currently viewed as inappropriate due prognostic uncertainty, elevated levels of brain Aβ among asymptomatic individuals may represent preclinical Alzheimer's disease. Amyloid imaging is likewise expected to play a role in the design of clinical trials. Though preliminary results suggest amyloid imaging to possess clinical utility and cost-effectiveness, both domains have yet to be assessed systematically. As the field moves toward adoption of a pro-disclosure stance for amyloid imaging findings, it is imperative that a broad range of stakeholders be involved to ensure the appropriateness of emerging policies and protocols.

Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation

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Schultz, Sebastian Wolfgang; Nilsson, K. Peter R.; Westermark, Gunilla Torstensdotter

2011-01-01

Background Recent research supports that aggregation of islet amyloid polypeptide (IAPP) leads to cell death and this makes islet amyloid a plausible cause for the reduction of beta cell mass, demonstrated in patients with type 2 diabetes. IAPP is produced by the beta cells as a prohormone, and proIAPP is processed into IAPP by the prohormone convertases PC1/3 and PC2 in the secretory granules. Little is known about the pathogenesis for islet amyloid and which intracellular mechanisms are involved in amyloidogenesis and induction of cell death. Methodology/Principal Findings We have established expression of human proIAPP (hproIAPP), human IAPP (hIAPP) and the non-amyloidogenic mouse IAPP (mIAPP) in Drosophila melanogaster, and compared survival of flies with the expression driven to different cell populations. Only flies expressing hproIAPP in neurons driven by the Gal4 driver elavC155,Gal4 showed a reduction in lifespan whereas neither expression of hIAPP or mIAPP influenced survival. Both hIAPP and hproIAPP expression caused formation of aggregates in CNS and fat body region, and these aggregates were both stained by the dyes Congo red and pFTAA, both known to detect amyloid. Also, the morphology of the highly organized protein granules that developed in the fat body of the head in hIAPP and hproIAPP expressing flies was characterized, and determined to consist of 15.8 nm thick pentagonal rod-like structures. Conclusions/Significance These findings point to a potential for Drosophila melanogaster to serve as a model system for studies of hproIAPP and hIAPP expression with subsequent aggregation and developed pathology. PMID:21695120

Effectiveness of memantine on depression-like behavior, memory deficits and brain mRNA levels of BDNF and TrkB in rats subjected to repeated unpredictable stress

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Amidfar, Meysam; Kim, Yong-Ku; Wiborg, Ove

2018-01-01

downregulation. Administration of memantine reversed depression-like behavior and memory impairment and significantly increased BDNF and TrkB mRNA levels in both prefrontal cortex and hippocampus of stress exposed rats. CONCLUSIONS: Our study supports the hypothesis that drugs with antagonistic properties...... administration in rats subjected to the repeated unpredictable stress (RUS) paradigm. METHODS: Rats were split into four groups at random including control + saline, control + memantine, stressed + saline and stressed + memantine. After 10 days of exposure to the RUS paradigm, rats were administered memantine...... (20 mg/kg) intraperitoneally (ip) for 14 days. Depression-like behavior and memory performance were assessed by measuring immobility time in the forced swim test and passive avoidance test, respectively. The mRNA levels of BDNF and TrkB in the prefrontal cortex and hippocampus were measured by real...

Chronic apocynin treatment attenuates beta amyloid plaque size and microglial number in hAPP(751(SL mice.

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Melinda E Lull

Full Text Available NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer's Disease (AD. Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM, to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751(SL.Four month old hAPP(751(SL mice were treated daily with saline, 15 mg/kg DM, 7.5 mg/kg DM, or 10 mg/kg apocynin by gavage for four months.Only hAPP(751(SL mice treated with apocynin showed reduced plaque size and a reduction in the number of cortical microglia, when compared to the saline treated group. Analysis of whole brain homogenates from all treatments tested (saline, DM, and apocynin demonstrated low levels of TNFα, protein nitration, lipid peroxidation, and NADPH oxidase activation, indicating a low level of neuroinflammation and oxidative stress in hAPP(751(SL mice at 8 months of age that was not significantly affected by any drug treatment. Despite in vitro analyses demonstrating that apocynin and DM ameliorate Aβ-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751(SL mice. To discern how apocynin was affecting plaque levels (plaque load and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Aβ phagocytosis, microglial proliferation, or microglial survival.Together, this study suggests that while hAPP(751(SL mice show increases in microglial number and plaque load, they fail to exhibit elevated markers of neuroinflammation consistent with AD at 8 months of age, which may be a limitation of this animal model. Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional

Amyloid and immune homeostasis.

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Wang, Ying-Hui; Zhang, Yu-Gen

2018-03-01

Extracellular amyloid deposition defines a range of amyloidosis and amyloid-related disease. Addition to primary and secondary amyloidosis, amyloid-related disease can be observed in different tissue/organ that sharing the common pathogenesis based on the formation of amyloid deposition. Currently, both Alzheimer's disease and type 2 diabetes can be diagnosed with certainly only based on the autopsy results, by which amyloidosis of the associative tissue/organ is observed. Intriguingly, since it demonstrated that amyloid deposits trigger inflammatory reaction through the activation of cascaded immune response, wherein several lines of evidence implies a protective role of amyloid in preventing autoimmunity. Furthermore, attempts for preventing amyloid formation and/or removing amyloid deposits from the brain have caused meningoencephalitis and consequent deaths among the subjects. Hence, it is important to note that amyloid positively participates in maintaining immune homeostasis and contributes to irreversible inflammatory response. In this review, we will focus on the interactive relationship between amyloid and the immune system, discussing the potential functional roles of amyloid in immune tolerance and homeostasis. Copyright © 2017 Elsevier GmbH. All rights reserved.

Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: A meta-analysis.

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Chen, Ruey; Chan, Pi-Tuan; Chu, Hsin; Lin, Yu-Cih; Chang, Pi-Chen; Chen, Chien-Yu; Chou, Kuei-Ru

2017-01-01

This is the first meta-analysis to compare the treatment effects and safety of administering donepezil alone versus a combination of memantine and donepezil to treat patients with moderate to severe Alzheimer Disease, particularly regarding cognitive functions, behavioral and psychological symptoms in dementia (BPSD), and global functions. PubMed, Medline, Embase, PsycINFO, and Cochrane databases were used to search for English and non-English articles for inclusion in the meta-analysis to evaluate the effect size and incidence of adverse drug reactions of different treatments. Compared with patients who received donepezil alone, those who received donepezil in combination with memantine exhibited limited improvements in cognitive functions (g = 0.378, p Alzheimer Disease.

Real-time amyloid aggregation monitoring with a photonic crystal-based approach.

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Santi, Sara; Musi, Valeria; Descrovi, Emiliano; Paeder, Vincent; Di Francesco, Joab; Hvozdara, Lubos; van der Wal, Peter; Lashuel, Hilal A; Pastore, Annalisa; Neier, Reinhard; Herzig, Hans Peter

2013-10-21

We propose the application of a new label-free optical technique based on photonic nanostructures to real-time monitor the amyloid-beta 1-42 (Aβ(1-42)) fibrillization, including the early stages of the aggregation process, which are related to the onset of the Alzheimer's Disease (AD). The aggregation of Aβ peptides into amyloid fibrils has commonly been associated with neuronal death, which culminates in the clinical features of the incurable degenerative AD. Recent studies revealed that cell toxicity is determined by the formation of soluble oligomeric forms of Aβ peptides in the early stages of aggregation. At this phase, classical amyloid detection techniques lack in sensitivity. Upon a chemical passivation of the sensing surface by means of polyethylene glycol, the proposed approach allows an accurate, real-time monitoring of the refractive index variation of the solution, wherein Aβ(1-42) peptides are aggregating. This measurement is directly related to the aggregation state of the peptide throughout oligomerization and subsequent fibrillization. Our findings open new perspectives in the understanding of the dynamics of amyloid formation, and validate this approach as a new and powerful method to screen aggregation at early stages. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Curcumin Decreases Amyloid-β Peptide Levels by Attenuating the Maturation of Amyloid-β Precursor Protein*

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Zhang, Can; Browne, Andrew; Child, Daniel; Tanzi, Rudolph E.

2010-01-01

Alzheimer disease (AD) is a devastating neurodegenerative disease with no cure. The pathogenesis of AD is believed to be driven primarily by amyloid-β (Aβ), the principal component of senile plaques. Aβ is an ∼4-kDa peptide generated via cleavage of the amyloid-β precursor protein (APP). Curcumin is a compound in the widely used culinary spice, turmeric, which possesses potent and broad biological activities, including anti-inflammatory and antioxidant activities, chemopreventative effects, and effects on protein trafficking. Recent in vivo studies indicate that curcumin is able to reduce Aβ-related pathology in transgenic AD mouse models via unknown molecular mechanisms. Here, we investigated the effects of curcumin on Aβ levels and APP processing in various cell lines and mouse primary cortical neurons. We show for the first time that curcumin potently lowers Aβ levels by attenuating the maturation of APP in the secretory pathway. These data provide a mechanism of action for the ability of curcumin to attenuate amyloid-β pathology. PMID:20622013

Unfolding, aggregation, and seeded amyloid formation of lysine-58-cleaved beta(2)-microglobulin

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Heegaard, N.H.H.; Jørgensen, T.J.D.; Rozlosnik, N.

2005-01-01

. Using amide hydrogen/deuterium exchange monitored by mass spectrometry, we show that Delta K58-beta(2)m has increased unfolding rates compared to wt-beta(2)m and that unfolding is highly temperature dependent. The unfolding rate is I order of magnitude faster in Delta K58-beta(2)M than in wt-beta(2)m...... in the circulation of dialysis patients. This beta(2)M variant, Delta K58-beta(2)m, is a disulfide-linked two-chain molecule consisting of amino acid residues 1-57 and 59-99 of intact beta(2)m, and we here demonstrate and characterize its decreased conformational stability as compared to wild-type (wt) beta(2)M...

In vivo detection of amyloid plaques by gadolinium-stained MRI can be used to demonstrate the efficacy of an anti-amyloid immunotherapy

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Mathieu D. Santin

2016-03-01

Full Text Available Extracellular deposition of β amyloid plaques is an early event associated to Alzheimer's disease. Here we have used in vivo gadolinium-stained high resolution (29*29*117µm3 MRI to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952 directed against protofibrillar and fibrillary forms of Aβ. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR255952 reduced amyloid load in 8.5-month-old animals, but not in 5.5-month animals compared to mice treated with a control antibody (DM4. Histological evaluation confirmed the reduction of amyloid load and revealed a lower density of amyloid plaques in 8.5-month SAR255952-treated animals. The longitudinal follow-up of individual amyloid plaques by MRI revealed that plaques that were visible at 5.5 months were still visible at 8.5 months in both SAR255952 and DM4-treated mice. This suggests that the amyloid load reduction induced by SAR255952 is related to a slowing down in the formation of new plaques rather than to the clearance of already formed plaques.

Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice.

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He, Xiao-Fei; Liu, Dong-Xu; Zhang, Qun; Liang, Feng-Ying; Dai, Guang-Yan; Zeng, Jin-Sheng; Pei, Zhong; Xu, Guang-Qing; Lan, Yue

2017-01-01

Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood-brain barrier (BBB) or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer's disease (AD), but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4), astrocyte and microglial activation, and the accumulation of amyloid beta (Aβ) were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA); synaptic function was investigated with Thy1 -green fluorescent protein (GFP) transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aβ accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95) increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition. These data suggest

Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice

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Xiao-fei He

2017-05-01

Full Text Available Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood–brain barrier (BBB or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF and the interstitial fluid (ISF. A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer’s disease (AD, but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4, astrocyte and microglial activation, and the accumulation of amyloid beta (Aβ were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA; synaptic function was investigated with Thy1–green fluorescent protein (GFP transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aβ accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95 increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition

Methyl Salicylate Lactoside Protects Neurons Ameliorating Cognitive Disorder Through Inhibiting Amyloid Beta-Induced Neuroinflammatory Response in Alzheimer’s Disease

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Li, Jinze; Ma, Xiaowei; Wang, Yu; Chen, Chengjuan; Hu, Min; Wang, Linlin; Fu, Junmin; Shi, Gaona; Zhang, Dongming; Zhang, Tiantai

2018-01-01

Neuroinflammatory reactions mediated by microglia and astrocytes have been shown to play a key role in early progression of Alzheimer’s disease (AD). Increased evidences have demonstrated that neurons exacerbate local inflammatory reactions by producing inflammatory mediators and act as an important participant in the pathogenesis of AD. Methyl salicylate lactoside (MSL) is an isolated natural product that is part of a class of novel non-steroidal anti-inflammatory drugs (NSAID). In our previous studies, we demonstrated that MSL exhibited therapeutic effects on arthritis-induced mice and suppressed the activation of glial cells. In the current study, we investigated the effects of MSL on cognitive function and neuronal protection induced by amyloid-beta peptides (Aβ) and explored potential underlying mechanisms involved. Amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice were used to evaluate the effects of MSL through behavioral testing and neuronal degenerative changes. In addition, copper-injured APP Swedish mutation overexpressing SH-SY5Y cells were used to determine the transduction of cyclooxygenase (COX) and mitogen-activated protein kinase (MAPK) pathways. Our results indicated that at an early stage, MSL treatment ameliorated cognitive impairment and neurodegeneration in APP/PS1 mice. Moreover, in an in vitro AD model, MSL treatment protected injured cells by increasing cell viability, improving mitochondrial dysfunction, and decreasing oxidative damage. In addition, MSL inhibited the phosphorylated level of c-Jun N-terminal kinase (JNK) and p38 MAPK, and suppressed the expression of COX-1/2. As a novel NSAIDs and used for the treatment in early stage of AD, MSL clearly demonstrated cognitive preservation by protecting neurons via a pleiotropic anti-inflammatory effect in the context of AD-associated deficits. Therefore, early treatment of anti-inflammatory therapy may be an effective strategy for treating AD. PMID:29636677

Insulin amyloid fibrillation studied by terahertz spectroscopy and other biophysical methods

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Liu, Rui [State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072 (China); He, Mingxia [College of Precision Instrument and Optoelectronics Engineering, Tianjin University, Tianjin 300072 (China); Su, Rongxin, E-mail: surx@tju.edu.cn [State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072 (China); Tianjin Key Laboratory of Membrane Science and Desalination Technology, Tianjin University, Tianjin 300072 (China); Yu, Yanjun [State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072 (China); Qi, Wei; He, Zhimin [State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072 (China); Tianjin Key Laboratory of Membrane Science and Desalination Technology, Tianjin University, Tianjin 300072 (China)

2010-01-01

Assembly and fibrillation of amyloid proteins are believed to play a key role in the etiology of various human diseases, including Alzheimer's, Parkinson's, Huntington's and type II diabetes. Insights into conformational changes and formation processes during amyloid fibrillation are essential for the clinical diagnosis and drug discovery. To study the changes in secondary, tertiary, quaternary structures, and the alteration in the collective vibrational mode density of states during the amyloid fibrillation, bovine insulin in 20% acetic acid was incubated at 60 {sup o}C, and its multi-level structures were followed by various biophysical techniques, including circular dichroism (CD), thioflavin T fluorescence (ThT), dynamic light scattering (DLS), electron microscopy, and terahertz (THz) absorption spectroscopy. The experimental data demonstrated a transformation of {alpha}-helix into {beta}-sheet starting at 26 h. This was followed by the aggregation of insulin, as shown by ThT binding, with a transition midpoint at 41 h, and by the bulk formation of mature aggregates after about 71 h. THz is a quick and non-invasive technique, which has the advantage of allowing the study of the conformational state of biomolecules and tissues. We first applied THz spectroscopy to study the amyloid fibrillation. At the terahertz frequency range of 0.2-2.0 THz, there was an apparent increase in both the absorbance and refractive index in THz spectra. Thus, THz is expected to provide a new way of looking into amyloid fibrillation.

Effect of memantine on CBF and CMRO2 in patients with early Parkinson's disease

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Borghammer, P; Vafaee, M; Ostergaard, K

2008-01-01

Objectives –  Parkinson’s disease (PD) may be associated with increased energy metabolism in overactive regions of the basal ganglia. Therefore, we hypothesized that treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine would decrease regional cerebral blood flow (rCBF) an...... ganglia oxygen consumption, our data suggest that treatment with memantine actively modulates neuronal activity and/or hemodynamic response in basal ganglia of PD patients. This finding may be relevant to the putative neuroprotective properties of NMDAR antagonists.......CBF) and oxygen metabolism in the basal ganglia of patients with early-stage PD. Methods –  Quantitative positron emission tomography (PET) recordings were obtained with [15O]water and [15O]oxygen in 10 patients, scanned first in a baseline condition, and again 6 weeks after treatment with a daily dose of 20 mg...

Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability.

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Allaman, Igor; Gavillet, Mathilde; Bélanger, Mireille; Laroche, Thierry; Viertl, David; Lashuel, Hilal A; Magistretti, Pierre J

2010-03-03

Amyloid-beta (Abeta) peptides play a key role in the pathogenesis of Alzheimer's disease and exert various toxic effects on neurons; however, relatively little is known about their influence on glial cells. Astrocytes play a pivotal role in brain homeostasis, contributing to the regulation of local energy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of Abeta peptides on glucose metabolism in cultured astrocytes. Following Abeta(25-35) exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. Abeta increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content. A causal link between the effects of Abeta on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Abeta impair neuronal viability. The effects of the Abeta(25-35) fragment were reproduced by Abeta(1-42) but not by Abeta(1-40). Finally, the phosphoinositide 3-kinase (PI3-kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that Abeta aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability.

Cerebral Amyloid Angiopathy

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Mahmut Edip Gürol

2009-03-01

Full Text Available Cerebral amyloid angiopathy (CAA is characterized by the accumulation of amyloid beta-peptides (Ab in the walls of leptomeningeal arteries, arterioles, and veins. Despite the fact that these pathological changes were first described in 1909, major advancement in our understanding of the clinicoradiological manifestations, neurobiology, and course of CAA has occurred only during the last 30 years. No significant associations have been shown between CAA and other systemic/visceral amyloidoses or vascular risk factors, including hypertension. CAA is well known as the most common cause of spontaneous and anticoagulant-related lobar parenchymal ICH in the elderly. It also causes lobar cerebral microbleeds (CMBs, small dot-like dark susceptibility artifacts visible with gradient recalled echo (GRE-magnetic resonance imaging (MRI. CMBs are important markers of disease severity and predictors of CAA progression. Amyloid angiopathy is also a common cause of ischemic microvascular white matter disease (WMD and deep cerebral infarctions. Such WMD is defined as subcortical and periventricular white matter changes without obvious infarction, as well as a dark appearance on computerized tomography (CT and a bright appearance on fluid attenuated inversion recovery (FLAIR-MRI. CAA-related vascular dysfunction, with its hemorrhagic and ischemic complications, is a recognized contributor to vascular cognitive impairment in the elderly, an independent effect that is synergistically increased by Alzheimer pathologies, such as plaques and tangles. A set of clinicoradiological criteria was established for the accurate diagnosis of CAA. According to the Boston Criteria, patients aged 55 years and older with multiple hemorrhages (on CT or GRE-MRI restricted to the lobar, cortical, or corticosubcortical regions (cerebellar hemorrhage allowed are diagnosed as probable CAA when no other etiology is found; a single hemorrhage in the same region is classified as possible

Comparison and Analysis of 3,4 dihydrocylmandelic acid (DHMA) and noremetanephrine (NMN) on Amyloid-Beta 40 Monomer for treatment of Alzheimer's Disease using Molecular Dynamics Simulation

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Choi, Woosung; Jee, Sang Eun; Jang, Seung Soon

Alzheimer's disease (AD) is type of degenerative dementia caused memory loss and behavior problem. Main reason of AD is Amyloid-Beta 40(A β) mostly composed of α -helix form misfolds to insoluble fibrils and soluble oilgomer. This insoluble fibrils aggregate with beta sheet structure and form the plaque which is caused nurotoxicity in brain. Both 3,4 dihydrocylmandelic acid (DHMA) and noremetanephrine (NMN) are the metabolite of norepinephrine in brain . Also these are inhibit the changing formation of fibrils and maintain the α -helix structure. In this computational modeling study, both NMN and DHMA molecules were modified and analyzed for specific effect on the A β-monomer using molecular dynamics simulation. Using molecular dynamic simulation, NMN and DHMA act as modulator on three A β-monomer batches and could observe the conformational changing of these A β-monomer under the physiologocal condition. This computational experiment is designed to compare and analyze both of chemicals for determining which chamecal would be more effective on the conformation of A β 40 monomer.

Neurofibrillary tangles and the deposition of a beta amyloid peptide with a novel N-terminal epitope in the brains of wild Tsushima leopard cats.

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James K Chambers

Full Text Available Beta amyloid (Aβ deposits are seen in aged individuals in many of the mammalian species that possess the same Aβ amino acid sequence as humans. Conversely, neurofibrillary tangles (NFT, the other hallmark lesion of Alzheimer's disease (AD, are extremely rare in these animals. We detected Aβ deposits in the brains of Tsushima leopard cats (Prionailurus bengalensis euptilurus that live exclusively on Tsushima Island, Japan. Aβ42 was deposited in a granular pattern in the neuropil of the pyramidal cell layer, but did not form argyrophilic senile plaques. These Aβ deposits were not immunolabeled with antibodies to the N-terminal of human Aβ. Sequence analysis of the amyloid precursor protein revealed an amino acid substitution at the 7th residue of the Aβ peptide. In a comparison with other mammalian animals that do develop argyrophilic senile plaques, we concluded that the alternative Aβ amino acid sequence displayed by leopard cats is likely to be related to its distinctive deposition pattern. Interestingly, most of the animals with these Aβ deposits also developed NFTs. The distributions of hyperphosphorylated tau-positive cells and the two major isoforms of aggregated tau proteins were quite similar to those seen in Alzheimer's disease. In addition, the unphosphorylated form of GSK-3β colocalized with hyperphosphorylated tau within the affected neurons. In conclusion, this animal species develops AD-type NFTs without argyrophilic senile plaques.

Interconverting conformations of variants of the human amyloidogenic protein beta2-microglobulin quantitatively characterized by dynamic capillary electrophoresis and computer simulation

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Heegaard, Niels H H; Jørgensen, Thomas J D; Cheng, Lei

2006-01-01

Capillary electrophoretic separation profiles of cleaved variants of beta2-microglobulin (beta2m) reflect the conformational equilibria existing in solutions of these proteins. The characterization of these equilibria is of interest since beta2m is responsible for amyloid formation in dialysis-re...

Open-label pilot study of memantine in the treatment of compulsive buying.

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Grant, Jon E; Odlaug, Brian L; Mooney, Marc; O'Brien, Robert; Kim, Suck Won

2012-05-01

Although compulsive buying (CB) is relatively common, pharmacotherapy research for CB is limited. Memantine, an N-methyl-D-aspartate receptor antagonist, appears to reduce glutamate excitability and improve impulsive behaviors, suggesting it may help individuals with CB. Nine patients (8 females) with CB were enrolled in a 10-week open-label treatment study of memantine (dose ranging from 10 to 30 mg/d). Participants were enrolled from December 2008 until May 2010. The primary outcome measure was change from baseline to study endpoint on the Yale-Brown Obsessive Compulsive Scale-Shopping Version (Y-BOCS-SV). Of the 9 participants, 8 (88.9%) completed the 10-week study. Y-BOCS-SV scores decreased from a mean of 22.0 ± 1.3 at baseline to 11.0 ± 5.3 at endpoint (P impulsive buying and improvements on cognitive tasks of impulsivity. In addition, the medication was well-tolerated. These findings suggest that pharmacologic manipulation of the glutamate system may target the impulsive behavior underlying CB. Placebo-controlled, double-blind studies are warranted in order to confirm these preliminary findings in a controlled design.

Beta-amyloid deposition in patients with major depressive disorder with differing levels of treatment resistance: a pilot study.

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Li, Peng; Hsiao, Ing-Tsung; Liu, Chia-Yih; Chen, Chia-Hsiang; Huang, She-Yao; Yen, Tzu-Chen; Wu, Kuan-Yi; Lin, Kun-Ju

2017-12-01

Lack of treatment response in patients with late-life depression is common. The role of brain beta-amyloid (Aβ) deposition in treatment outcome in subjects with late-life depression remains unclear. The present study aimed to investigate brain Aβ deposition in patients with major depressive disorder (MDD) with differing treatment outcomes in vivo using 18 F-florbetapir imaging. This study included 62 MDD patients and 18 healthy control subjects (HCs).We first employed the Maudsley staging method (MSM) to categorize MDD patients into two groups according to treatment response: mild treatment resistance (n = 29) and moderate-to-severe treatment resistance (n = 33).The standard uptake value ratio (SUVR) of each volume of interest was analysed, and voxel-wise comparisons were made between the MDD patients and HCs. Vascular risk factors, serum homocysteine level, and apolipoprotein E (ApoE) genotype were also determined. The MDD patients with moderate-to-severe treatment resistance had higher 18 F-florbetapir SUVRs than the HCs in the parietal region (P depressive symptoms may represent prodromal manifestations of Alzheimer's disease (AD). Depressive symptomatology in old age, particularly in subjects with a poor treatment response, may underscore early changes of AD-related pathophysiology.

Structural and conformational variants of human beta2-microglobulin characterized by capillary electrophoresis and complementary separation methods

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Heegaard, Niels H H; Rovatti, Luca; Nissen, Mogens H

2003-01-01

The small (Mr = 11729) serum protein beta2-microglobulin is prone to precipitate as amyloid in a protein conformational disorder (PCD) that occurs in a significant number of patients on chronic hemodialysis. Analyses by capillary electrophoresis (CE) were undertaken to study beta2-microglobulin...

Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer's disease

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Ya-Ru Wen

2018-01-01

Full Text Available Impaired amyloid-β clearance from the brain is a core pathological event in Alzheimer's disease. The therapeutic effect of current pharmacotherapies is unsatisfactory, and some treatments cause severe side effects. The meningeal lymphatic vessels might be a new route for amyloid-β clearance. This study investigated whether promoting dural lymphangiogenesis facilitated the clearance of amyloid-β from the brain. First, human lymphatic endothelial cells were treated with 100 ng/mL recombinant human vascular endothelial growth factor-C (rhVEGF-C protein. Light microscopy verified that rhVEGF-C, a specific ligand for vascular endothelial growth factor receptor-3 (VEGFR-3, significantly promoted tube formation of human lymphatic endothelial cells in vitro. In an in vivo study, 200 μg/mL rhVEGF-C was injected into the cisterna magna of APP/PS1 transgenic mice, once every 2 days, four times in total. Immunofluorescence staining demonstrated high levels of dural lymphangiogenesis in Alzheimer's disease mice. One week after rhVEGF-C administration, enzyme-linked immunosorbent assay results showed that levels of soluble amyloid-β were decreased in cerebrospinal fluid and brain. The Morris water maze test demonstrated that spatial cognition was restored. These results indicate that the upregulation of dural lymphangiogenesis facilities amyloid-β clearance from the brain of APP/PS1 mice, suggesting the potential of the VEGF-C/VEGFR-3 signaling pathway as a therapeutic target for Alzheimer's disease.

Increased tau phosphorylation and beta amyloid in the hipocampus of mouse pups by early life lead exposure.

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Li, N; Yu, Z L; Wang, L; Zheng, Y T; Jia, J X; Wang, Q; Zhu, M J; Liu, X L; Xia, X; Li, W J

2010-06-01

The aim of this study was to investigate the effects of maternal lead exposure on the learning and memory ability and expression of tau protein phosphorylation (P-tau) and beta amyloid protein (Abeta) in hippocampus of mice offspring. Pb exposure initiated from beginning of gestation to weaning. Pb acetate administered in drinking solutions was dissolved in distilled deionized water at the concentrations of 0.1%, 0.5% and 1% groups. On the 21 th of postnatal day, the learning and memory ability of the mouse pups was tested by Water Maze test and the Pb levels in blood and hippocampus of the offspring were also determined. The expression of P-tau and Abeta in hippocampus was measured by immunohistochemistry and Western blotting. The Pb levels in blood and hippocampus of all exposure groups were significantly higher than that of the control group ( P < 0.05). In Water Maze test, the performances of 0.5% and 1% groups were worse than that of the control group ( P < 0.05). The expression of P-tau and Abeta was increased in Pb exposed groups than that of the control group ( P < 0.05). Tau hyper-phosphorylation and Abeta increase in the hippocampus of pups may contribute to the impairment of learning and memory associated with maternal Pb exposure.

Preventing effect of L-type calcium channel blockade on electrophysiological alterations in dentate gyrus granule cells induced by entorhinal amyloid pathology.

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Hamid Gholami Pourbadie

Full Text Available The entorhinal cortex (EC is one of the earliest affected brain regions in Alzheimer's disease (AD. EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs, nimodipine and isradipine, were investigated. The amyloid beta (Aβ 1-42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Aβ treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days, almost preserved the normal excitability against Aβ. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer's disease.

Conjugated Quantum Dots Inhibit the Amyloid β (1–42 Fibrillation Process

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Garima Thakur

2011-01-01

Full Text Available Nanoparticles have enormous potential in diagnostic and therapeutic studies. We have demonstrated that the amyloid beta mixed with and conjugated to dihydrolipoic acid- (DHLA capped CdSe/ZnS quantum dots (QDs of size approximately 2.5 nm can be used to reduce the fibrillation process. Transmission electron microscopy (TEM and atomic force microscopy (AFM were used as tools for analysis of fibrillation. There is a significant change in morphology of fibrils when amyloid β (1–42 (Aβ (1–42 is mixed or conjugated to the QDs. The length and the width of the fibrils vary under modified conditions. Thioflavin T (ThT fluorescence supports the decrease in fibril formation in presence of DHLA-capped QDs.

Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

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Cheng, Pin-Nan; Liu, Cong; Zhao, Minglei; Eisenberg, David; Nowick, James S.

2012-11-01

The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

Functional Amyloids in Reproduction.

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Hewetson, Aveline; Do, Hoa Quynh; Myers, Caitlyn; Muthusubramanian, Archana; Sutton, Roger Bryan; Wylie, Benjamin J; Cornwall, Gail A

2017-06-29

Amyloids are traditionally considered pathological protein aggregates that play causative roles in neurodegenerative disease, diabetes and prionopathies. However, increasing evidence indicates that in many biological systems nonpathological amyloids are formed for functional purposes. In this review, we will specifically describe amyloids that carry out biological roles in sexual reproduction including the processes of gametogenesis, germline specification, sperm maturation and fertilization. Several of these functional amyloids are evolutionarily conserved across several taxa, including human, emphasizing the critical role amyloids perform in reproduction. Evidence will also be presented suggesting that, if altered, some functional amyloids may become pathological.

Functional amyloids in bacteria.

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Romero, Diego; Kolter, Roberto

2014-06-01

The term amyloidosis is used to refer to a family of pathologies altering the homeostasis of human organs. Despite having a name that alludes to starch content, the amyloid accumulations are made up of proteins that polymerize as long and rigid fibers. Amyloid proteins vary widely with respect to their amino acid sequences but they share similarities in their quaternary structure; the amyloid fibers are enriched in β-sheets arranged perpendicular to the axis of the fiber. This structural feature provides great robustness, remarkable stability, and insolubility. In addition, amyloid proteins specifically stain with certain dyes such as Congo red and thioflavin-T. The aggregation into amyloid fibers, however, it is not restricted to pathogenic processes, rather it seems to be widely distributed among proteins and polypeptides. Amyloid fibers are present in insects, fungi and bacteria, and they are important in maintaining the homeostasis of the organism. Such findings have motivated the use of the term "functional amyloid" to differentiate these amyloid proteins from their toxic siblings. This review focuses on systems that have evolved in bacteria that control the expression and assembly of amyloid proteins on cell surfaces, such that the robustness of amyloid proteins are used towards a beneficial end. Copyright© by the Spanish Society for Microbiology and Institute for Catalan Studies.

Calcium signaling and amyloid toxicity in Alzheimer disease.

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Demuro, Angelo; Parker, Ian; Stutzmann, Grace E

2010-04-23

Intracellular Ca(2+) signaling is fundamental to neuronal physiology and viability. Because of its ubiquitous roles, disruptions in Ca(2+) homeostasis are implicated in diverse disease processes and have become a major focus of study in multifactorial neurodegenerative diseases such as Alzheimer disease (AD). A hallmark of AD is the excessive production of beta-amyloid (Abeta) and its massive accumulation in amyloid plaques. In this minireview, we highlight the pathogenic interactions between altered cellular Ca(2+) signaling and Abeta in its different aggregation states and how these elements coalesce to alter the course of the neurodegenerative disease. Ca(2+) and Abeta intersect at several functional levels and temporal stages of AD, thereby altering neurotransmitter receptor properties, disrupting membrane integrity, and initiating apoptotic signaling cascades. Notably, there are reciprocal interactions between Ca(2+) pathways and amyloid pathology; altered Ca(2+) signaling accelerates Abeta formation, whereas Abeta peptides, particularly in soluble oligomeric forms, induce Ca(2+) disruptions. A degenerative feed-forward cycle of toxic Abeta generation and Ca(2+) perturbations results, which in turn can spin off to accelerate more global neuropathological cascades, ultimately leading to synaptic breakdown, cell death, and devastating memory loss. Although no cause or cure is currently known, targeting Ca(2+) dyshomeostasis as an underlying and integral component of AD pathology may result in novel and effective treatments for AD.

High molecular weight of polysaccharides from Hericium erinaceus against amyloid beta-induced neurotoxicity.

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Cheng, Jai-Hong; Tsai, Chia-Ling; Lien, Yi-Yang; Lee, Meng-Shiou; Sheu, Shyang-Chwen

2016-06-07

Hericium erinaceus (HE) is a well-known mushroom in traditional Chinese food and medicine. HE extracts from the fruiting body and mycelia not only exhibit immunomodulatory, antimutagenic and antitumor activity but also have neuroprotective properties. Here, we purified HE polysaccharides (HEPS), composed of two high molecular weight polysaccharides (1.7 × 10(5) Da and 1.1 × 10(5) Da), and evaluated their protective effects on amyloid beta (Aβ)-induced neurotoxicity in rat pheochromocytoma PC12 cells. HEPS were prepared and purified using a 95 % ethanol extraction method. The components of HEPS were analyzed and the molecular weights of the polysaccharides were determined using high-pressure liquid chromatography (HPLC). The neuroprotective effects of the polysaccharides were evaluated through a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and an MTT assay and by quantifying reactive oxygen species (ROS) and mitochondrial membrane potentials (MMP) of Aβ-induced neurotoxicity in cells. Our results showed that 250 μg/ml HEPS was harmless and promoted cell viability with 1.2 μM Aβ treatment. We observed that the free radical scavenging rate exceeded 90 % when the concentration of HEPS was higher than 1 mg/mL in cells. The HEPS decreased the production of ROS from 80 to 58 % in a dose-dependent manner. Cell pretreatment with 250 μg/mL HEPS significantly reduced Aβ-induced high MMPs from 74 to 51 % and 94 to 62 % at 24 and 48 h, respectively. Finally, 250 μg/mL of HEPS prevented Aβ-induced cell shrinkage and nuclear degradation of PC12 cells. Our results demonstrate that HEPS exhibit antioxidant and neuroprotective effects on Aβ-induced neurotoxicity in neurons.

Exploring the early steps of aggregation of amyloid-forming peptide KFFE

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Wei Guanghong [Departement de Physique and Regroupement Quebecois sur les Materiaux de Pointe, Universite de Montreal, CP 6128, succursale centre-ville, Montreal, QC, H3C 3J7 (Canada); Mousseau, Normand [Departement de Physique and Regroupement Quebecois sur les Materiaux de Pointe, Universite de Montreal, CP 6128, succursale centre-ville, Montreal, QC, H3C 3J7 (Canada); Derreumaux, Philippe [Laboratoire de Biochimie, Theorique, UPR 9080 CNRS, IBPC, Universite Paris 7 Denis-Diderot, 13 rue Pierre et Marie Curie, 75005 Paris (France)

2004-11-10

It has been shown recently that even a tetrapeptide can form amyloid fibrils sharing all the characteristics of amyloid fibrils built from large proteins. Recent experimental studies also suggest that the toxicity observed in several neurodegenerative diseases, such as Alzheimer's disease and Creutzfeldt-Jakob disease, is not only related to the mature fibrils themselves, but also to the soluble oligomers formed early in the process of fibrillogenesis. This raises the interest in studying the early steps of the aggregation process. Although fibril formation follows the nucleation-condensation process, characterized by the presence of lag phase, the exact pathways remain to be determined. In this study, we used the activation-relaxation technique and a generic energy model to explore the process of self-assembly and the structures of the resulting aggregates of eight KFFE peptides. Our simulations show, starting from different states with a preformed antiparallel dimer, that eight chains can self-assemble to adopt, with various orientations, four possible distant oligomeric well-aligned structures of similar energy. Two of these structures show a double-layer {beta}-sheet organization, in agreement with the structure of amyloid fibrils as observed by x-ray diffraction; another two are mixtures of dimers and trimers. Our results also suggest that octamers are likely to be below the critical size for nucleation of amyloid fibrils for small peptides.

Treatment of alcohol dependence in patients with co-morbid major depressive disorder – predictors for the outcomes with memantine and escitalopram medication

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Lönnqvist Jouko

2008-10-01

Full Text Available Abstract Background Alcohol dependence comorbid with major depressive disorder poses a major challenge in the clinical setting. The results in the treatment with selective serotonin re-uptake inhibitors have been conflicting. Thus, we compared in alcohol-dependent patients with co-morbid major depressive disorder the selective serotonin re-uptake inhibitor escitalopram to a compound that acts on different transporter system and may reduce craving, the glutamate receptor antagonist memantine. Methods Eighty alcohol-dependent patients comorbid with major depressive disorder in municipal alcohol clinics were randomized 1:1 to receive memantine 20 mg or escitalopram 20 mg in a double-blind manner. During the 26-week study period patients continued their routine treatment at the clinics. Abstinence was not required but encouraged. The patients attended visits weekly during the first month, and then at 3 and at 6 months. Outcome measures were Alcohol Use Disorders Identification Test (AUDIT, Obsessive Compulsive Drinking Scale (OCDS and Drinking Diary. Results The completion rate was high in both groups, especially among the patients who had been abstinent at the beginning of the study. However, among those patients who were not abstinent at baseline, 47% in both groups discontinued the study. Numbers of abstinent days were high in both groups throughout the study. Alcohol consumption measured by the AUDIT QF (quantity-frequency score was significantly reduced in both groups, as was the craving for alcohol measured by the OCDS. Early age at first alcohol intoxication predicted poor treatment outcomes in patients treated with escitalopram, and the same was seen with the early onset of the first depressive episode. The same predictive effects were not found in patients treated with memantine. Conclusion Our results indicate that both memantine and escitalopram are useful adjunct medications for the treatment of alcohol dependence co-morbid with major

Antiamnesic Effect of Broccoli (Brassica oleracea var. italica) Leaves on Amyloid Beta (Aβ)1-42-Induced Learning and Memory Impairment.

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Park, Seon Kyeong; Ha, Jeong Su; Kim, Jong Min; Kang, Jin Yong; Lee, Du Sang; Guo, Tian Jiao; Lee, Uk; Kim, Dae-Ok; Heo, Ho Jin

2016-05-04

To examine the antiamnesic effects of broccoli (Brassica oleracea var. italica) leaves, we performed in vitro and in vivo tests on amyloid beta (Aβ)-induced neurotoxicity. The chloroform fraction from broccoli leaves (CBL) showed a remarkable neuronal cell-protective effect and an inhibition against acetylcholinesterase (AChE). The ameliorating effect of CBL on Aβ1-42-induced learning and memory impairment was evaluated by Y-maze, passive avoidance, and Morris water maze tests. The results indicated improving cognitive function in the CBL group. After the behavioral tests, antioxidant effects were detected by superoxide dismutase (SOD), oxidized glutathione (GSH)/total GSH, and malondialdehyde (MDA) assays, and inhibition against AChE was also presented in the brain. Finally, oxo-dihydroxy-octadecenoic acid (oxo-DHODE) and trihydroxy-octadecenoic acid (THODE) as main compounds were identified by quadrupole time-of-flight ultraperformance liquid chromatography (Q-TOF UPLC-MS) analysis. Therefore, our studies suggest that CBL could be used as a natural resource for ameliorating Aβ1-42-induced learning and memory impairment.

Effect of Memantine on Serum Levels of Neuron-Specific Enolase and on the Glasgow Coma Scale in Patients With Moderate Traumatic Brain Injury.

Science.gov (United States)

Mokhtari, Majid; Nayeb-Aghaei, Hossein; Kouchek, Mehran; Miri, Mir Mohammad; Goharani, Reza; Amoozandeh, Arash; Akhavan Salamat, Sina; Sistanizad, Mohammad

2018-01-01

Traumatic brain injury (TBI) is a major cause of disability and death globally. Despite significant progress in neuromonitoring and neuroprotection, pharmacological interventions have failed to generate favorable results. We examined the effect of memantine on serum levels of neuron-specific enolase (NSE), a marker of neuronal damage, and the Glasgow Coma Scale (GCS) in patients with moderate TBI. Patients were randomly assigned to the control group (who received standard TBI management) and the treatment group (who, alongside their standard management, received enteral memantine 30 mg twice daily for 7 days). Patients' clinical data, GCS, findings of head computed tomography, and serum NSE levels were collected during the study. Forty-one patients were randomized into the control and treatment groups, 19 and 22 patients respectively. Baseline characteristics and serum NSE levels were not significantly different between the 2 groups. The mean serum NSE levels for the memantine and the control groups on day 3 were 7.95 ± 2.86 and 12.33 ± 7.09 ng/mL, respectively (P = .05), and on day 7 were 5.03 ± 3.25 and 10.04 ± 5.72 ng/mL, respectively (P = .003). The mean GCS on day 3 was 12.3 ± 2.0 and 10.9 ± 1.9 in the memantine and control groups, respectively (P = .03). Serum NSE levels and GCS changes were negatively correlated (r = -0.368, P = .02). Patients with moderate TBI who received memantine had significantly reduced serum NSE levels by day 7 and marked improvement in their GCS scores on day 3 of the study. © 2017, The American College of Clinical Pharmacology.

Hubungan Konsumsi Antioksidan dari Makanan dengan Beta-Amyloid Plasma sebagai Penanda Gangguan Fungsi Kognitif pada Lanjut Usia

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Ratna D Siregar

2015-01-01

Full Text Available AbstrakPenelitian ini bertujuan untuk mengetahui hubungan antara konsumsi vitamin A, vitamin C, vitamin E, zink dan selenium dari makanan dengan fungsi kognitif pada lanjut usia. Metoda penelitian adalah cross sectional study terhadap 145 lansia umur ≥ 60 tahun, pada dua kecamatan di Kabupaten Lima Puluh Kota Sumatra Barat. Wawancara konsumsi antioksidan menggunakan Food Frequency Questionnaires (FFQ, fungsi kognitif diperiksa dengan Montreal Cognitive Assesment versi Indonesia (MoCA-Ina, Aβ40 dan Aβ42 plasma diperiksa dengan metode ELISA. Data dianalisis menggunakan uji Mann-Whitney dan Chi-square. Pada hasil penelitian ditemukan 83 orang (57,2% lansia yang mengalami gangguan fungsi kognitif. Terdapat hubungan yang signifikan antara konsumsi vitamin C (p<0,049 dan vitamin E (p<0,037 tetapi tidak terdapat hubungan signifikan antara vitamin A, zink dan selenium dengan fungsi kognitif. Tidak terdapat hubungan yang signifikan antara konsumsi antioksidan dengan tingkat Aβ40 dan Aβ42 serta antara tingkat Aβ40 dan Aβ42 dengan fungsi kognitif masing-masing (p<0,058 dan p<0,350. Kesimpulan hasil penelitian ini didapatkan hubungan antara konsumsi vitamin C dan vitamin E dari makanan dengan fungsi kognitif. Tetapi tidak terdapat hubungan antara konsumsi antioksidan dengan Aβ40 dan Aβ42 plasma dan Aβ40 dan Aβ42 dengan fungsi kognitif.Kata kunci: antioksidan, beta-amyloid, fungsi kognitif, lanjut usiaAbstractThe objective of this study was to determine the relationship between consumption of vitamin A, vitamin C, vitamin E, zinc and selenium from foods with cognitive function in elderly. This was a cross-sectional study that was conducted to 145 elderly with age ≥ 60 years, in two districts in West Sumatra, in Lima Puluh Kota city. Interview antioxidant intake using a Food Frequency Questionnaires (FFQ, cognitive function was checked by Montreal Cognitive Assessment Indonesian version (MoCA-Ina, plasma Aβ40 dan Aβ42 were examined by ELISA

Beta-amyloid deposition and cognitive function in patients with major depressive disorder with different subtypes of mild cognitive impairment: 18F-florbetapir (AV-45/Amyvid) PET study

International Nuclear Information System (INIS)

Wu, Kuan-Yi; Liu, Chia-Yih; Chen, Chia-Hsiang; Lee, Chin-Pang; Chen, Cheng-Sheng; Hsiao, Ing-Tsung; Hsieh, Chia-Ju; Yen, Tzu-Chen; Lin, Kun-Ju

2016-01-01

The objective of this study was to evaluate the amyloid burden, as assessed by 18 F-florbetapir (AV-45/Amyvid) positron emission tomography PET, in patients with major depressive disorder (MDD) with different subtypes of mild cognitive impairment (MCI) and the relationship between amyloid burden and cognition in MDD patients. The study included 55 MDD patients without dementia and 21 healthy control subjects (HCs) who were assessed using a comprehensive cognitive test battery and 18 F-florbetapir PET imaging. The standardized uptake value ratios (SUVR) in eight cortical regions using the whole cerebellum as reference region were determined and voxel-wise comparisons between the HC and MDD groups were performed. Vascular risk factors, serum homocysteine level and the apolipoprotein E (ApoE) genotype were also determined. Among the 55 MDD patients, 22 (40.0 %) had MCI, 12 (21.8 %) non-amnestic MCI (naMCI) and 10 (18.2 %) amnestic MCI (aMCI). The MDD patients with aMCI had the highest relative 18 F-florbetapir uptake in all cortical regions, and a significant difference in relative 18 F-florbetapir uptake was found in the parietal region as compared with that in naMCI subjects (P < 0.05) and HCs (P < 0.01). Voxel-wise analyses revealed significantly increased relative 18 F-florbetapir uptake in the MDD patients with aMCI and naMCI in the frontal, parietal, temporal and occipital areas (P < 0.005). The global cortical SUVR was significantly negatively correlated with MMSE score (r = -0.342, P = 0.010) and memory function (r = -0.328, P = 0.015). The negative correlation between the global SUVR and memory in the MDD patients remained significant in multiple regression analyses that included age, educational level, ApoE genotype, and depression severity (β = -3.607, t = -2.874, P = 0.006). We found preliminary evidence of brain beta-amyloid deposition in MDD patients with different subtypes of MCI. Our findings in MDD patients support the hypothesis that a higher

18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial

DEFF Research Database (Denmark)

Vandenberghe, Rik; Van Laere, Koen; Ivanoiu, Adrian

2010-01-01

The most widely studied positron emission tomography ligand for in vivo beta-amyloid imaging is (11)C-Pittsburgh compound B ((11)C-PIB). Its availability, however, is limited by the need for an on-site cyclotron. Validation of the (18)F-labeled PIB derivative (18)F-flutemetamol could significantl...

Memantine, an antagonist of the NMDA glutamate receptor, affects cell proliferation, differentiation and the intracellular cycle and induces apoptosis in Trypanosoma cruzi.

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Flávia Silva Damasceno

2014-02-01

Full Text Available Chagas' disease is caused by the protozoan parasite Trypanosoma cruzi and affects approximately 10 million people in endemic areas of Mexico and Central and South America. Currently available chemotherapies are limited to two compounds: Nifurtimox and Benznidazole. Both drugs reduce the symptoms of the disease and mortality among infected individuals when used during the acute phase, but their efficacy during the chronic phase (during which the majority of cases are diagnosed remains controversial. Moreover, these drugs have several side effects. The aim of this study was to evaluate the effect of Memantine, an antagonist of the glutamate receptor in the CNS of mammals, on the life cycle of T. cruzi. Memantine exhibited a trypanocidal effect, inhibiting the proliferation of epimastigotes (IC50 172.6 µM. Furthermore, this compound interfered with metacyclogenesis (approximately 30% reduction and affected the energy metabolism of the parasite. In addition, Memantine triggered mechanisms that led to the apoptosis-like cell death of epimastigotes, with extracellular exposure of phosphatidylserine, increased production of reactive oxygen species, decreased ATP levels, increased intracellular Ca(2+ and morphological changes. Moreover, Memantine interfered with the intracellular cycle of the parasite, specifically the amastigote stage (IC50 31 µM. Interestingly, the stages of the parasite life cycle that require more energy (epimastigote and amastigote were more affected as were the processes of differentiation and cell invasion.

The effects of a single memantine treatment on behavioral alterations associated with binge alcohol exposure in neonatal rats.

Science.gov (United States)

Idrus, Nirelia M; McGough, Nancy N H; Spinetta, Michael J; Thomas, Jennifer D; Riley, Edward P

2011-01-01

The third trimester in human fetal development represents a critical time of brain maturation referred to as the "brain growth spurt". This period occurs in rats postnatally, and exposure to ethanol during this time can increase the risk of impairments on a variety of cognitive and motor tasks. It has been proposed that one potential mechanism for the teratogenic effects of ethanol is NMDA receptor-mediated excitotoxicity during periods of ethanol withdrawal. In neonatal rats, antagonism of NMDA receptors during ethanol withdrawal, with drugs such as MK-801 and eliprodil, has been shown to mitigate some of the behavioral deficits induced by developmental ethanol exposure. The current study examined whether memantine, an NMDA receptor antagonist and a drug used clinically in Alzheimer's patients, would attenuate impairments associated with binge ethanol exposure in neonatal rats. On postnatal day 6, rats were exposed to 6 g/kg ethanol via intubation with controls receiving an isocaloric maltose dextrin solution. Twenty-one hours following the ethanol binge, rats received intraperitoneal injections of memantine at 0, 10, 15, or 20 mg/kg. Ethanol's teratogenic effects were assessed using multiple behavioral tasks: open field activity, parallel bars and spatial discrimination reversal learning. Ethanol-treated rats were overactive in the open field and were impaired on both reversal learning and motor performance. Administration of 15 or 20 mg/kg memantine during withdrawal significantly attenuated ethanol's adverse effects on motor coordination, but did not significantly alter activity levels or improve the spatial learning deficits associated with neonatal alcohol exposure. These results indicate that a single memantine administration during ethanol withdrawal can mitigate motor impairments but not spatial learning impairments or overactivity observed following a binge ethanol exposure during development in the rat. Copyright © 2011 Elsevier Inc. All rights reserved.

Administration of memantine during withdrawal mitigates overactivity and spatial learning impairments associated with neonatal alcohol exposure in rats.

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Idrus, Nirelia M; McGough, Nancy N H; Riley, Edward P; Thomas, Jennifer D

2014-02-01

Prenatal alcohol exposure can disrupt central nervous system development, manifesting as behavioral deficits that include motor, emotional, and cognitive dysfunction. Both clinical and animal studies have reported binge drinking during development to be highly correlated with an increased risk of fetal alcohol spectrum disorders (FASD). We hypothesized that binge drinking may be especially damaging because it is associated with episodes of alcohol withdrawal. Specifically, we have been investigating the possibility that NMDA receptor-mediated excitotoxicity occurs during alcohol withdrawal and contributes to developmental alcohol-related neuropathology. Consistent with this hypothesis, administration of the NMDA receptor antagonists MK-801 or eliprodil during withdrawal attenuates behavioral alterations associated with early alcohol exposure. In this study, we investigated the effects of memantine, a clinically used NMDA receptor antagonist, on minimizing ethanol-induced overactivity and spatial learning deficits. Sprague-Dawley pups were exposed to 6.0 g/kg ethanol via intubation on postnatal day (PD) 6, a period of brain development that models late gestation in humans. Controls were intubated with a calorically matched maltose solution. During withdrawal, 24 and 36 hours after ethanol exposure, subjects were injected with a total of either 0, 20, or 30 mg/kg memantine. The subjects' locomotor levels were recorded in open field activity monitors on PDs 18 to 21 and on a serial spatial discrimination reversal learning task on PDs 40 to 43. Alcohol exposure induced overactivity and impaired performance in spatial learning. Memantine administration significantly attenuated the ethanol-associated behavioral alterations in a dose-dependent manner. Thus, memantine may be neuroprotective when administered during ethanol withdrawal. These data have important implications for the treatment of EtOH's neurotoxic effects and provide further support that ethanol withdrawal

Memantine Can Reduce Ethanol-Induced Caspase-3 Activity and Apoptosis in H4 Cells by Decreasing Intracellular Calcium.

Science.gov (United States)

Wang, Xiaolong; Chen, Jiajun; Wang, Hongbo; Yu, Hao; Wang, Changliang; You, Jiabin; Wang, Pengfei; Feng, Chunmei; Xu, Guohui; Wu, Xu; Zhao, Rui; Zhang, Guohua

2017-08-01

Caspase-3 activation and apoptosis are associated with various neurodegenerative disorders. Calcium activation is an important factor in promoting apoptosis. We, therefore, assessed the role of intracellular calcium in ethanol-induced activation of caspase-3 in H4 human neuroglioma cells and the protective effect of the NMDA receptor antagonist, memantine, on ethanol-induced apoptosis in H4 cells. H4 cells were treated with 100 mM EtOH (in culture medium) for 2 days. For interaction studies, cells were treated with memantine (4 μM), EDTA (1 mM), or BAPTA-AM (10 μM) before treatment with EtOH. Knockdown of the gene encoding the NR1 subunit of the NMDA receptor was performed using RNAi. Apoptosis was detected by Annexin V-FITC/PI staining and flow cytometry. Cell viability was detected using an MTS cell proliferation kit. Fluorescence dual wavelength spectrophotometry was used to determine the intracellular calcium concentration. The levels of NR1, caspase-3, IP3R1, and SERCA1 proteins were detected by western blotting. NR1, IP3R1, and SERCA1 mRNA levels were detected by qPCR. We observed increased expression of NR1, IP3R1, SERCA1, and increased intracellular levels of calcium ions in H4 cells exposed to ethanol. In addition, the calcium chelators, EDTA and BAPTA, and RNAi disruption of the NMDA receptor reduced ethanol-induced caspase-3 activation in H4 cells. Memantine treatment reduced the ethanol-induced increase of intracellular calcium, caspase-3 activation, apoptosis, and the ethanol-induced decrease in cell viability. Our results indicate that ethanol-induced caspase-3 activation and apoptosis are likely to be dependent on cytosolic calcium levels and that they can be reduced by memantine treatment.

Iron Biochemistry is Correlated with Amyloid Plaque Morphology in an Established Mouse Model of Alzheimer's Disease.

Science.gov (United States)

Telling, Neil D; Everett, James; Collingwood, Joanna F; Dobson, Jon; van der Laan, Gerrit; Gallagher, Joseph J; Wang, Jian; Hitchcock, Adam P

2017-10-19

A signature characteristic of Alzheimer's disease (AD) is aggregation of amyloid-beta (Aβ) fibrils in the brain. Nevertheless, the links between Aβ and AD pathology remain incompletely understood. It has been proposed that neurotoxicity arising from aggregation of the Aβ 1-42 peptide can in part be explained by metal ion binding interactions. Using advanced X-ray microscopy techniques at sub-micron resolution, we investigated relationships between iron biochemistry and AD pathology in intact cortex from an established mouse model over-producing Aβ. We found a direct correlation of amyloid plaque morphology with iron, and evidence for the formation of an iron-amyloid complex. We also show that iron biomineral deposits in the cortical tissue contain the mineral magnetite, and provide evidence that Aβ-induced chemical reduction of iron could occur in vivo. Our observations point to the specific role of iron in amyloid deposition and AD pathology, and may impact development of iron-modifying therapeutics for AD. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

A semi-automated motion-tracking analysis of locomotion speed in the C. elegans transgenics overexpressing beta-amyloid in neurons

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Kevin eMachino

2014-07-01

Full Text Available Multi-Worm Tracker (MWT is a real-time computer vision system that can simultaneously quantify motional patterns of multiple worms. MWT provides several behavioral parameters, including analysis of accurate real-time locomotion speed in the nematode, Caenorhabditis elegans. Here, we determined locomotion speed of the Alzheimer’s disease (AD transgenic strain that over-expresses human beta-amyloid1-42 (Aβ in the neurons. The MWT analysis showed that the AD strain logged a slower average speed than the wild type worms. The results may be consistent with the observation that the AD patients with dementia tend to show deficits in physical activities, including frequent falls. The AD strain showed reduced ability of the eggs to hatch and slowed hatching of the eggs. Thus, over-expression of Aβ in neurons causes negative effects on locomotion and hatchability. This study sheds light on new examples of detrimental effects that Aβ deposits can exhibit using C. elegans as a model system. The information gathered from this study indicates that the motion tracking analysis is a cost-effective, efficient way to assess the deficits of Aβ over-expression in the C. elegans system.

Synaptic transmission block by presynaptic injection of oligomeric amyloid beta

Science.gov (United States)

Moreno, Herman; Yu, Eunah; Pigino, Gustavo; Hernandez, Alejandro I.; Kim, Natalia; Moreira, Jorge E.; Sugimori, Mutsuyuki; Llinás, Rodolfo R.

2009-01-01

Early Alzheimer's disease (AD) pathophysiology is characterized by synaptic changes induced by degradation products of amyloid precursor protein (APP). The exact mechanisms of such modulation are unknown. Here, we report that nanomolar concentrations of intraaxonal oligomeric (o)Aβ42, but not oAβ40 or extracellular oAβ42, acutely inhibited synaptic transmission at the squid giant synapse. Further characterization of this phenotype demonstrated that presynaptic calcium currents were unaffected. However, electron microscopy experiments revealed diminished docked synaptic vesicles in oAβ42-microinjected terminals, without affecting clathrin-coated vesicles. The molecular events of this modulation involved casein kinase 2 and the synaptic vesicle rapid endocytosis pathway. These findings open the possibility of a new therapeutic target aimed at ameliorating synaptic dysfunction in AD. PMID:19304802

Amyloid beta-peptide(25-35) changes [Ca2+] in hippocampal neurons

DEFF Research Database (Denmark)

Mogensen, Helle Smidt; Beatty, D M; Morris, S J

1998-01-01

of A beta(25-35) on [Ca2+]i and intracellular H+ concentration ([H+]i) in single hippocampal neurons by real time fluorescence imaging using the Ca(2+)- and H(+)-specific ratio dyes, indo-1 and SNARF-1. Incubation of these cultures with A beta(25-35) for 3-12 days in vitro increased [Ca2+]i and [H......+]i in large, NMDA-responsive neurons....

Beta-amyloid deposition and cognitive function in patients with major depressive disorder with different subtypes of mild cognitive impairment: {sup 18}F-florbetapir (AV-45/Amyvid) PET study

Energy Technology Data Exchange (ETDEWEB)

Wu, Kuan-Yi; Liu, Chia-Yih; Chen, Chia-Hsiang; Lee, Chin-Pang [Chang Gung Memorial Hospital and Chang Gung University, Department of Psychiatry, Tao-Yuan (China); Chen, Cheng-Sheng [Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Department of Psychiatry, Kaohsiung (China); Hsiao, Ing-Tsung; Hsieh, Chia-Ju; Yen, Tzu-Chen; Lin, Kun-Ju [Chang Gung Memorial Hospital, Department of Nuclear Medicine and Molecular Imaging Center, Kuei Shan Hsiang, Taoyuan (China); Chang Gung University, Department of Medical Imaging and Radiological Sciences and Healthy Aging Research Center, Tao-Yuan (China)

2016-06-15

The objective of this study was to evaluate the amyloid burden, as assessed by {sup 18}F-florbetapir (AV-45/Amyvid) positron emission tomography PET, in patients with major depressive disorder (MDD) with different subtypes of mild cognitive impairment (MCI) and the relationship between amyloid burden and cognition in MDD patients. The study included 55 MDD patients without dementia and 21 healthy control subjects (HCs) who were assessed using a comprehensive cognitive test battery and {sup 18}F-florbetapir PET imaging. The standardized uptake value ratios (SUVR) in eight cortical regions using the whole cerebellum as reference region were determined and voxel-wise comparisons between the HC and MDD groups were performed. Vascular risk factors, serum homocysteine level and the apolipoprotein E (ApoE) genotype were also determined. Among the 55 MDD patients, 22 (40.0 %) had MCI, 12 (21.8 %) non-amnestic MCI (naMCI) and 10 (18.2 %) amnestic MCI (aMCI). The MDD patients with aMCI had the highest relative {sup 18}F-florbetapir uptake in all cortical regions, and a significant difference in relative {sup 18}F-florbetapir uptake was found in the parietal region as compared with that in naMCI subjects (P < 0.05) and HCs (P < 0.01). Voxel-wise analyses revealed significantly increased relative {sup 18}F-florbetapir uptake in the MDD patients with aMCI and naMCI in the frontal, parietal, temporal and occipital areas (P < 0.005). The global cortical SUVR was significantly negatively correlated with MMSE score (r = -0.342, P = 0.010) and memory function (r = -0.328, P = 0.015). The negative correlation between the global SUVR and memory in the MDD patients remained significant in multiple regression analyses that included age, educational level, ApoE genotype, and depression severity (β = -3.607, t = -2.874, P = 0.006). We found preliminary evidence of brain beta-amyloid deposition in MDD patients with different subtypes of MCI. Our findings in MDD patients support the

Cerebral amyloid angiopathy, blood-brain barrier disruption and amyloid accumulation in SAMP8 mice.

Science.gov (United States)

del Valle, Jaume; Duran-Vilaregut, Joaquim; Manich, Gemma; Pallàs, Mercè; Camins, Antoni; Vilaplana, Jordi; Pelegrí, Carme

2011-01-01

Cerebrovascular dysfunction and β-amyloid peptide deposition on the walls of cerebral blood vessels might be an early event in the development of Alzheimer's disease. Here we studied the time course of amyloid deposition in blood vessels and blood-brain barrier (BBB) disruption in the CA1 subzone of the hippocampus of SAMP8 mice and the association between these two variables. We also studied the association between the amyloid deposition in blood vessels and the recently described amyloid clusters in the parenchyma, as well as the association of these clusters with vessels in which the BBB is disrupted. SAMP8 mice showed greater amyloid deposition in blood vessels than age-matched ICR-CD1 control mice. Moreover, at 12 months of age the number of vessels with a disrupted BBB had increased in both strains, especially SAMP8 animals. At this age, all the vessels with amyloid deposition showed BBB disruption, but several capillaries with an altered BBB showed no amyloid on their walls. Moreover, amyloid clusters showed no spatial association with vessels with amyloid deposition, nor with vessels in which the BBB had been disrupted. Finally, we can conclude that vascular amyloid deposition seems to induce BBB alterations, but BBB disruption may also be due to other factors. Copyright © 2011 S. Karger AG, Basel.

IS BRAIN AMYLOID PRODUCTION A CAUSE OR A RESULT OF DEMENTIA OF THE ALZHEIMER TYPE?

Science.gov (United States)

Ala, Tom; Patrylo, Peter R.; Brewer, Gregory J.; Yan, Xiao-Xin

2011-01-01

The amyloid cascade hypothesis has guided much of research into Alzheimer disease (AD) over the last 25 years. We argue that the hypothesis of beta amyloid (Aβ) as the primary cause of dementia may not be fully correct. Rather, we propose that decline in brain metabolic activity, which is tightly linked to synaptic activity, actually underlies both the cognitive decline and the deposition of Aβ. Aβ may further exacerbate metabolic decline and result in a downward spiral of cognitive function, leading to dementia. This novel interpretation can tie the disparate risk factors for dementia to a unifying hypothesis and present a roadmap for interventions to decrease the prevalence of dementia in the elderly population. PMID:20847431

Beneficial characteristics of mechanically functional amyloid fibrils evolutionarily preserved in natural adhesives

Energy Technology Data Exchange (ETDEWEB)

Mostaert, Anika S; Jarvis, Suzanne P [Centre for Research on Adaptive Nanostructures and Nanodevices, Trinity College Dublin, Dublin 2 (Ireland)

2007-01-31

While biological systems are notorious for their complexity, nature sometimes displays mechanisms that are elegant in their simplicity. We have recently identified such a mechanism at work to enhance the mechanical properties of certain natural adhesives. The mechanism is simple because it utilizes a non-specific protein folding and subsequent aggregation process, now thought to be generic for any polypeptide under appropriate conditions. This non-specific folding forms proteinaceous crossed {beta}-sheet amyloid fibrils, which are usually associated with neurodegenerative diseases. Here we show evidence for the beneficial mechanical characteristics of these fibrils discovered in natural adhesives. We suggest that amyloid protein quaternary structures should be considered as a possible generic mechanism for mechanical strength in a range of natural adhesives and other natural materials due to their many beneficial mechanical features and apparent ease of self-assembly.

Salvianolic acid B, an antioxidant from Salvia miltiorrhiza, prevents A beta(25-35)-induced reduction in BPRP in PC12 cells

NARCIS (Netherlands)

Lin, Yan-Hua; Liu, Ai-Hua; Wu, Hong-Li; Westenbroek, Christel; Song, Qian-Liu; Yu, He-Ming; Ter Horst, Gert J.; Li, Xue-Jun; Li, Xiang-yi

2006-01-01

Several lines of evidence support that beta-amyloid (A beta)-induced neurotoxicity is mediated through the generation of reactive oxygen species (ROS) and elevation of intracellular calcium. Salvianolic acid B (Sal B), the major and most active anti-oxidant from Salvia miltiorrhiza. protects diverse

Intracellular trafficking of the β-secretase and processing of amyloid precursor protein.

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Zhi, Pei; Chia, Pei Zhi Cheryl; Chia, Cheryl; Gleeson, Paul A

2011-09-01

The main component of the amyloid plaques found in the brains of those with Alzheimer's disease (AD) is a polymerized form of the β-amyloid peptide (Aβ) and is considered to play a central role in the pathogenesis of this neurodegenerative disorder. Aβ is derived from the proteolytic processing of the amyloid precursor protein (APP). Beta site APP-cleaving enzyme, BACE1 (also known as β-secretase) is a membrane-bound aspartyl protease responsible for the initial step in the generation of Aβ peptide and is thus a prime target for therapeutic intervention. Substantive evidence now indicates that the processing of APP by BACE1 is regulated by the intracellular sorting of the enzyme and, moreover, perturbations in these intracellular trafficking pathways have been linked to late-onset AD. In this review, we highlight the recent advances in the understanding of the regulation of the intracellular sorting of BACE1 and APP and illustrate why the trafficking of these cargos represent a key issue for understanding the membrane-mediated events associated with the generation of the neurotoxic Aβ products in AD. Copyright © 2011 International Union of Biochemistry and Molecular Biology, Inc.

Human Islet Amyloid Polypeptide Transgenic Mice: In Vivo and Ex Vivo Models for the Role of hIAPP in Type 2 Diabetes Mellitus

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J. W. M. Höppener

2008-01-01

Full Text Available Human islet amyloid polypeptide (hIAPP, a pancreatic islet protein of 37 amino acids, is the main component of islet amyloid, seen at autopsy in patients with type 2 diabetes mellitus (DM2. To investigate the roles of hIAPP and islet amyloid in DM2, we generated transgenic mice expressing hIAPP in their islet beta cells. In this study, we found that after a long-term, high-fat diet challenge islet amyloid was observed in only 4 of 19 hIAPP transgenic mice. hIAPP transgenic females exhibited severe glucose intolerance, which was associated with a downregulation of GLUT-2 mRNA expression. In isolated islets from hIAPP males cultured for 3 weeks on high-glucose medium, the percentage of amyloid containing islets increased from 5.5% to 70%. This ex vivo system will allow a more rapid, convenient, and specific study of factors influencing islet amyloidosis as well as of therapeutic strategies to interfere with this pathological process.

Regional correlations between [11C]PIB PET and post-mortem burden of amyloid-beta pathology in a diverse neuropathological cohort

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Sang Won Seo

2017-01-01

Full Text Available Imaging-pathological correlation studies show that in vivo amyloid-β (Aβ positron emission tomography (PET strongly predicts the presence of significant Aβ pathology at autopsy. We sought to determine whether regional PiB-PET uptake would improve sensitivity for amyloid detection in comparison with global measures (experiment 1, and to estimate the relative contributions of different Aβ aggregates to in vivo PET signal (experiment 2. In experiment 1, 54 subjects with [11C] PiB-PET during life and postmortem neuropathologic examination (85.2% with dementia, interval from PET to autopsy 3.1 ± 1.9 years were included. We assessed Thal amyloid phase (N = 36 and CERAD score (N = 54 versus both global and regional PiB SUVRs. In experiment 2 (N = 42, PiB SUVR and post-mortem amyloid β burden was analyzed in five customized regions of interest matching regions sampled at autopsy. We assessed the relative contribution of neuritic plaques (NPs, diffuse plaques (DPs and cerebral amyloid angiopathy (CAA to regional PIB SUVR using multi-linear regression. In experiment 1, there were no differences in Area Under the Curve for amyloid phase ≥ A2 and CERAD score ≥ C2 between global and highest regional PiB SUVR (p = 0.186 and 0.230. In experiment 2, when NPs, DPs, and/or CAA were included in the same model, moderate to severe NPs were independently correlated with PiB SUVR in all regions except for the inferior temporal and calcarine ROI (β = 0.414–0.804, p < 0.05, whereas DPs were independently correlated with PiB SUVR in the angular gyrus ROI (β = 0.446, p = 0.010. CAA was also associated with PiB SUVR in the inferior temporal and calcarine ROI (β = 0.222–0.355, p < 0.05. In conclusion, global PiB-PET SUVR performed as well as regional values for amyloid detection in our cohort. The substrate-specific binding of PiB might differ among the brain specific regions.

Targeting the Nrf2/Amyloid-Beta Liaison in Alzheimer's Disease: A Rational Approach.

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Simoni, Elena; Serafini, Melania M; Caporaso, Roberta; Marchetti, Chiara; Racchi, Marco; Minarini, Anna; Bartolini, Manuela; Lanni, Cristina; Rosini, Michela

2017-07-19

Amyloid is a prominent feature of Alzheimer's disease (AD). Yet, a linear linkage between amyloid-β peptide (Aβ) and the disease onset and progression has recently been questioned. In this context, the crucial partnership between Aβ and Nrf2 pathways is acquiring paramount importance, offering prospects for deciphering the Aβ-centered disease network. Here, we report on a new class of antiaggregating agents rationally designed to simultaneously activate transcription-based antioxidant responses, whose lead 1 showed interesting properties in a preliminary investigation. Relying on the requirements of Aβ recognition, we identified the catechol derivative 12. In SH-SY5Y neuroblastoma cells, 12 combined remarkable free radical scavenger properties to the ability to trigger the Nrf2 pathway and induce the Nrf2-dependent defensive gene NQO1 by means of electrophilic activation of the transcriptional response. Moreover, 12 prevented the formation of cytotoxic stable oligomeric intermediates, being significantly more effective, and per se less toxic, than prototype 1. More importantly, as different chemical features were exploited to regulate Nrf2 and Aβ activities, the two pathways could be tuned independently. These findings point to compound 12 and its derivatives as promising tools for investigating the therapeutic potential of the Nrf2/Aβ cellular network, laying foundation for generating new drug leads to confront AD.

Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease.

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Edrey, Yael H; Medina, David X; Gaczynska, Maria; Osmulski, Pawel A; Oddo, Salvatore; Caccamo, Antonella; Buffenstein, Rochelle

2013-10-01

Amyloid beta (Aβ) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of Aβ similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in Aβ levels in the individuals examined (2-20+ years). The NMR Aβ peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR Aβ was less prone to aggregation than human Aβ. Nevertheless, both NMR and human Aβ were equally toxic to mouse hippocampal neurons, suggesting that Aβ neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of Aβ with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression. Copyright © 2013 Elsevier Inc. All rights reserved.

Amyloid beta 25-35 impairs reconsolidation of object recognition memory in rats and this effect is prevented by lithium carbonate.

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Álvarez-Ruíz, Yarummy; Carrillo-Mora, Paul

2013-08-26

Previous studies in transgenic mice models of Alzheimer's disease (AD) have demonstrated an age dependent memory reconsolidation failure, suggesting that this may be an additional mechanism that contributes to the memory impairment observed in AD. However, so far it is unknown whether this effect can be caused by exogenous administration of amyloid beta (Aβ). The purpose was to determine the effects of soluble Aβ 25-35 on reconsolidation of object recognition memory (ORM) in rats, and assess whether these effects can be prevented by lithium carbonate (LiCa). In this study, male Wistar rats were used and the following groups were formed (N=6-13): (a) control, given saline solution; (b) [NMDA antagonist] MK-801 (0.1 mg/kg); (c) LiCa (350 mg/kg); (d) Aβ 25-35 (100 μM) injected into both hippocampi; and (e) Aβ 25-35+LiCa. In all cases, treatments were administered with or without reactivation of memory. The results showed that soluble Aβ 25-35 produces ORM impairment similar to MK-801 when given shortly after memory reactivation, and this effect is prevented by prior administration of LiCa. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Protective effects of components of the Chinese herb grassleaf sweetflag rhizome on PC12 cells incubated with amyloid-beta42

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Zi-hao Liang

2015-01-01

Full Text Available The major ingredients of grassleaf sweetflag rhizome are β-asarone and eugenol, which can cross the blood-brain barrier and protect neurons. This study aimed to observe the neuroprotective effects and mechanisms of β-asarone and eugenol, components of the Chinese herb grassleaf sweetflag rhizome, on PC12 cells. First, PC12 cells were cultured with different concentrations (between 1 × 10 -10 M and 1 × 10 -5 M of β-asarone and eugenol. Survival rates of PC12 cells were not significantly affected. Second, PC12 cells incubated with amyloid-beta42, which reduced cell survival, were cultured under the same conditions (1 × 10 -6 M β-asarone and eugenol. The survival rates of PC12 cells significantly increased, while expression levels of the mRNAs for the pro-apoptotic protein Bax decreased, and those for the anti-apoptotic protein Bcl mRNA increased. In addition, the combination of β-asarone with eugenol achieved better results than either component alone. Our experimental findings indicate that both β-asarone and eugenol protect PC12 cells through inhibiting apoptosis, and that the combination of the two is better than either alone.

Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin

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Langen Ralf

2008-10-01

Full Text Available Abstract Background The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD, age-related macular degeneration (AMD, atherosclerosis, systemic amyloidoses, and glomerulonephritis. The extent to which vitronectin contributes to amyloid formation within these plaques, which contain misfolded, amyloidogenic proteins, and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin aggregation is significant since the formation of oligomeric and fibrillar structures are common features of amyloid proteins. Results We observed vitronectin immunoreactivity in senile plaques of AD brain, which exhibited overlap with the amyloid fibril-specific OC antibody, suggesting that vitronectin is deposited at sites of amyloid formation. Of particular interest is the growing body of evidence indicating that soluble nonfibrillar oligomers may be responsible for the development and progression of amyloid diseases. In this study we demonstrate that both plasma-purified and recombinant human vitronectin readily form spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured neuroblastoma and retinal pigment epithelium (RPE cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Oligomer toxicity was attenuated in RPE cells by the anti-oligomer A11 antibody. Vitronectin fibrils contain a C-terminal protease-resistant fragment, which may approximate the core region of residues essential to amyloid formation. Conclusion These data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases.

A Validated Stability-indicating Reverse Phase HPLC Assay Method for the Determination of Memantine Hydrochloride Drug Substance with UV-Detection Using Precolumn Derivatization Technique

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Bhavil Narola

2010-01-01

Full Text Available This present paper deals with the development and validation of a stability indicating high performance liquid chromatographic method for the quantitative determination of Memantine hydrochloride. Memantine hydrochloride was derivatized with 0.015 M 9-fluorenylmethyl chloroformate (FMOC and 0.5 M borate buffer solution by keeping it at room temperature for about 20 minutes and the chromatographic separation achieved by injecting 10 μL of the derivatized mixture into a Waters HPLC system with photodiode array detector using a kromasil C18 column (150 × 4.6 mm, 5 μ, The mobile phase consisting of 80% acetonitrile and 20% phosphate buffer solution and a flow rate of 2 milliliter/minute. The Memantine was eluted at approximately 7.5 minutes. The volume of FMOC used in derivatization, concentration of FMOC and derivatization time was optimized and used. Forced degradation studies were performed on bulk sample of Memantine hydrochloride using acid (5.0 Normal (N hydrochloric acid, base (1.0 N sodium hydroxide, oxidation (30% hydrogen peroxide, thermal (105 ° C, photolytic and humidity conditions. The developed LC method was validated with respect to specificity, precision (% RSD about 0.70%, linearity (linearity of range about 70-130 μg/mL, ruggedness (Overall % RSD about 0.35%, stability in analytical solution (Cumulative % RSD about 0.11% after 1450 min. and robustness.

A Validated Stability-indicating Reverse Phase HPLC Assay Method for the Determination of Memantine Hydrochloride Drug Substance with UV-Detection Using Precolumn Derivatization Technique

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Bhavil Narola

2010-07-01

Full Text Available This present paper deals with the development and validation of a stability indicating high performance liquid chromatographic method for the quantitative determination of Memantine hydrochloride. Memantine hydrochloride was derivatized with 0.015 M 9-fluorenylmethyl chloroformate (FMOC and 0.5 M borate buffer solution by keeping it at room temperature for about 20 minutes and the chromatographic separation achieved by injecting 10 µL of the derivatized mixture into a Waters HPLC system with photodiode array detector using a kromasil C18 column (150 × 4.6 mm, 5 µ. The mobile phase consisting of 80% acetonitrile and 20% phosphate buffer solution and a flow rate of 2 milliliter/minute. The Memantine was eluted at approximately 7.5 minutes. The volume of FMOC used in derivatization, concentration of FMOC and derivatization time was optimized and used. Forced degradation studies were performed on bulk sample of Memantine hydrochloride using acid (5.0 Normal (N hydrochloric acid, base (1.0 N sodium hydroxide, oxidation (30% hydrogen peroxide, thermal (105°C, photolytic and humidity conditions. The developed LC method was validated with respect to specificity, precision (% RSD about 0.70%, linearity (linearity of range about 70–130 µg/mL, ruggedness (Overall % RSD about 0.35%, stability in analytical solution (Cumulative % RSD about 0.11% after 1450 min. and robustness.

Reduction of Alzheimer's disease beta-amyloid pathology in the absence of gut microbiota

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Harach, T.; Marungruang, N.; Dutilleul, N.; Cheatham, V.; Coy, K. D. Mc; Neher, J. J.; Jucker, M.; Fåk, F.; T.; Lasser; Bolmont, T.

2015-01-01

Alzheimer's disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer's disease is not known. We generated a germ-free mouse model of Alzheimer's disease and discovered a drastic reduction of cerebral Ab amyloid pathology when compared to control Alzheimer's disease a...

Intravenous immunglobulin binds beta amyloid and modifies its aggregation, neurotoxicity and microglial phagocytosis in vitro.

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Susann Cattepoel

Full Text Available Intravenous Immunoglobulin (IVIG has been proposed as a potential therapeutic for Alzheimer's disease (AD and its efficacy is currently being tested in mild-to-moderate AD. Earlier studies reported the presence of anti-amyloid beta (Aβ antibodies in IVIG. These observations led to clinical studies investigating the potential role of IVIG as a therapeutic agent in AD. Also, IVIG is known to mediate beneficial effects in chronic inflammatory and autoimmune conditions by interfering with various pathological processes. Therefore, we investigated the effects of IVIG and purified polyclonal Aβ-specific antibodies (pAbs-Aβ on aggregation, toxicity and phagocytosis of Aβ in vitro, thus elucidating some of the potential mechanisms of action of IVIG in AD patients. We report that both IVIG and pAbs-Aβ specifically bound to Aβ and inhibited its aggregation in a dose-dependent manner as measured by Thioflavin T assay. Additionally, IVIG and the purified pAbs-Aβ inhibited Aβ-induced neurotoxicity in the SH-SY5Y human neuroblastoma cell line and prevented Aβ binding to rat primary cortical neurons. Interestingly, IVIG and pAbs-Aβ also increased the number of phagocytosing cells as well as the amount of phagocytosed fibrillar Aβ by BV-2 microglia. Phagocytosis of Aβ depended on receptor-mediated endocytosis and was accompanied by upregulation of CD11b expression. Importantly, we could also show that Privigen dose-dependently reversed Aβ-mediated LTP inhibition in mouse hippocampal slices. Therefore, our in vitro results suggest that IVIG may have an impact on different processes involved in AD pathogenesis, thereby promoting further understanding of the effects of IVIG observed in clinical studies.

Amyloid positron emission tomography in sporadic cerebral amyloid angiopathy: A systematic critical update

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Karim Farid

2017-01-01

Full Text Available Sporadic cerebral amyloid angiopathy (CAA is a very common small vessel disease of the brain, showing preferential and progressive amyloid-βdeposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex. CAA now encompasses not only a specific cerebrovascular pathological trait, but also different clinical syndromes - including spontaneous lobar intracerebral haemorrhage (ICH, dementia and ‘amyloid spells’ - an expanding spectrum of brain parenchymal MRI lesions and a set of diagnostic criteria – the Boston criteria, which have resulted in increasingly detecting CAA during life. Although currently available validated diagnostic criteria perform well in multiple lobar ICH, a formal diagnosis is currently lacking unless a brain biopsy is performed. This is partly because in practice CAA MRI biomarkers provide only indirect evidence for the disease. An accurate diagnosis of CAA in different clinical settings would have substantial impact for ICH risk stratification and antithrombotic drug use in elderly people, but also for sample homogeneity in drug trials. It has recently been demonstrated that vascular (in addition to parenchymal amyloid-βdeposition can be detected and quantified in vivo by positron emission tomography (PET amyloid tracers. This non-invasive approach has the potential to provide a molecular signature of CAA, and could in turn have major clinical impact. However, several issues around amyloid-PET in CAA remain unsettled and hence its diagnostic utility is limited. In this article we systematically review and critically appraise the published literature on amyloid-PET (PiB and other tracers in sporadic CAA. We focus on two key areas: (a the diagnostic utility of amyloid-PET in CAA and (b the use of amyloid-PET as a window to understand pathophysiological mechanism of the disease. Key issues around amyloid-PET imaging in CAA, including relevant technical aspects are also covered in depth

β - amyloid imaging probes

International Nuclear Information System (INIS)

Jeong, Jae Min

2007-01-01

Imaging distribution of β - amyloid plaques in Alzheimer's disease is very important for early and accurate diagnosis. Early trial of the β -amyloid plaques includes using radiolabeled peptides which can be only applied for peripheral β - amyloid plaques due to limited penetration through the blood brain barrier (BBB). Congo red or Chrysamine G derivatives were labeled with Tc-99m for imaging β - amyloid plaques of Alzheimer patient's brain without success due to problem with BBB penetration. Thioflavin T derivatives gave breakthrough for β - amyloid imaging in vivo, and a benzothiazole derivative [C-11]6-OH-BTA-1 brought a great success. Many other benzothiazole, benzoxazole, benzofuran, imidazopyridine, and styrylbenzene derivatives have been labeled with F-18 and I-123 to improve the imaging quality. However, [C-11]6-OH-BTA-1 still remains as the best. However, short half-life of C-11 is a limitation of wide distribution of this agent. So, it is still required to develop an Tc-99m, F-18 or I-123 labeled agent for β - amyloid imaging agent

Computational identification of potential multitarget treatments for ameliorating the adverse effects of amyloid-beta on synaptic plasticity

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Thomas J. Anastasio

2014-05-01

Full Text Available The leading hypothesis on Alzheimer Disease (AD is that it is caused by buildup of the peptide amyloid-beta (Abeta, which initially causes dysregulation of synaptic plasticity and eventually causes destruction of synapses and neurons. Pharmacological efforts to limit Abeta buildup have proven ineffective, and this raises the twin challenges of understanding the adverse effects of Abeta on synapses and of suggesting pharmacological means to prevent it. The purpose of this paper is to initiate a computational approach to understanding the dysregulation by Abeta of synaptic plasticity and to offer suggestions whereby combinations of various chemical compounds could be arrayed against it. This data-driven approach confronts the complexity of synaptic plasticity by representing findings from the literature in a course-grained manner, and focuses on understanding the aggregate behavior of many molecular interactions. The same set of interactions is modeled by two different computer programs, each written using a different programming modality: one imperative, the other declarative. Both programs compute the same results over an extensive test battery, providing an essential crosscheck. Then the imperative program is used for the computationally intensive purpose of determining the effects on the model of every combination of ten different compounds, while the declarative program is used to analyze model behavior using temporal logic. Together these two model implementations offer new insights into the mechanisms by which Abeta dysregulates synaptic plasticity and suggest many drug combinations that potentially may reduce or prevent it.

Microfluidic Isoelectric Focusing of Amyloid Beta Peptides Followed by Micropillar-Matrix-Assisted Laser Desorption Ionization-Mass Spectrometry.

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Mikkonen, Saara; Jacksén, Johan; Roeraade, Johan; Thormann, Wolfgang; Emmer, Åsa

2016-10-18

A novel method for preconcentration and purification of the Alzheimer's disease related amyloid beta (Aβ) peptides by isoelectric focusing (IEF) in 75 nL microchannels combined with their analysis by micropillar-matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS) is presented. A semiopen chip-based setup, consisting of open microchannels covered by a lid of a liquid fluorocarbon, was used. IEF was performed in a mixture of four small and chemically well-defined amphoteric carriers, glutamic acid, aspartyl-histidine (Asp-His), cycloserine (cSer), and arginine, which provided a stepwise pH gradient tailored for focusing of the C-terminal Aβ peptides with a pI of 5.3 in the boundary between cSer and Asp-His. Information about the focusing dynamics and location of the foci of Aβ peptides and other compounds was obtained using computer simulation and by performing MALDI-MS analysis directly from the open microchannel. With the established configuration, detection was performed by direct sampling of a nanoliter volume containing the focused Aβ peptides from the microchannel, followed by deposition of this volume onto a chip with micropillar MALDI targets. In addition to purification, IEF preconcentration provides at least a 10-fold increase of the MALDI-MS-signal. After immunoprecipitation and concentration of the eluate in the microchannel, IEF-micropillar-MALDI-MS is demonstrated to be a suitable platform for detection of Aβ peptides in human cerebrospinal fluid as well as in blood plasma.

General amyloid inhibitors? A critical examination of the inhibition of IAPP amyloid formation by inositol stereoisomers.

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Hui Wang

Full Text Available Islet amyloid polypeptide (IAPP or amylin forms amyloid deposits in the islets of Langerhans; a process that is believed to contribute to the progression of type 2 diabetes and to the failure of islet transplants. An emerging theme in amyloid research is the hypothesis that the toxic species produced during amyloid formation by different polypeptides share common features and exert their effects by common mechanisms. If correct, this suggests that inhibitors of amyloid formation by one polypeptide might be effective against other amyloidogenic sequences. IAPP and Aβ, the peptide responsible for amyloid formation in Alzheimer's disease, are particularly interesting in this regard as they are both natively unfolded in their monomeric states and share some common characteristics. Comparatively little effort has been expended on the design of IAPP amyloid inhibitors, thus it is natural to inquire if Aβ inhibitors are effective against IAPP, especially since no IAPP inhibitors have been clinically approved. A range of compounds inhibit Aβ amyloid formation, including various stereoisomers of inositol. Myo-, scyllo-, and epi-inositol have been shown to induce conformational changes in Aβ and prevent Aβ amyloid fibril formation by stabilizing non-fibrillar β-sheet structures. We investigate the ability of inositol stereoisomers to inhibit amyloid formation by IAPP. The compounds do not induce a conformational change in IAPP and are ineffective inhibitors of IAPP amyloid formation, although some do lead to modest apparent changes in IAPP amyloid fibril morphology. Thus not all classes of Aβ inhibitors are effective against IAPP. This work provides a basis of comparison to work on polyphenol based inhibitors of IAPP amyloid formation and helps provide clues as to the features which render them effective. The study also helps provide information for further efforts in rational inhibitor design.

Alzheimer's disease - input of vitamin D with mEmantine assay (AD-IDEA trial: study protocol for a randomized controlled trial

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Gautier Jennifer

2011-10-01

Full Text Available Abstract Background Current treatments for Alzheimer's disease and related disorders (ADRD are symptomatic and can only temporarily slow down ADRD. Future possibilities of care rely on multi-target drugs therapies that address simultaneously several pathophysiological processes leading to neurodegeneration. We hypothesized that the combination of memantine with vitamin D could be neuroprotective in ADRD, thereby limiting neuronal loss and cognitive decline. The aim of this trial is to compare the effect after 24 weeks of the oral intake of vitamin D3 (cholecalciferol with the effect of a placebo on the change of cognitive performance in patients suffering from moderate ADRD and receiving memantine. Methods The AD-IDEA Trial is a unicentre, double-blind, randomized, placebo-controlled, intent-to-treat, superiority trial. Patients aged 60 years and older presenting with moderate ADRD (i.e., Mini-Mental State Examination [MMSE] score between 10-20, hypovitaminosis D (i.e., serum 25-hydroxyvitamin D [25OHD] Discussion The combination of memantine plus vitamin D may represent a new multi-target therapeutic class for the treatment of ADRD. The AD-IDEA Trial seeks to provide evidence on its efficacy in limiting cognitive and functional declines in ADRD. Trial Registration ClinicalTrials.gov number, NCT01409694

Cerebrospinal fluid markers in dementia with lewy bodies compared with Alzheimer disease.

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Gómez-Tortosa, Estrella; Gonzalo, Isabel; Fanjul, Samira; Sainz, Maria José; Cantarero, Susana; Cemillán, Carlos; Yébenes, Justo García; del Ser, Teodoro

2003-09-01

Most patients with dementia with Lewy bodies (DLB) exhibit diffuse plaque-only pathology with rare neocortical neurofibrillary tangles (NFTs), as opposed to the widespread cortical neurofibrillary-tau involvement in Alzheimer disease (AD). Another pathological difference is the astrocytic and microglial inflammatory responses, including release of interleukins (ILs), around the neuritic plaques and NFTs in AD brains that are absent or much lower in DLB. We analyzed cerebrospinal fluid (CSF) markers that reflect the pathological differences between AD and DLB. To determine CSF concentrations of tau, beta-amyloid, IL-1beta, and IL-6 as potential diagnostic clues to distinguish between AD and DLB. We measured total tau, beta-amyloid1-42, IL-1beta, and IL-6 levels in CSF samples of 33 patients with probable AD without parkinsonism, 25 patients with all the core features of DLB, and 46 age-matched controls. Patients with AD had significantly higher levels of tau protein than patients with DLB and controls (P<.001). The most efficient cutoff value provided 76% specificity to distinguish AD and DLB cases. Patients with AD and DLB had lower, but not significantly so, beta-amyloid levels than controls. The combination of tau and beta-amyloid levels provided the best sensitivity (84%) and specificity (79%) to differentiate AD vs controls but was worse than tau values alone in discriminating between AD and DLB. Beta-amyloid levels had the best correlation with disease progression in both AD and DLB (P =.01). There were no significant differences in IL-1beta levels among patients with AD, patients with DLB, and controls. Patients with AD and DLB showed slightly, but not significantly, higher IL-6 levels than controls. The tau levels in CSF may contribute to the clinical distinction between AD and DLB. Beta-amyloid CSF levels are similar in both dementia disorders and reflect disease progression better than tau levels. Interleukin CSF concentrations do not distinguish between

The Efficacy of Licensed-Indication Use of Donepezil and Memantine Monotherapies for Treating Behavioural and Psychological Symptoms of Dementia in Patients with Alzheimer’s Disease: Systematic Review and Meta-Analysis

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I.A. Lockhart

2011-07-01

Full Text Available Background/Aims: Behavioural and psychological symptoms of dementia (BPSD in Alzheimer’s disease (AD greatly increase caregiver burden. The abilities of donepezil and memantine to manage BPSD within their licensed indications in AD were compared. Methods: A systematic review, random effects meta-analysis and Bucher indirect comparison were conducted. Results: Six randomised controlled studies (4 donepezil and 2 memantine reported use within the licensed indication and had Neuropsychiatric Inventory (NPI data suitable for meta-analysis. BPSD showed significant improvement with donepezil compared with placebo [weighted mean difference (WMD in NPI –3.51, 95% confidence interval (CI –5.75, –1.27], whereas this was not the case for memantine (WMD –1.65, 95% CI –4.78, 1.49. WMD in NPI for donepezil versus memantine favoured donepezil but was not statistically significant (–1.86, 95% CI –5.71, 1.99; p = 0.34. Conclusion: Within its licensed indication, donepezil is efficacious for the management of BPSD in AD compared with placebo.

Clinical and imaging correlates of amyloid deposition in dementia with Lewy bodies.

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Donaghy, Paul C; Firbank, Michael J; Thomas, Alan J; Lloyd, Jim; Petrides, George; Barnett, Nicola; Olsen, Kirsty; O'Brien, John T

2018-04-19

Amyloid deposition is common in dementia with Lewy bodies, but its pathophysiological significance is unclear. The objective of this study was to investigate the relationship between amyloid deposition and clinical profile, gray matter volume, and brain perfusion in dementia with Lewy bodies. Dementia with Lewy bodies (n = 37), Alzheimer's disease (n = 20), and controls (n = 20) underwent a thorough clinical assessment, 3T MRI, and early- and late-phase 18 F-Florbetapir PET-CT to assess cortical perfusion and amyloid deposition, respectively. Amyloid scans were visually categorized as positive or negative. Image analysis was carried out using statistical parametric mapping (SPM) 8. There were no significant differences between amyloid-positive and amyloid-negative dementia with Lewy bodies cases in age (P = .78), overall cognitive impairment (P = .83), level of functional impairment (P = .80), or any other clinical or cognitive scale. There were also no significant differences in hippocampal or gray matter volumes. However, amyloid-positive dementia with Lewy bodies cases had lower medial temporal lobe perfusion (P = .03) than amyloid-negative cases, although a combination of medial temporal lobe perfusion, hippocampal volume, and cognitive measures was unable to accurately predict amyloid status in dementia with Lewy bodies. Amyloid deposition was not associated with differences in clinical or neuropsychological profiles in dementia with Lewy bodies, but was associated with imaging evidence of medial temporal lobe dysfunction. The presence of amyloid in dementia with Lewy bodies cannot be identified on the basis of clinical and other imaging features and will require direct assessment via PET imaging or CSF. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf

Aggregation and toxicity of amyloid-beta peptide in relation to peptide sequence variation

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Vandersteen, A.

2012-01-01

Generally, aggregation of the amyloid-ß peptide is considered the cause of neuronal death in Alzheimer disease. The heterogenous Aß peptide occurs in various lengths in vivo: Aß40 and Aß42 are the predominant forms while both shorter and longer peptides exist. Aß40 and shorter isoforms are less aggregation-prone and hence considered less dangerous than Aß42 and longer isoforms, which are more aggregation-prone. Up to now research mainly focussed on the predominant Aß peptides and their indivi...

Down's Syndrome with Alzheimer's Disease-Like Pathology: What Can It Teach Us about the Amyloid Cascade Hypothesis?

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Rania M. Bakkar

2010-01-01

Full Text Available Down's syndrome (DS, trisomy 21 represents a complex genetic abnormality that leads to pathology in later life that is similar to Alzheimer's disease (AD. We compared two cases of DS with APOE 3/3 genotypes, a similar age at death, and comparable amyloid-beta 42 peptide (A42 burdens in the brain but that differed markedly in the severity of AD-like pathology. One exhibited extensive neurofibrillary pathology whereas the other showed minimal features of this type. Comparable loads of A42 could relate to the cases' similar life-time accumulation of A due to trisomy 21-enhanced metabolism of amyloid precursor protein (APP. The cases' significant difference in AD-like pathology, however, suggests that parenchymal deposition of A42, even when extensive, may not inevitably trigger AD-like tau pathology (though it may be necessary. Thus, these observations of a natural experiment may contribute to understanding the nuances of the amyloid cascade hypothesis of AD pathogenesis.

Perforin Promotes Amyloid Beta Internalisation in Neurons.

Science.gov (United States)

Lana, Erica; Khanbolouki, Mahbod; Degavre, Charline; Samuelsson, Eva-Britt; Åkesson, Elisabet; Winblad, Bengt; Alici, Evren; Lithner, Christina Unger; Behbahani, Homira

2017-03-01

Studies on the mechanisms of neuronal amyloid-β (Aβ) internalisation are crucial for understanding the neuropathological progression of Alzheimer's disease (AD). We here investigated how extracellular Aβ peptides are internalised and focused on three different pathways: (i) via endocytic mechanisms, (ii) via the receptor for advanced glycation end products (RAGE) and (iii) via the pore-forming protein perforin. Both Aβ 40 and Aβ 42 were internalised in retinoic acid differentiated neuroblastoma (RA-SH-SY5Y) cells. A higher concentration was required for Aβ 40 (250 nM) compared with Aβ 42 (100 nM). The internalised Aβ 40 showed a dot-like pattern of distribution whereas Aβ 42 accumulated in larger and distinct formations. By confocal microscopy, we showed that Aβ 40 and Aβ 42 co-localised with mitochondria, endoplasmic reticulum (ER) and lysosomes. Aβ treatment of human primary cortical neurons (hPCN) confirmed our findings in RA-SH-SY5Y cells, but hPCN were less sensitive to Aβ; therefore, a 20 (Aβ 40 ) and 50 (Aβ 42 ) times higher concentration was needed for inducing uptake. The blocking of endocytosis completely inhibited the internalisation of Aβ peptides in RA-SH-SY5Y cells and hPCN, indicating that this is a major pathway by which Aβ enters the cells. In addition, the internalisation of Aβ 42 , but not Aβ 40 , was reduced by 55 % by blocking RAGE. Finally, for the first time we showed that pore formation in cell membranes by perforin led to Aβ internalisation in hPCN. Understanding how Aβ is internalised sheds light on the pathological role of Aβ and provides further ideas of inhibitory strategies for preventing Aβ internalisation and the spreading of neurodegeneration in AD.

Administration of memantine during ethanol withdrawal in neonatal rats: effects on long-term ethanol-induced motor incoordination and cerebellar Purkinje cell loss.

Science.gov (United States)

Idrus, Nirelia M; McGough, Nancy N H; Riley, Edward P; Thomas, Jennifer D

2011-02-01

Alcohol consumption during pregnancy can damage the developing fetus, illustrated by central nervous system dysfunction and deficits in motor and cognitive abilities. Binge drinking has been associated with an increased risk of fetal alcohol spectrum disorders, likely due to increased episodes of ethanol withdrawal. We hypothesized that overactivity of the N-methyl-D-aspartate (NMDA) receptor during ethanol withdrawal leads to excitotoxic cell death in the developing brain. Consistent with this, administration of NMDA receptor antagonists (e.g., MK-801) during withdrawal can attenuate ethanol's teratogenic effects. The aim of this study was to determine whether administration of memantine, an NMDA receptor antagonist, during ethanol withdrawal could effectively attenuate ethanol-related deficits, without the adverse side effects associated with other NMDA receptor antagonists. Sprague-Dawley pups were exposed to 6.0 g/kg ethanol or isocaloric maltose solution via intubation on postnatal day 6, a period of brain development equivalent to a portion of the 3rd trimester. Twenty-four and 36 hours after ethanol, subjects were injected with 0, 10, or 15 mg/kg memantine, totaling doses of 0, 20, or 30 mg/kg. Motor coordination was tested on a parallel bar task and the total number of cerebellar Purkinje cells was estimated using unbiased stereology. Alcohol exposure induced significant parallel bar motor incoordination and reduced Purkinje cell number. Memantine administration significantly attenuated both ethanol-associated motor deficits and cerebellar cell loss in a dose-dependent manner. Memantine was neuroprotective when administered during ethanol withdrawal. These data provide further support that ethanol withdrawal contributes to fetal alcohol spectrum disorders. Copyright © 2010 by the Research Society on Alcoholism.

Effects of diet-induced hypercholesterolemia on amyloid ...

Indian Academy of Sciences (India)

2012-10-27

Oct 27, 2012 ... A central hypothesis in the study of Alzheimer's disease (AD) is the accumulation and aggregation of β-amyloid ... protein (APP) and estrogen has been implicated in the pre- .... inant in HCL in the intensity of the expression was lower ..... estrogen replacement therapy of the Women's Health Initiative.

Formation of a stable oligomer of beta-2 microglobulin requires only transient encounter with Cu(II).

Science.gov (United States)

Calabrese, Matthew F; Miranker, Andrew D

2007-03-16

Beta-2 Microglobulin (beta2m) is a small, globular protein, with high solubility under conditions comparable to human serum. A complication of hemodialysis in renal failure patients is the deposition of unmodified beta2m as amyloid fibers. In vitro, exposure of beta2m to equimolar Cu(2+) under near-physiological conditions can result in self-association leading to amyloid fiber formation. Previously, we have shown that the early steps in this process involve a catalyzed structural rearrangement followed by formation of discrete oligomers. These oligomers, however, have a continued requirement for Cu(2+) while mature fibers are resistant to addition of metal chelate. Here, we report that the transition from Cu(2+) dependent to chelate resistant states occurs in the context of small oligomers, dimeric to hexameric in size. These species require Cu(2+) to form, but once generated, do not need metal cation for stability. Importantly, this transition occurs gradually over several days and the resulting oligomers are isolatable and kinetically stable on timescales exceeding weeks. In addition, formation is enhanced by levels of urea similar to those found in hemodialysis patients. Our results are consistent with our hypothesis that transient encounter of full-length wild-type beta2m with transition metal cation at the dialysis membrane interface is causal to dialysis related amyloidosis.

Nanomechanical properties of single amyloid fibrils

International Nuclear Information System (INIS)

Sweers, K K M; Bennink, M L; Subramaniam, V

2012-01-01

Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils. (topical review)

Does sleep disturbance affect the amyloid clearance mechanisms in Alzheimer's disease?

Science.gov (United States)

Yulug, Burak; Hanoglu, Lutfu; Kilic, Ertugrul

2017-10-01

Sleep is an important factor that plays a key role in Alzheimer's disease pathogenesis. However, it is still unclear whether poor-quality sleep may overlap with sleep disturbances in the underlying dysfunctional mechanisms of amyloid beta (Aβ) clearance metabolism. Here, we aimed to evaluate the current evidence on the role of sleep deprivation in Aβ clearance metabolism. To that end, we discuss possible mechanisms underlying the bidirectional interaction between the sleep deprivation and Aβ clearance pathways. © 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.

Amyloid PET in pseudotumoral multiple sclerosis.

Science.gov (United States)

Matías-Guiu, Jordi A; Cabrera-Martín, María Nieves; Cortés-Martínez, Ana; Pytel, Vanesa; Moreno-Ramos, Teresa; Oreja-Guevara, Celia; Carreras, José Luis; Matías-Guiu, Jorge

2017-07-01

Pseudotumoral multiple sclerosis is a rare form of demyelinating disease of the central nervous system. Positron emission tomography (PET) using amyloid-tracers has also been suggested as a marker of damage in white matter lesions in multiple sclerosis due to the nonspecific uptake of these tracers in white matter. We present the case of a 59 year-old woman with a pathological-confirmed pseudotumoral multiple sclerosis, who was studied with the amyloid tracer 18 F-florbetaben. The patient had developed word-finding difficulties and right hemianopia twelve years ago. In that time, MRI showed a lesion on the left hemisphere with an infiltrating aspect in frontotemporal lobes. Brain biopsy showed demyelinating areas and inflammation. During the following years, two new clinical relapses occurred. 18 F-florbetaben PET showed lower uptake in the white matter lesion visualized in the CT and MRI images. Decreased tracer uptake was also observed in a larger area of the left hemisphere beyond the lesions observed on MRI or CT. White matter lesion volume on FLAIR was 44.2mL, and tracer uptake change between damaged white matter and normal appearing white matter was - 40.5%. Standardized uptake value was inferior in the pseudotumoral lesion than in the other white matter lesions. We report the findings of amyloid PET in a patient with pseudotumoral multiple sclerosis. This case provides further evidence on the role of amyloid PET in the assessment of white matter and demyelinating diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

The Role of Oxidative Stress-Induced Epigenetic Alterations in Amyloid- ? Production in Alzheimer's Disease

OpenAIRE

Zuo, Li; Hemmelgarn, Benjamin T.; Chuang, Chia-Chen; Best, Thomas M.

2015-01-01

An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS)-induced oxidative stress (OS) and the pathogenesis of Alzheimer’s disease (AD). With over five million people diagnosed in the United States alone, AD is the most common type of dementia worldwide. AD includes progressive neurodegeneration, followed by memory loss and reduced cognitive ability. Characterized by the formation of amyloid-beta (Aβ) plaques as a hallmark, the connection betwee...

Is verbal episodic memory in elderly with amyloid deposits preserved through altered neuronal function?

Science.gov (United States)

Ossenkoppele, Rik; Madison, Cindee; Oh, Hwamee; Wirth, Miranka; van Berckel, Bart N M; Jagust, William J

2014-08-01

A potential mechanism that enables intellectual preservation in cognitively normal elderly that harbor beta-amyloid (Aβ) pathology is heightened cerebral glucose metabolism. To investigate cross-sectional inter-relationships between Aβ, glucose metabolism, and cognition, 81 subjects (mean age: 75 ± 7 years) underwent [(11)C]Pittsburgh Compound-B and [(18)F]fluorodeoxyglucose positron emission tomography scans and neuropsychological testing. They were divided into low-Aβ (n = 53), intermediate-Aβ (n = 13) and high-Aβ (n = 15) groups as defined by their global cortical [(11)C]PIB retention. Glucose metabolism was assessed using a MetaROI mask that covers metabolically critical regions in Alzheimer's disease (AD) (i.e., posterior cingulate and bilateral angular and inferior temporal gyri). Previously validated factor scores for verbal and visual episodic memory, semantic memory, working memory, and executive functioning were used to evaluate cognitive performances. Greater Aβ deposition in the precuneus was associated with higher metabolic activity (at trend level) and lower visual episodic memory scores. Glucose metabolism did not correlate with cognition across all subjects. However, heightened metabolic activity was associated with better verbal episodic memory performance in subjects with elevated amyloid levels. This preliminary study suggests that neural compensation, as a manifestation of brain reserve, enables elderly supposedly on the path to AD, at least temporarily, to preserve cognitive function. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Vascular remodeling versus amyloid beta-induced oxidative stress in the cerebrovascular dysfunctions associated with Alzheimer's disease.

Science.gov (United States)

Tong, Xin-Kang; Nicolakakis, Nektaria; Kocharyan, Ara; Hamel, Edith

2005-11-30

The roles of oxidative stress and structural alterations in the cerebrovascular dysfunctions associated with Alzheimer's disease (AD) were investigated in transgenic mice overexpressing amyloid precusor protein (APP+) or transforming growth factor-beta1 (TGF+). Age-related impairments and their in vitro reversibility were evaluated, and underlying pathogenic mechanisms were assessed and compared with those seen in AD brains. Vasoconstrictions to 5-HT and endothelin-1 were preserved, except in the oldest (18-21 months of age) TGF+ mice. Despite unaltered relaxations to sodium nitroprusside, acetylcholine (ACh) and calcitonin gene-related peptide-mediated dilatations were impaired, and there was an age-related deficit in the basal availability of nitric oxide (NO) that progressed more gradually in TGF+ mice. The expression and progression of these deficits were unrelated to the onset or extent of thioflavin-S-positive vessels. Manganese superoxide dismutase (SOD2) was upregulated in pial vessels and around brain microvessels of APP+ mice, pointing to a role of superoxide in the dysfunctions elicited by amyloidosis. In contrast, vascular wall remodeling associated with decreased levels of endothelial NO synthase and cyclooxygenase-2 and increased contents of vascular endothelial growth factor and collagen-I and -IV characterized TGF+ mice. Exogenous SOD or catalase normalized ACh dilatations and NO availability in vessels from aged APP+ mice but had no effect in those of TGF+ mice. Increased perivascular oxidative stress was not evidenced in AD brains, but vascular wall alterations compared well with those seen in TGF+ mice. We conclude that brain vessel remodeling and associated alterations in levels of vasoactive signaling molecules are key contributors to AD cerebrovascular dysfunctions.

Alzheimer's Toxic Amyloid Beta Oligomers: Unwelcome Visitors to the Na/K ATPase alpha3 Docking Station.

Science.gov (United States)

DiChiara, Thomas; DiNunno, Nadia; Clark, Jeffrey; Bu, Riana Lo; Cline, Erika N; Rollins, Madeline G; Gong, Yuesong; Brody, David L; Sligar, Stephen G; Velasco, Pauline T; Viola, Kirsten L; Klein, William L

2017-03-01

Toxic amyloid beta oligomers (AβOs) are known to accumulate in Alzheimer's disease (AD) and in animal models of AD. Their structure is heterogeneous, and they are found in both intracellular and extracellular milieu. When given to CNS cultures or injected ICV into non-human primates and other non-transgenic animals, AβOs have been found to cause impaired synaptic plasticity, loss of memory function, tau hyperphosphorylation and tangle formation, synapse elimination, oxidative and ER stress, inflammatory microglial activation, and selective nerve cell death. Memory loss and pathology in transgenic models are prevented by AβO antibodies, while Aducanumab, an antibody that targets AβOs as well as fibrillar Aβ, has provided cognitive benefit to humans in early clinical trials. AβOs have now been investigated in more than 3000 studies and are widely thought to be the major toxic form of Aβ. Although much has been learned about the downstream mechanisms of AβO action, a major gap concerns the earliest steps: How do AβOs initially interact with surface membranes to generate neuron-damaging transmembrane events? Findings from Ohnishi et al (PNAS 2005) combined with new results presented here are consistent with the hypothesis that AβOs act as neurotoxins because they attach to particular membrane protein docks containing Na/K ATPase-α3, where they inhibit ATPase activity and pathologically restructure dock composition and topology in a manner leading to excessive Ca++ build-up. Better understanding of the mechanism that makes attachment of AβOs to vulnerable neurons a neurotoxic phenomenon should open the door to therapeutics and diagnostics targeting the first step of a complex pathway that leads to neural damage and dementia.

Reduced amyloidogenic processing of the amyloid beta-protein precursor by the small-molecule Differentiation Inducing Factor-1.

Science.gov (United States)

Myre, Michael A; Washicosky, Kevin; Moir, Robert D; Tesco, Giuseppina; Tanzi, Rudolph E; Wasco, Wilma

2009-04-01

The detection of cell cycle proteins in Alzheimer's disease (AD) brains may represent an early event leading to neurodegeneration. To identify cell cycle modifiers with anti-Abeta properties, we assessed the effect of Differentiation-Inducing Factor-1 (DIF-1), a unique, small-molecule from Dictyostelium discoideum, on the proteolysis of the amyloid beta-protein precursor (APP) in a variety of different cell types. We show that DIF-1 slows cell cycle progression through G0/G1 that correlates with a reduction in cyclin D1 protein levels. Western blot analysis of DIF-treated cells and conditioned medium revealed decreases in the levels of secreted APP, mature APP, and C-terminal fragments. Assessment of conditioned media by sandwich ELISA showed reduced levels of Abeta40 and Abeta42, also demonstrating that treatment with DIF-1 effectively decreases the ratio of Abeta42 to Abeta40. In addition, DIF-1 significantly diminished APP phosphorylation at residue T668. Interestingly, site-directed mutagenesis of APP residue Thr668 to alanine or glutamic acid abolished the effect of DIF-1 on APP proteolysis and restored secreted levels of Abeta. Finally, DIF-1 prevented the accumulation of APP C-terminal fragments induced by the proteasome inhibitor lactacystin, and calpain inhibitor N-acetyl-leucyl-leucyl-norleucinal (ALLN). Our findings suggest that DIF-1 affects G0/G1-associated amyloidogenic processing of APP by a gamma-secretase-, proteasome- and calpain-insensitive pathway, and that this effect requires the presence of residue Thr668.

Optimization of o-phtaldialdehyde/2-mercaptoethanol postcolumn reaction for the hydrophilic interaction liquid chromatography determination of memantine utilizing a silica hydride stationary phase.

Science.gov (United States)

Douša, Michal; Pivoňková, Veronika; Sýkora, David

2016-08-01

A rapid procedure for the determination of memantine based on hydrophilic interaction chromatography with fluorescence detection was developed. Fluorescence detection after postcolumn derivatization with o-phtaldialdehyde/2-mercaptoethanol was performed at excitation and emission wavelengths of 345 and 450 nm, respectively. The postcolumn reaction conditions such as reaction temperature, derivatization reagent flow rate, and reagents concentration were studied due to steric hindrance of amino group of memantine. The derivatization reaction was applied for the hydrophilic interaction liquid chromatography method which was based on Cogent Silica-C stationary phase with a mobile phase consisting of a mixture of 10 mmol/L citric acid and 10 mmol/L o-phosphoric acid (pH 6.0) with acetonitrile using an isocratic composition of 2:8 v/v. The benefit of the reported approach consists in a simple sample pretreatment and a quick and sensitive hydrophilic interaction chromatography method. The developed method was validated in terms of linearity, accuracy, precision, and selectivity according to the International Conference on Harmonisation guidelines. The developed method was successfully applied for the analysis of commercial memantine tablets. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Extracellular vesicles from human pancreatic islets suppress human islet amyloid polypeptide amyloid formation

OpenAIRE

Ribeiro, Diana; Horvath, Istvan; Heath, Nikki; Hicks, Ryan; Forslöw, Anna; Wittung-Stafshede, Pernilla

2017-01-01

Protein assembly into amyloid fibers underlies such neurodegenerative disorders as Alzheimer’s disease and Parkinson’s disease. Type 2 diabetes (T2D) also involves amyloid formation, although in the pancreas. Because there are no cures for amyloid diseases and T2D is on the rise due to an increasing prevalence of obesity, identifying involved mechanisms and control processes is of utmost importance. Extracellular vesicles (EVs) can mediate physiological and pathological communication both loc...

Relationships between sleep quality and brain volume, metabolism, and amyloid deposition in late adulthood.

Science.gov (United States)

Branger, Pierre; Arenaza-Urquijo, Eider M; Tomadesso, Clémence; Mézenge, Florence; André, Claire; de Flores, Robin; Mutlu, Justine; de La Sayette, Vincent; Eustache, Francis; Chételat, Gaël; Rauchs, Géraldine

2016-05-01

Recent studies in mouse models of Alzheimer's disease (AD) and in humans suggest that sleep disruption and amyloid-beta (Aβ) accumulation are interrelated, and may, thus, exacerbate each other. We investigated the association between self-reported sleep variables and neuroimaging data in 51 healthy older adults. Participants completed a questionnaire assessing sleep quality and quantity and underwent positron emission tomography scans using [18F]florbetapir and [18F]fluorodeoxyglucose and an magnetic resonance imaging scan to measure Aβ burden, hypometabolism, and atrophy, respectively. Longer sleep latency was associated with greater Aβ burden in prefrontal areas. Moreover, the number of nocturnal awakenings was negatively correlated with gray matter volume in the insular region. In asymptomatic middle-aged and older adults, lower self-reported sleep quality was associated with greater Aβ burden and lower volume in brain areas relevant in aging and AD, but not with glucose metabolism. These results highlight the potential relevance of preserving sleep quality in older adults and suggest that sleep may be a factor to screen for in individuals at risk for AD. Copyright © 2016 Elsevier Inc. All rights reserved.

Novel squarylium dyes for detection of amyloid fibrils in vitro

Directory of Open Access Journals (Sweden)

K. O. Vus

2015-04-01

Full Text Available A series of novel symmetrical and asymmetrical squarylium dyes with the different substituents in the donor moieties have been tested for their ability to detect and characterize insulin and lysozyme amyloid fibrils prepared in acidic buffer at elevated temperature. The dye-protein binding parameters were estimated in terms of the one-site Langmuir adsorption model using the data of direct and reverse fluorimetric titrations. By comparing the dye quantum yields, binding affinities, and extents of the fluorescence enhancement in the protein-bound state, G6 and G7 were selected as the most prospective amyloid tracers. Furthermore, these probes provided evidence for the lower polarity of the lysozyme fibrillar grooves compared to insulin aggregates. The novel dyes G6 and G7 were recommended for amyloid fibril detection and characterization in the near-infrared region.

Modeling Cerebrovascular Pathophysiology in Amyloid-β Metabolism using Neural-Crest-Derived Smooth Muscle Cells

Directory of Open Access Journals (Sweden)

Christine Cheung

2014-10-01

Full Text Available Summary: There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs from neural crest progenitors, recapitulating brain-vasculature-specific attributes of Aβ metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate Aβ uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Aβ clearance by suppressing LRP1 expression. This enabled us to develop an assay of Aβ uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden. : The contribution of blood vessel pathologies to neurodegenerative disorders is relatively neglected, partly due to inadequate human tissues for research. By using human stem cells, Cheung et al. establish a method of generating vascular smooth muscle cells (SMCs from neural crest progenitors, the primary precursors that give rise to brain blood vessels. These stem-cell-derived SMCs display defective amyloid processing under chronic hypoxia, a phenomenon well documented in the cerebral vasculatures of aged people and patients with Alzheimer’s disease.

Why are Functional Amyloids Non-Toxic in Humans?

Directory of Open Access Journals (Sweden)

Matthew P. Jackson

2017-09-01

Full Text Available Amyloids were first identified in association with amyloidoses, human diseases in which proteins and peptides misfold into amyloid fibrils. Subsequent studies have identified an array of functional amyloid fibrils that perform physiological roles in humans. Given the potential for the production of toxic species in amyloid assembly reactions, it is remarkable that cells can produce these functional amyloids without suffering any obvious ill effect. Although the precise mechanisms are unclear, there are a number of ways in which amyloid toxicity may be prevented. These include regulating the level of the amyloidogenic peptides and proteins, minimising the production of prefibrillar oligomers in amyloid assembly reactions, sequestrating amyloids within membrane bound organelles, controlling amyloid assembly by other molecules, and disassembling the fibrils under physiological conditions. Crucially, a better understanding of how toxicity is avoided in the production of functional amyloids may provide insights into the prevention of amyloid toxicity in amyloidoses.

High frequency NcoI RFLP detected in the Alzheimer amyloid peptide gene

Energy Technology Data Exchange (ETDEWEB)

Wu, Y; Dobkin, C; Devine-Gage, E; Ramakrishna, N; Brown, W T; Wisniewski, H M; Robakis, N K

1988-02-25

Probe pAMB2.3 contains a 778bp cDNA fragment encoding the amyloid polypeptide of Alzheimer disease and Down Syndrome (beta protein) inserted into pUC18. The probe was sublocalized to chromosome 21q21. NcoI identifies a two allele polymorphism of a band at either 15 kb or 8.5 kb. Autosomal codominant inheritance was shown in five informative families. Two non polymorphic bands, 7.0kb and 6.0kb, are seen only occasionally. Their presence seems to depend on the particular DNA preparation.

Shear-Induced Amyloid Formation in the Brain: I. Potential Vascular and Parenchymal Processes.

Science.gov (United States)

Trumbore, Conrad N

2016-09-06

Shear distortion of amyloid-beta (Aβ) solutions accelerates amyloid cascade reactions that may yield different toxic oligomers than those formed in quiescent solutions. Recent experiments indicate that cerebrospinal fluid (CSF) and interstitial fluid (ISF) containing Aβ flow through narrow brain perivascular pathways and brain parenchyma. This paper suggests that such flow causes shear distortion of Aβ molecules involving conformation changes that may be one of the initiating events in the etiology of Alzheimer's disease. Aβ shearing can occur in or around brain arteries and arterioles and is suggested as the origin of cerebral amyloid angiopathy deposits in cerebrovascular walls. Comparatively low flow rates of ISF within the narrow extracellular spaces (ECS) of the brain parenchyma are suggested as a possible initiating factor in both the formation of neurotoxic Aβ42 oligomers and amyloid fibrils. Aβ42 in slow-flowing ISF can gain significant shear energy at or near the walls of tortuous brain ECS flow paths, promoting the formation of a shear-distorted, excited state hydrophobic Aβ42* conformation. This Aβ42* molecule could possibly be involved in one of two paths, one involving rapid adsorption to a brain membrane surface, ultimately forming neurotoxic oligomers on membranes, and the other ultimately forming plaque within the ECS flow pathways. Rising Aβ concentrations combined with shear at or near critical brain membranes are proposed as contributing factors to Alzheimer's disease neurotoxicity. These hypotheses may be applicable in other neurodegenerative diseases, including tauopathies and alpha-synucleinopathies, in which shear-distorted proteins also may form in the brain ECS.

Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation

Directory of Open Access Journals (Sweden)

Cláudia Caldeira

2017-08-01

Full Text Available Alzheimer’s disease (AD is characterized by a progressive cognitive decline and believed to be driven by the self-aggregation of amyloid-β (Aβ peptide into oligomers and fibrils that accumulate as senile plaques. It is widely accepted that microglia-mediated inflammation is a significant contributor to disease pathogenesis; however, different microglia phenotypes were identified along AD progression and excessive Aβ production was shown to dysregulate cell function. As so, the contribution of microglia to AD pathogenesis remains to be elucidated. In this study, we wondered if isolated microglia cultured for 16 days in vitro (DIV would react differentially from the 2 DIV cells upon treatment with 1000 nM Aβ1–42 for 24 h. No changes in cell viability were observed and morphometric alterations associated to microglia activation, such as volume increase and process shortening, were obvious in 2 DIV microglia, but less evident in 16 DIV cells. These cells showed lower phagocytic, migration and autophagic properties after Aβ treatment than the 2 DIV cultured microglia. Reduced phagocytosis may derive from increased CD33 expression, reduced triggering receptor expressed on myeloid cells 2 (TREM2 and milk fat globule-EGF factor 8 protein (MFG-E8 levels, which were mainly observed in 16 DIV cells. Activation of inflammatory mediators, such as high mobility group box 1 (HMGB1 and pro-inflammatory cytokines, as well as increased expression of Toll-like receptor 2 (TLR2, TLR4 and fractalkine/CX3C chemokine receptor 1 (CX3CR1 cell surface receptors were prominent in 2 DIV microglia, while elevation of matrix metalloproteinase 9 (MMP9 was marked in 16 DIV cells. Increased senescence-associated β-galactosidase (SA-β-gal and upregulated miR-146a expression that were observed in 16 DIV cells showed to increase by Aβ in 2 DIV microglia. Additionally, Aβ downregulated miR-155 and miR-124, and reduced the CD11b+ subpopulation in 2 DIV microglia, while

Cholinergic Neurons - Keeping Check on Amyloid beta in the Cerebral Cortex

Directory of Open Access Journals (Sweden)

Saak V. Ovsepian

2013-12-01

Full Text Available The physiological relevance of the uptake of ligands with no apparent trophic functions via the p75 neurotrophin receptor (p75NTR remains unclear. Herein, we propose a homeostatic role for this in clearance of amyloid β (Aβ in the brain. We hypothesize that uptake of Aβ in conjunction with p75NTR followed by its degradation in lysosomes endows cholinergic basalo-cortical projections enriched in this receptor a facility for maintaining physiological levels of Aβ in target areas. Thus, in addition to the diffuse modulator influence and channeling of extra-thalamic signals, cholinergic innervations could supply the cerebral cortex with an elaborate system for Aβ drainage. Interpreting the emerging relationship of new molecular data with established role of cholinergic modulator system in regulating cortical network dynamics should provide new insights into the brain physiology and mechanisms of neuro-degenerative diseases.

Lower Serum Paraoxonase-1 Activity Is Related to Higher Serum Amyloid A Levels in Metabolic Syndrome

NARCIS (Netherlands)

Kappelle, Paul Jan Willem Herman; Bijzet, Johan; Hazenberg, Bouke Pier; Dullaart, Robin Pieter Frank

Background and Aims. High-density lipoproteins (HDL) contain the anti-oxidative enzyme, paraoxonase-1 (PON-1), which is important for atheroprotection. The acute phase reactant, serum amyloid A (SAA), an HDL-associated apolipoprotein, may impair PON-1 activity, whereas SAA and PON-1 are reciprocally

A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies.

Science.gov (United States)

Lathuilière, Aurélien; Laversenne, Vanessa; Astolfo, Alberto; Kopetzki, Erhard; Jacobsen, Helmut; Stampanoni, Marco; Bohrmann, Bernd; Schneider, Bernard L; Aebischer, Patrick

2016-05-01

Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease

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Yokokura, Masamichi; Mori, Norio; Yoshihara, Yujiro; Wakuda, Tomoyasu; Takebayashi, Kiyokazu; Iwata, Yasuhide; Nakamura, Kazuhiko [Hamamatsu University School of Medicine, Department of Psychiatry and Neurology, Hamamatsu (Japan); Yagi, Shunsuke; Ouchi, Yasuomi [Hamamatsu University School of Medicine, Laboratory of Human Imaging Research, Molecular Imaging Frontier Research Center, Hamamatsu (Japan); Yoshikawa, Etsuji [Hamamatsu Photonics K.K., Central Research Laboratory, Hamamatsu (Japan); Kikuchi, Mitsuru [Kanazawa University, Department of Psychiatry and Neurobiology, Graduate School of Medical Science, Kanazawa (Japan); Sugihara, Genichi; Suda, Shiro; Tsuchiya, Kenji J.; Suzuki, Katsuaki [Hamamatsu University School of Medicine, Research Center for Child Mental Development, Hamamatsu (Japan); Ueki, Takatoshi [Hamamatsu University School of Medicine, Department of Anatomy, Hamamatsu (Japan)

2011-02-15

Amyloid {beta} protein (A{beta}) is known as a pathological substance in Alzheimer's disease (AD) and is assumed to coexist with a degree of activated microglia in the brain. However, it remains unclear whether these two events occur in parallel with characteristic hypometabolism in AD in vivo. The purpose of the present study was to clarify the in vivo relationship between A{beta} accumulation and neuroinflammation in those specific brain regions in early AD. Eleven nootropic drug-naive AD patients underwent a series of positron emission tomography (PET) measurements with [{sup 11}C](R)PK11195, [{sup 11}C]PIB and [{sup 18}F]FDG and a battery of cognitive tests within the same day. The binding potentials (BPs) of [{sup 11}C](R)PK11195 were directly compared with those of [{sup 11}C]PIB in the brain regions with reduced glucose metabolism. BPs of [{sup 11}C](R)PK11195 and [{sup 11}C]PIB were significantly higher in the parietotemporal regions of AD patients than in ten healthy controls. In AD patients, there was a negative correlation between dementia score and [{sup 11}C](R)PK11195 BPs, but not [{sup 11}C]PIB, in the limbic, precuneus and prefrontal regions. Direct comparisons showed a significant negative correlation between [{sup 11}C](R)PK11195 and [{sup 11}C]PIB BPs in the posterior cingulate cortex (PCC) (p < 0.05, corrected) that manifested the most severe reduction in [{sup 18}F]FDG uptake. A lack of coupling between microglial activation and amyloid deposits may indicate that A{beta} accumulation shown by [{sup 11}C]PIB is not always the primary cause of microglial activation, but rather the negative correlation present in the PCC suggests that microglia can show higher activation during the production of A{beta} in early AD. (orig.)

Amyloid Goiter Secondary to Ulcerative Colitis

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Bunyamin Aydin

2016-01-01

Full Text Available Diffuse amyloid goiter (AG is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn’s disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis.

Chiral recognition in amyloid fiber growth.

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Torbeev, Vladimir; Grogg, Marcel; Ruiz, Jérémy; Boehringer, Régis; Schirer, Alicia; Hellwig, Petra; Jeschke, Gunnar; Hilvert, Donald

2016-05-01

Insoluble amyloid fibers represent a pathological signature of many human diseases. To treat such diseases, inhibition of amyloid formation has been proposed as a possible therapeutic strategy. d-Peptides, which possess high proteolytic stability and lessened immunogenicity, are attractive candidates in this context. However, a molecular understanding of chiral recognition phenomena for d-peptides and l-amyloids is currently incomplete. Here we report experiments on amyloid growth of individual enantiomers and their mixtures for two distinct polypeptide systems of different length and structural organization: a 44-residue covalently-linked dimer derived from a peptide corresponding to the [20-41]-fragment of human β2-microglobulin (β2m) and the 99-residue full-length protein. For the dimeric [20-41]β2m construct, a combination of electron paramagnetic resonance of nitroxide-labeled constructs and (13) C-isotope edited FT-IR spectroscopy of (13) C-labeled preparations was used to show that racemic mixtures precipitate as intact homochiral fibers, i.e. undergo spontaneous Pasteur-like resolution into a mixture of left- and right-handed amyloids. In the case of full-length β2m, the presence of the mirror-image d-protein affords morphologically distinct amyloids that are composed largely of enantiopure domains. Removal of the l-component from hybrid amyloids by proteolytic digestion results in their rapid transformation into characteristic long straight d-β2m amyloids. Furthermore, the full-length d-enantiomer of β2m was found to be an efficient inhibitor of l-β2m amyloid growth. This observation highlights the potential of longer d-polypeptides for future development into inhibitors of amyloid propagation. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

A single amino acid difference between the intracellular domains of amyloid precursor protein and amyloid-like precursor protein 2 enables induction of synaptic depression and block of long-term potentiation.

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Trillaud-Doppia, Emilie; Paradis-Isler, Nicolas; Boehm, Jannic

2016-07-01

Alzheimer disease (AD) is initially characterized as a disease of the synapse that affects synaptic transmission and synaptic plasticity. While amyloid-beta and tau have been traditionally implicated in causing AD, recent studies suggest that other factors, such as the intracellular domain of the amyloid-precursor protein (APP-ICD), can also play a role in the development of AD. Here, we show that the expression of APP-ICD induces synaptic depression, while the intracellular domain of its homolog amyloid-like precursor protein 2 (APLP2-ICD) does not. We are able to show that this effect by APP-ICD is due to a single alanine vs. proline difference between APP-ICD and APLP2-ICD. The alanine in APP-ICD and the proline in APLP2-ICD lie directly behind a conserved caspase cleavage site. Inhibition of caspase cleavage of APP-ICD prevents the induction of synaptic depression. Finally, we show that the expression of APP-ICD increases and facilitates long-term depression and blocks induction of long-term potentiation. The block in long-term potentiation can be overcome by mutating the aforementioned alanine in APP-ICD to the proline of APLP2. Based on our results, we propose the emergence of a new APP critical domain for the regulation of synaptic plasticity and in consequence for the development of AD. Copyright © 2016 Elsevier Inc. All rights reserved.

Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells.

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Fonseca, Ana Catarina R G; Ferreiro, Elisabete; Oliveira, Catarina R; Cardoso, Sandra M; Pereira, Cláudia F

2013-12-01

Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. Finally, Aβ1-40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration. © 2013.

Direct exposure of guinea pig CNS to human luteinizing hormone increases cerebrospinal fluid and cerebral beta amyloid levels.

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Wahjoepramono, Eka J; Wijaya, Linda K; Taddei, Kevin; Bates, Kristyn A; Howard, Matthew; Martins, Georgia; deRuyck, Karl; Matthews, Paul M; Verdile, Giuseppe; Martins, Ralph N

2011-01-01

Luteinizing hormone (LH) has been shown to alter the metabolism of beta amyloid (Aβ), a key protein in Alzheimer's disease (AD) pathogenesis. While LH and components required for LH receptor signalling are present in the brain, their role in the CNS remains unclear. In vitro, LH has been shown to facilitate neurosteroid production and alter Aβ metabolism. However, whether LH can directly modulate cerebral Aβ levels in vivo has not previously been studied. In this study, we investigated the effect of chronic administration of LH to the guinea pig CNS on cerebral Aβ levels. Gonadectomised male animals were administered, via cortical placement, either placebo or LH slow-release pellets. At 14 and 28 days after treatment, animals were sacrificed. Brain, plasma and CSF were collected and Aβ levels measured via ELISA. Levels of the Aβ precursor protein (APP) and the neurosteroidogenic enzyme cytochrome P450 side-chain cleavage enzyme (P450scc) were also assayed. An increase in CSF Aβ40 levels was observed 28 days following treatment. These CSF data also reflected changes in Aβ40 levels observed in brain homogenates. No change was observed in plasma Aβ40 levels but APP and its C-terminal fragments (APP-CTF) were significantly increased in response to LH exposure. Protein expression of P450scc was increased after 28 days of LH exposure, suggesting activation of the LH receptor. These data indicate that direct exposure of guinea pig CNS to LH results in altered brain Aβ levels, perhaps due to altered APP expression/metabolism. Copyright © 2011 S. Karger AG, Basel.

Effects of memantine on cognition in patients with moderate to severe Alzheimer's disease: post-hoc analyses of ADAS-cog and SIB total and single-item scores from six randomized, double-blind, placebo-controlled studies.

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Mecocci, Patrizia; Bladström, Anna; Stender, Karina

2009-05-01

The post-hoc analyses reported here evaluate the specific effects of memantine treatment on ADAS-cog single-items or SIB subscales for patients with moderate to severe AD. Data from six multicentre, randomised, placebo-controlled, parallel-group, double-blind, 6-month studies were used as the basis for these post-hoc analyses. All patients with a Mini-Mental State Examination (MMSE) score of less than 20 were included. Analyses of patients with moderate AD (MMSE: 10-19), evaluated with the Alzheimer's disease Assessment Scale (ADAS-cog) and analyses of patients with moderate to severe AD (MMSE: 3-14), evaluated using the Severe Impairment Battery (SIB), were performed separately. The mean change from baseline showed a significant benefit of memantine treatment on both the ADAS-cog (p ADAS-cog single-item analyses showed significant benefits of memantine treatment, compared to placebo, for mean change from baseline for commands (p < 0.001), ideational praxis (p < 0.05), orientation (p < 0.01), comprehension (p < 0.05), and remembering test instructions (p < 0.05) for observed cases (OC). The SIB subscale analyses showed significant benefits of memantine, compared to placebo, for mean change from baseline for language (p < 0.05), memory (p < 0.05), orientation (p < 0.01), praxis (p < 0.001), and visuospatial ability (p < 0.01) for OC. Memantine shows significant benefits on overall cognitive abilities as well as on specific key cognitive domains for patients with moderate to severe AD. (c) 2009 John Wiley & Sons, Ltd.

Expression and antimicrobial function of beta-defensin 1 in the lower urinary tract.

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Brian Becknell

Full Text Available Beta defensins (BDs are cationic peptides with antimicrobial activity that defend epithelial surfaces including the skin, gastrointestinal, and respiratory tracts. However, BD expression and function in the urinary tract are incompletely characterized. The purpose of this study was to describe Beta Defensin-1 (BD-1 expression in the lower urinary tract, regulation by cystitis, and antimicrobial activity toward uropathogenic Escherichia coli (UPEC in vivo. Human DEFB1 and orthologous mouse Defb1 mRNA are detectable in bladder and ureter homogenates, and human BD-1 protein localizes to the urothelium. To determine the relevance of BD-1 to lower urinary tract defense in vivo, we evaluated clearance of UPEC by Defb1 knockout (Defb1(-/- mice. At 6, 18, and 48 hours following transurethral UPEC inoculation, no significant differences were observed in bacterial burden in bladders or kidneys of Defb1(-/- and wild type C57BL/6 mice. In wild type mice, bladder Defb1 mRNA levels decreased as early as two hours post-infection and reached a nadir by six hours. RT-PCR profiling of BDs identified expression of Defb3 and Defb14 mRNA in murine bladder and ureter, which encode for mBD-3 and mBD-14 protein, respectively. MBD-14 protein expression was observed in bladder urothelium following UPEC infection, and both mBD-3 and mBD-14 displayed dose-dependent bactericidal activity toward UPEC in vitro. Thus, whereas mBD-1 deficiency does not alter bladder UPEC burden in vivo, we have identified mBD-3 and mBD-14 as potential mediators of mucosal immunity in the lower urinary tract.

Expression and Antimicrobial Function of Beta-Defensin 1 in the Lower Urinary Tract

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Becknell, Brian; Spencer, John David; Carpenter, Ashley R.; Chen, Xi; Singh, Aspinder; Ploeger, Suzanne; Kline, Jennifer; Ellsworth, Patrick; Li, Birong; Proksch, Ehrhardt; Schwaderer, Andrew L.; Hains, David S.; Justice, Sheryl S.; McHugh, Kirk M.

2013-01-01

Beta defensins (BDs) are cationic peptides with antimicrobial activity that defend epithelial surfaces including the skin, gastrointestinal, and respiratory tracts. However, BD expression and function in the urinary tract are incompletely characterized. The purpose of this study was to describe Beta Defensin-1 (BD-1) expression in the lower urinary tract, regulation by cystitis, and antimicrobial activity toward uropathogenic Escherichia coli (UPEC) in vivo. Human DEFB1 and orthologous mouse Defb1 mRNA are detectable in bladder and ureter homogenates, and human BD-1 protein localizes to the urothelium. To determine the relevance of BD-1 to lower urinary tract defense in vivo, we evaluated clearance of UPEC by Defb1 knockout (Defb1 -/-) mice. At 6, 18, and 48 hours following transurethral UPEC inoculation, no significant differences were observed in bacterial burden in bladders or kidneys of Defb1 -/- and wild type C57BL/6 mice. In wild type mice, bladder Defb1 mRNA levels decreased as early as two hours post-infection and reached a nadir by six hours. RT-PCR profiling of BDs identified expression of Defb3 and Defb14 mRNA in murine bladder and ureter, which encode for mBD-3 and mBD-14 protein, respectively. MBD-14 protein expression was observed in bladder urothelium following UPEC infection, and both mBD-3 and mBD-14 displayed dose-dependent bactericidal activity toward UPEC in vitro. Thus, whereas mBD-1 deficiency does not alter bladder UPEC burden in vivo, we have identified mBD-3 and mBD-14 as potential mediators of mucosal immunity in the lower urinary tract. PMID:24204930

Amyloid beta Fibril Elongation by Monomers Involves Disorder at the Tip

Czech Academy of Sciences Publication Activity Database

Bacci, M.; Vymětal, Jiří; Mihajlovic, M.; Caflisch, A.; Vitalis, A.

2017-01-01

Roč. 13, č. 10 (2017), s. 5117-5130 ISSN 1549-9618 Institutional support: RVO:61388963 Keywords : molecular dynamics simulations * atomic resolution structure * A beta Subject RIV: CF - Physical ; Theoretical Chemistry OBOR OECD: Physical chemistry Impact factor: 5.245, year: 2016

The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors.

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Grossberg, George T; Manes, Facundo; Allegri, Ricardo F; Gutiérrez-Robledo, Luis Miguel; Gloger, Sergio; Xie, Lei; Jia, X Daniel; Pejović, Vojislav; Miller, Michael L; Perhach, James L; Graham, Stephen M

2013-06-01

Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer's disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors. In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3-14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran-Mantel-Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations. A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS-ADL19 (p = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9�

Catalpol ameliorates beta amyloid-induced degeneration of cholinergic neurons by elevating brain-derived neurotrophic factors.

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Wang, Z; Liu, Q; Zhang, R; Liu, S; Xia, Z; Hu, Y

2009-11-10

The purpose of this work is to study the effect of catalpol, an iridoid from Rehmannia glutinosa on neurodegenerative changes induced by beta-amyloid peptide Abeta(25-35) or Abeta(25-35)+ibotenic acid and the underlying mechanism. Results showed that catalpol significantly improved the memory deficits in the neurodegenerative mouse model produced by injection of Abeta(25-35)+ibotenic acid to the nucleus magnocellularis basalis, yet it is neither a cholinesterase inhibitor nor a muscarinic (M) receptor agonist. Instead, the choline acetyl transferase (ChAT) activity and the M receptor density in brain were significantly decreased in the model mice and catalpol could significantly elevate their levels. Furthermore, the brain-derived neurotrophic factor (BDNF) content in brain was significantly decreased in the model mice and catalpol elevated it to normal level (83%+/-3% and 102%+/-2% of normal respectively). There is a significant positive correlation between BDNF content and memory. Primary culture of forebrain neurons revealed that aggregated Abeta(25-35) induced significant decrease of ChAT positive neuron number, neurite outgrowth length, and M receptor density, while catalpol added to the culture medium 2 h prior to Abeta addition showed significant dose dependent protective effect. Notably, 24 h and 48 h after the addition of Abeta to the cultured cells, the BDNF mRNA level in the neurons decreased to 76%+/-7% and 66%+/-3% of control without catalpol treatment, but became 128%+/-17% and 131%+/-23% of control with catalpol treatment. When the action of BDNF was inhibited by k252a in the cultured neurons, the protective effect of catalpol was completely (neurite outgrowth length) or partially (ChAT positive neuron number and the M receptor density) abolished. Taken together, catalpol improves memory and protects the forebrain neurons from neurodegeneration through increasing BDNF expression. Whether catalpol could reverse the neurodegenerative changes already

[Memantine as add-on medication to acetylcholinesterase inhibitor therapy for Alzheimer dementia].

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Haussmann, R; Donix, M

2017-01-01

Currently available data indicate superior therapeutic effects of combination treatment for Alzheimer dementia with memantine and acetylcholine esterase inhibitors in certain clinical contexts. Out of five randomized, placebo-controlled, double-blind trials two showed superior therapeutic effects in comparison to monotherapy with acetylcholinesterase inhibitors regarding various domains. Recently published meta-analyses and cost-benefit analyses also showed positive results. Recently published German guidelines for dementia treatment also take these new data into account and recommend combination treatment in patients with severe dementia on stable donepezil medication. This article gives an overview of current evidence for combination therapy.

Mitogen-activated protein kinase signaling pathways promote low-density lipoprotein receptor-related protein 1-mediated internalization of beta-amyloid protein in primary cortical neurons.

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Yang, Wei-Na; Ma, Kai-Ge; Qian, Yi-Hua; Zhang, Jian-Shui; Feng, Gai-Feng; Shi, Li-Li; Zhang, Zhi-Chao; Liu, Zhao-Hui

2015-07-01

Mounting evidence suggests that the pathological hallmarks of Alzheimer's disease (AD) are caused by the intraneuronal accumulation of beta-amyloid protein (Aβ). Reuptake of extracellular Aβ is believed to contribute significantly to the intraneuronal Aβ pool in the early stages of AD. Published reports have claimed that the low-density lipoprotein receptor-related protein 1 (LRP1) mediates Aβ1-42 uptake and lysosomal trafficking in GT1-7 neuronal cells and mouse embryonic fibroblast non-neuronal cells. However, there is no direct evidence supporting the role of LRP1 in Aβ internalization in primary neurons. Our recent study indicated that p38 MAPK and ERK1/2 signaling pathways are involved in regulating α7 nicotinic acetylcholine receptor (α7nAChR)-mediated Aβ1-42 uptake in SH-SY5Y cells. This study was designed to explore the regulation of MAPK signaling pathways on LRP1-mediated Aβ internalization in neurons. We found that extracellular Aβ1-42 oligomers could be internalized into endosomes/lysosomes and mitochondria in cortical neurons. Aβ1-42 and LRP1 were also found co-localized in neurons during Aβ1-42 internalization, and they could form Aβ1-42-LRP1 complex. Knockdown of LRP1 expression significantly decreased neuronal Aβ1-42 internalization. Finally, we identified that p38 MAPK and ERK1/2 signaling pathways regulated the internalization of Aβ1-42 via LRP1. Therefore, these results demonstrated that LRP1, p38 MAPK and ERK1/2 mediated the internalization of Aβ1-42 in neurons and provided evidence that blockade of LRP1 or inhibitions of MAPK signaling pathways might be a potential approach to lowering brain Aβ levels and served a potential therapeutic target for AD. Copyright © 2015 Elsevier Ltd. All rights reserved.

Proteomic screening for amyloid proteins.

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Anton A Nizhnikov

Full Text Available Despite extensive study, progress in elucidation of biological functions of amyloids and their role in pathology is largely restrained due to the lack of universal and reliable biochemical methods for their discovery. All biochemical methods developed so far allowed only identification of glutamine/asparagine-rich amyloid-forming proteins or proteins comprising amyloids that form large deposits. In this article we present a proteomic approach which may enable identification of a broad range of amyloid-forming proteins independently of specific features of their sequences or levels of expression. This approach is based on the isolation of protein fractions enriched with amyloid aggregates via sedimentation by ultracentrifugation in the presence of strong ionic detergents, such as sarkosyl or SDS. Sedimented proteins are then separated either by 2D difference gel electrophoresis or by SDS-PAGE, if they are insoluble in the buffer used for 2D difference gel electrophoresis, after which they are identified by mass-spectrometry. We validated this approach by detection of known yeast prions and mammalian proteins with established capacity for amyloid formation and also revealed yeast proteins forming detergent-insoluble aggregates in the presence of human huntingtin with expanded polyglutamine domain. Notably, with one exception, all these proteins contained glutamine/asparagine-rich stretches suggesting that their aggregates arose due to polymerization cross-seeding by human huntingtin. Importantly, though the approach was developed in a yeast model, it can easily be applied to any organism thus representing an efficient and universal tool for screening for amyloid proteins.

Natural triple beta-stranded fibrous folds.

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Mitraki, Anna; Papanikolopoulou, Katerina; Van Raaij, Mark J

2006-01-01

A distinctive family of beta-structured folds has recently been described for fibrous proteins from viruses. Virus fibers are usually involved in specific host-cell recognition. They are asymmetric homotrimeric proteins consisting of an N-terminal virus-binding tail, a central shaft or stalk domain, and a C-terminal globular receptor-binding domain. Often they are entirely or nearly entirely composed of beta-structure. Apart from their biological relevance and possible gene therapy applications, their shape, stability, and rigidity suggest they may be useful as blueprints for biomechanical design. Folding and unfolding studies suggest their globular C-terminal domain may fold first, followed by a "zipping-up" of the shaft domains. The C-terminal domains appear to be important for registration because peptides corresponding to shaft domains alone aggregate into nonnative fibers and/or amyloid structures. C-terminal domains can be exchanged between different fibers and the resulting chimeric proteins are useful as a way to solve structures of unknown parts of the shaft domains. The following natural triple beta-stranded fibrous folds have been discovered by X-ray crystallography: the triple beta-spiral, triple beta-helix, and T4 short tail fiber fold. All have a central longitudinal hydrophobic core and extensive intermonomer polar and nonpolar interactions. Now that a reasonable body of structural and folding knowledge has been assembled about these fibrous proteins, the next challenge and opportunity is to start using this information in medical and industrial applications such as gene therapy and nanotechnology.

Interaction of magnetic nanoparticles with lysozyme amyloid fibrils

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Gdovinová, Veronika [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia); Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Tomašovičová, Natália, E-mail: nhudak@saske.sk [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia); Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Batko, Ivan; Batková, Marianna; Balejčíková, Lucia [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia); Garamus, Vasyl M. [Helmholtz-Zentrum Geesthacht: Zentrum fr Material, und Kstenforschung GmbH, Max-Plank-Strae 1, Geesthacht 216502 (Germany); Petrenko, Viktor I. [Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Physics Department, Taras Shevchenko Kyiv National University, Volodymyrska Street 64, 01601 Kyiv (Ukraine); Avdeev, Mikhail V. [Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, Joliot-Curie 6, 141980 Dubna, Moscow Region (Russian Federation); Kopčanský, Peter [Institute of Experimental Physics SAS, Watsonova 47, 040 01 Košice (Slovakia)

2017-06-01

This work is devoted to the structural study of complex solutions of magnetic nanoparticles with lysozyme amyloid fibrils due to possible ordering of such system by applying the external magnetic field. The interaction of magnetic nanoparticles with amyloid fibrils has been followed by atomic force microscopy and small-angle X-ray scattering. It has been observed that magnetic nanoparticles (MNPs) adsorb to lysozyme amyloid fibrils. It was found that MNPs alter amyloids structures, namely the diameter of lysozyme amyloid fibrils is increased whereas the length of fibrils is decreased. In the same time MNPs do not change the helical pitch significantly. - Highlights: • Solution of MNPs with lysozyme amyloid fibrils was characterized by AFM and SAXS. • MNPs adsorb to lysozyme amyloid fibrils. • Diameter and size of lysozyme amyloid fibrils change due to doping with MNPs.

Tetrahydroxystilbene glucoside modulates amyloid precursor protein processing via activation of AKT-GSK3β pathway in cells and in APP/PS1 transgenic mice.

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Yin, Xiaomin; Chen, Chen; Xu, Ting; Li, Lin; Zhang, Lan

2018-01-01

Alternative splicing of amyloid precursor protein (APP) exon 7 generates the isoforms containing a Kunitz protease inhibitor (KPI) domain. APP-KPI levels in the brain are correlated with amyloid beta (Aβ) production. Here, we determined the effect of Tetrahydroxystilbene glucoside (TSG) on the AKT-GSK3β pathway. We found GSK3β increased APP-KPI inclusion level and interacted with the splicing factor ASF. TSG was intragastrically administered to 5-month-old APP/PS1 transgenic mice for 12 months. We found that the activated the AKT-GSK3β signaling pathway suppressed APP-KPI inclusion. Moreover, TSG treatment attenuated amyloid deposition in APP/PS1 mice. This study demonstrates the neuroprotective effect of TSG on APP expression, suggesting that TSG may be beneficial for AD prevention and treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Key aromatic/hydrophobic amino acids controlling a cross-amyloid peptide interaction versus amyloid self-assembly.

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Bakou, Maria; Hille, Kathleen; Kracklauer, Michael; Spanopoulou, Anna; Frost, Christina V; Malideli, Eleni; Yan, Li-Mei; Caporale, Andrea; Zacharias, Martin; Kapurniotu, Aphrodite

2017-09-01

The interaction of the intrinsically disordered polypeptide islet amyloid polypeptide (IAPP), which is associated with type 2 diabetes (T2D), with the Alzheimer's disease amyloid-β (Aβ) peptide modulates their self-assembly into amyloid fibrils and may link the pathogeneses of these two cell-degenerative diseases. However, the molecular determinants of this interaction remain elusive. Using a systematic alanine scan approach, fluorescence spectroscopy, and other biophysical methods, including heterocomplex pulldown assays, far-UV CD spectroscopy, the thioflavin T binding assay, transmission EM, and molecular dynamics simulations, here we identified single aromatic/hydrophobic residues within the amyloid core IAPP region as hot spots or key residues of its cross-interaction with Aβ40(42) peptide. Importantly, we also find that none of these residues in isolation plays a key role in IAPP self-assembly, whereas simultaneous substitution of four aromatic/hydrophobic residues with Ala dramatically impairs both IAPP self-assembly and hetero-assembly with Aβ40(42). Furthermore, our experiments yielded several novel IAPP analogs, whose sequences are highly similar to that of IAPP but have distinct amyloid self- or cross-interaction potentials. The identified similarities and major differences controlling IAPP cross-peptide interaction with Aβ40(42) versus its amyloid self-assembly offer a molecular basis for understanding the underlying mechanisms. We propose that these insights will aid in designing intervention strategies and novel IAPP analogs for the management of type 2 diabetes, Alzheimer's disease, or other diseases related to IAPP dysfunction or cross-amyloid interactions. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Eicosanoyl-5-hydroxytryptamide (EHT prevents Alzheimer's disease-related cognitive and electrophysiological impairments in mice exposed to elevated concentrations of oligomeric beta-amyloid.

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Kesava Asam

Full Text Available Soluble forms of oligomeric beta-amyloid (Aβ are thought to play a central role in Alzheimer's disease (AD. Transgenic manipulation of methylation of the serine/threonine protein phosphatase, PP2A, was recently shown to alter the sensitivity of mice to AD-related impairments resulting from acute exposure to elevated levels of Aβ. In addition, eicosanoyl-5-hydroxytryptamide (EHT, a naturally occurring component from coffee beans that modulates PP2A methylation, was shown to confer therapeutic benefits in rodent models of AD and Parkinson's disease. Here, we tested the hypothesis that EHT protects animals from the pathological effects of exposure to elevated levels of soluble oligomeric Aβ. We treated mice with EHT-containing food at two different doses and assessed the sensitivity of these animals to Aβ-induced behavioral and electrophysiological impairments. We found that EHT administration protected animals from Aβ-induced cognitive impairments in both a radial-arm water maze and contextual fear conditioning task. We also found that both chronic and acute EHT administration prevented Aβ-induced impairments in long-term potentiation. These data add to the accumulating evidence suggesting that interventions with pharmacological agents, such as EHT, that target PP2A activity may be therapeutically beneficial for AD and other neurological conditions.

Specific recognition of the C-terminal end of A beta 42 by a high affinity monoclonal antibody

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Axelsen, Trine Veje; Holm, Arne; Birkelund, Svend

2009-01-01

The neurotoxic peptide A beta(42) is derived from the amyloid precursor protein by proteolytic cleavage and is deposited in the brain of patients suffering from Alzheimer's disease (AD). In this study we generate a high affinity monoclonal antibody that targets the C-terminal end of A beta(42......) with high specificity. By this is meant that the paratope of the antibody must enclose the C-terminal end of A beta(42) including the carboxy-group of amino acid 42, and not just recognize a linear epitope in the C-terminal part of A beta. This has been accomplished by using a unique antigen construct made...... by the Ligand Presenting Assembly technology (LPA technology). This strategy results in dimeric presentation of the free C-terminal end of A beta(42). The generated Mab A beta1.1 is indeed specific for the C-terminal end of A beta(42) to which it binds with high affinity. Mab A beta1.1 recognizes the epitope...

Critical appraisal of the long-term impact of memantine in treatment of moderate to severe Alzheimer’s disease

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Umamon Puangthong

2009-10-01

Full Text Available Umamon Puangthong, Ging-Yuek Robin HsiungDivision of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, CanadaAbstract: Alzheimer’s disease is the most common cause of dementia in older adults. The clinical features include progressive memory decline as well as cognitive deficits with executive dysfunction, language, visual perceptual difficulties, apraxia and agnosia. During the moderate to severe stage of the disease, there is a major decline in memory and function, while neuropsychiatric disturbances often emerge and patients become difficult to manage. These distressing symptoms increase caregiver burden and add to the direct costs of care of the patients. Any improvements in patient function and behavioral symptoms can reduce caregiver burden. Memantine has been available for a number of years in Europe and in North America. In this article, we examine the pharmacological rationale for its use, and the current clinical evidence for its efficacy and long-term effectiveness in the management of cognitive and behavioral symptoms in moderate to severe stages of Alzheimer’s disease.Keywords: memantine, Alzheimer’s disease, dementia

Astrocytic gap junctional communication is reduced in amyloid-β-treated cultured astrocytes, but not in Alzheimer's disease transgenic mice.

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Cruz, Nancy F; Ball, Kelly K; Dienel, Gerald A

2010-08-17

Alzheimer's disease is characterized by accumulation of amyloid deposits in brain, progressive cognitive deficits and reduced glucose utilization. Many consequences of the disease are attributed to neuronal dysfunction, but roles of astrocytes in its pathogenesis are not well understood. Astrocytes are extensively coupled via gap junctions, and abnormal trafficking of metabolites and signalling molecules within astrocytic syncytia could alter functional interactions among cells comprising the neurovascular unit. To evaluate the influence of amyloid-beta on astrocyte gap junctional communication, cultured astrocytes were treated with monomerized amyloid-β(1-40) (1 μmol/l) for intervals ranging from 2 h to 5 days, and the areas labelled by test compounds were determined by impaling a single astrocyte with a micropipette and diffusion of material into coupled cells. Amyloid-β-treated astrocytes had rapid, sustained 50-70% reductions in the area labelled by Lucifer Yellow, anionic Alexa Fluor® dyes and energy-related compounds, 6-NBDG (a fluorescent glucose analogue), NADH and NADPH. Amyloid-β treatment also caused a transient increase in oxidative stress. In striking contrast with these results, spreading of Lucifer Yellow within astrocytic networks in brain slices from three regions of 8.5-14-month-old control and transgenic Alzheimer's model mice was variable, labelling 10-2000 cells; there were no statistically significant differences in the number of dye-labelled cells among the groups or with age. Thus amyloid-induced dysfunction of gap junctional communication in cultured astrocytes does not reflect the maintenance of dye transfer through astrocytic syncytial networks in transgenic mice; the pathophysiology of Alzheimer's disease is not appropriately represented by the cell culture system.

AL amyloid imaging and therapy with a monoclonal antibody to a cryptic epitope on amyloid fibrils.

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Jonathan S Wall

Full Text Available The monoclonal antibody 2A4 binds an epitope derived from a cleavage site of serum amyloid protein A (sAA containing a -Glu-Asp- amino acid pairing. In addition to its reactivity with sAA amyloid deposits, the antibody was also found to bind amyloid fibrils composed of immunoglobulin light chains. The antibody binds to synthetic fibrils and human light chain (AL amyloid extracts with high affinity even in the presence of soluble light chain proteins. Immunohistochemistry with biotinylated 2A4 demonstrated positive reaction with ALκ and ALλ human amyloid deposits in various organs. Surface plasmon resonance analyses using synthetic AL fibrils as a substrate revealed that 2A4 bound with a K(D of ∼10 nM. Binding was inhibited in the presence of the -Glu-Asp- containing immunogen peptide. Radiolabeled 2A4 specifically localized with human AL amyloid extracts implanted in mice (amyloidomas as evidenced by single photon emission (SPECT imaging. Furthermore, co-localization of the radiolabeled mAb with amyloid was shown in biodistribution and micro-autoradiography studies. Treatment with 2A4 expedited regression of ALκ amyloidomas in mice, likely mediated by the action of macrophages and neutrophils, relative to animals that received a control antibody. These data indicate that the 2A4 mAb might be of interest for potential imaging and immunotherapy in patients with AL amyloidosis.

Perinatal Asphyxia May Influence the Level of Beta-Amyloid (1-42 in Cerebrospinal Fluid: An Experimental Study on Newborn Pigs.

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Torkil Benterud

Full Text Available Total tau (T-tau, phosphorylated tau (p-Tau and Beta-Amyloid 1-42 (AB42 in Cerebrospinal Fluid (CSF are useful biomarkers in neurodegenerative diseases. The aim of the study was to investigate the role of these and other CSF biomarkers (T-tau, p-Tau, AB42, S100B and NSE, during hypoxia-reoxygenation in a newborn pig model.Thirty newborn pigs were included in a study of moderate or severe hypoxia. The moderate hypoxia group (n = 12 was exposed to global hypoxia (8% O2 until Base excess (BE reached -15 mmol/l. The pigs in the group exposed to severe hypoxia (n = 12 received 8% O2 until BE reached -20 mmol/l or mean Blood Pressure fell below 20 mm Hg, The control group (n = 6 was kept at room air. For all treatments, the CSF was collected at 9.5 hours after the intervention.The level of AB42 in CSF was significantly lower in the pigs exposed to severe hypoxia compared with the control group, 922(SD +/-445pg/ml versus. 1290(SD +/-143 pg/ml (p<0.05, respectively. Further, a non-significant reduction of AB42 was observed in the group exposed to moderate hypoxia T-tau and p-Tau revealed no significant differences between the intervention groups and the control group, however a significantly higher level of S100B was seen in the CSF of pigs receiving hypoxia in comparison to the level in the control group. Further on, there was a moderate negative correlation between the levels of AB42 and S100B in CSF, as well as a moderate negative correlation between Lactate in blood at end of hypoxia and AB42 in CSF.This is the first study to our knowledge that demonstrated a significant drop in AB42 in CSF after neonatal hypoxia. Whether or not this has an etiological basis for adult neurodegenerative disorders needs to be studied with additional experiments and epidemiological studies. AB42 and S100B are significantly changed in neonatal pigs subjected to hypoxia compared to controls and thus may be valuable biomarkers of perinatal asphyxia.

Cost-utility analysis of memantine extended release added to cholinesterase inhibitors compared to cholinesterase inhibitor monotherapy for the treatment of moderate-to-severe dementia of the Alzheimer's type in the US.

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Saint-Laurent Thibault, Catherine; Özer Stillman, Ipek; Chen, Stephanie; Getsios, Denis; Proskorovsky, Irina; Hernandez, Luis; Dixit, Shailja

2015-01-01

This study evaluates the cost-effectiveness of memantine extended release (ER) as an add-on therapy to acetylcholinesterase inhibitor (AChEI) [combination therapy] for treatment of patients with moderate-to-severe Alzheimer's disease (AD) from both a healthcare payer and a societal perspective over 3 years when compared to AChEI monotherapy in the US. A phase III trial evaluated the efficacy and safety of memantine ER for treatment of AD patients taking an AChEI. The analysis assessed the long-term costs and health outcomes using an individual patient simulation in which AD progression is modeled in terms of cognition, behavior, and functioning changes. Input parameters are based on patient-level trial data, published literature, and publicly available data sources. Changes in anti-psychotic medication use are incorporated based on a published retrospective cohort study. Costs include drug acquisition and monitoring, total AD-related medical care, and informal care associated with caregiver time. Incremental cost-utility ratio (ICUR), life years, care time for caregiver, time in community and institution, time on anti-psychotics, time by disease severity, and time without severe symptoms are reported. Costs and health outcomes are discounted at 3% per annum. Considering a societal perspective over 3 years, this analysis shows that memantine ER combined with an AChEI provides better clinical outcomes and lower costs than AChEI monotherapy. Discounted average savings were estimated at $18,355 and $20,947 per patient and quality-adjusted life-years (QALYs) increased by an average of 0.12 and 0.13 from a societal and healthcare payer perspective, respectively. Patients on combination therapy spent an average of 4 months longer living at home and spend less time in moderate-severe and severe stages of the disease. Combination therapy for patients with moderate-to-severe AD is a cost-effective treatment compared to AChEI monotherapy in the US.

Amyloid-β Peptide Induces Prion Protein Amyloid Formation: Evidence for Its Widespread Amyloidogenic Effect.

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Honda, Ryo

2018-04-12

Transmissible spongiform encephalopathy is associated with misfolding of prion protein (PrP) into an amyloid β-rich aggregate. Previous studies have indicated that PrP interacts with Alzheimer's disease amyloid-β peptide (Aβ), but it remains elusive how this interaction impacts on the misfolding of PrP. This study presents the first in vitro evidence that Aβ induces PrP-amyloid formation at submicromolar concentrations. Interestingly, systematic mutagenesis of PrP revealed that Aβ requires no specific amino acid sequences in PrP, and induces the misfolding of other unrelated proteins (insulin and lysozyme) into amyloid fibrils in a manner analogous to PrP. This unanticipated nonspecific amyloidogenic effect of Aβ indicates that this peptide might be involved in widespread protein aggregation, regardless of the amino acid sequences of target proteins, and exacerbate the pathology of many neurodegenerative diseases. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The effect of resveratrol on beta amyloid-induced memory impairment involves inhibition of phosphodiesterase-4 related signaling.

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Wang, Gang; Chen, Ling; Pan, Xiaoyu; Chen, Jiechun; Wang, Liqun; Wang, Weijie; Cheng, Ruochuan; Wu, Fan; Feng, Xiaoqing; Yu, Yingcong; Zhang, Han-Ting; O'Donnell, James M; Xu, Ying

2016-04-05

Resveratrol, a natural polyphenol found in red wine, has wide spectrum of pharmacological properties including antioxidative and antiaging activities. Beta amyloid peptides (Aβ) are known to involve cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer's disease (AD). Activation of cAMP and/or cGMP activities can improve memory performance and decrease the neuroinflammation and apoptosis. However, it remains unknown whether the memory enhancing effect of resveratrol on AD associated cognitive disorders is related to the inhibition of phosphodiesterase 4 (PDE4) subtypes and subsequent increases in intracellular cAMP and/or cGMP activities. This study investigated the effect of resveratrol on Aβ1-42-induced cognitive impairment and the participation of PDE4 subtypes related cAMP or cGMP signaling. Mice microinfused with Aβ1-42 into bilateral CA1 subregions displayed learning and memory impairment, as evidenced by reduced memory acquisition and retrieval in the water maze and retention in the passive avoidance tasks; it was also significant that neuroinflammatory and pro-apoptotic factors were increased in Aβ1-42-treated mice. Aβ1-42-treated mice also increased in PDE4A, 4B and 4D expression, and decreased in PKA level. However, PKA inhibitor H89, but not PKG inhibitor KT5823, prevented resveratrol's effects on these parameters. Resveratrol also reversed Aβ1-42-induced decreases in phosphorylated cAMP response-element binding protein (pCREB), brain derived neurotrophic factor (BDNF) and anti-apoptotic factor BCl-2 expression, which were reversed by H89. These findings suggest that resveratrol reversing Aβ-induced learning and memory disorder may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related cAMP-CREB-BDNF signaling.

Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice.

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Ahmad, Ashfaq; Ali, Tahir; Park, Hyun Young; Badshah, Haroon; Rehman, Shafiq Ur; Kim, Myeong Ok

2017-04-01

Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease and is characterized pathologically by the accumulation of amyloid beta (Aβ) and the hyperphosphorylation of tau proteins in the brain. The deposition of Aβ aggregates triggers synaptic dysfunction, hyperphosphorylation of tau, and neurodegeneration, which lead to cognitive disorders. Here, we investigated the neuroprotective effect of fisetin in the Aβ 1-42 mouse model of AD. Single intracerebroventricular injections of Aβ 1-42 (3 μl/5 min/mouse) markedly induced memory/synaptic deficits, neuroinflammation, and neurodegeneration. Intraperitoneal injections of fisetin at a dose of 20 mg/kg/day for 2 weeks starting 24 h after Aβ 1-42 injection significantly decreased the Aβ 1-42 -induced accumulation of Aβ, BACE-1 expression, and hyperphosphorylation of tau protein at serine 413. Fisetin treatment also markedly reversed Aβ 1-42 -induced synaptic dysfunction by increasing the levels of both presynaptic (SYN and SNAP-25) and postsynaptic proteins (PSD-95, SNAP-23, p-GluR1 (Ser 845), p-CREB (Ser 133) and p-CAMKII (Thr 286) and ultimately improved mouse memory, as observed in the Morris water maze test. Fisetin significantly activated p-PI3K, p-Akt (Ser 473), and p-GSK3β (Ser 9) expression in Aβ 1-42 -treated mice. Moreover, fisetin prevented neuroinflammation by suppressing various activated neuroinflammatory mediators and gliosis; it also suppressed the apoptotic neurodegeneration triggered by Aβ 1-42 injections in the mouse hippocampus. Fluorojade-B and immunohistochemical staining for caspase-3 revealed that fisetin prevented neurodegeneration in Aβ 1-42 -treated mice. Our results suggest that fisetin has a potent neuroprotective effect against Aβ 1-42 -induced neurotoxicity. These results demonstrate that polyphenolic flavonoids such as fisetin could be a beneficial, effective and safe neuroprotective agent for preventing neurological disorders such as AD.

Functional amyloid formation by Streptococcus mutans

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Oli, M. W.; Otoo, H. N.; Crowley, P. J.; Heim, K. P.; Nascimento, M. M.; Ramsook, C. B.; Lipke, P. N.

2012-01-01

Dental caries is a common infectious disease associated with acidogenic and aciduric bacteria, including Streptococcus mutans. Organisms that cause cavities form recalcitrant biofilms, generate acids from dietary sugars and tolerate acid end products. It has recently been recognized that micro-organisms can produce functional amyloids that are integral to biofilm development. We now show that the S. mutans cell-surface-localized adhesin P1 (antigen I/II, PAc) is an amyloid-forming protein. This conclusion is based on the defining properties of amyloids, including binding by the amyloidophilic dyes Congo red (CR) and Thioflavin T (ThT), visualization of amyloid fibres by transmission electron microscopy and the green birefringent properties of CR-stained protein aggregates when viewed under cross-polarized light. We provide evidence that amyloid is present in human dental plaque and is produced by both laboratory strains and clinical isolates of S. mutans. We provide further evidence that amyloid formation is not limited to P1, since bacterial colonies without this adhesin demonstrate residual green birefringence. However, S. mutans lacking sortase, the transpeptidase enzyme that mediates the covalent linkage of its substrates to the cell-wall peptidoglycan, including P1 and five other proteins, is not birefringent when stained with CR and does not form biofilms. Biofilm formation is inhibited when S. mutans is cultured in the presence of known inhibitors of amyloid fibrillization, including CR, Thioflavin S and epigallocatechin-3-gallate, which also inhibited ThT uptake by S. mutans extracellular proteins. Taken together, these results indicate that S. mutans is an amyloid-forming organism and suggest that amyloidogenesis contributes to biofilm formation by this oral microbe. PMID:23082034

Comparison of the binding characteristics of [{sup 18}F]THK-523 and other amyloid imaging tracers to Alzheimer's disease pathology

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Harada, Ryuichi; Okamura, Nobuyuki; Yoshikawa, Takeo; Yanai, Kazuhiko [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Furumoto, Shozo [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Tago, Tetsuro; Iwata, Ren [Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Maruyama, Masahiro; Higuchi, Makoto [Molecular Imaging Center, National Institute of Radiological Sciences, Chiba (Japan); Arai, Hiroyuki [Tohoku University, Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Sendai (Japan); Kudo, Yukitsuka [Tohoku University, Innovation of New Biomedical Engineering Center, Sendai (Japan)

2013-01-15

Extensive deposition of senile plaques and neurofibrillary tangles in the brain is a pathological hallmark of Alzheimer's disease (AD). Although several PET imaging agents have been developed for in vivo detection of senile plaques, no PET probe is currently available for selective detection of neurofibrillary tangles in the living human brain. Recently, [{sup 18}F]THK-523 was developed as a potential in vivo imaging probe for tau pathology. The purpose of this study was to compare the binding properties of [{sup 18}F]THK-523 and other amyloid imaging agents, including PiB, BF-227 and FDDNP, to synthetic protein fibrils and human brain tissue. In vitro radioligand binding assays were conducted using synthetic amyloid {beta}{sub 42} and K18{Delta}K280-tau fibrils. Nonspecific binding was determined by the addition of unlabelled compounds at a concentration of 2 {mu}M. To examine radioligand binding to neuropathological lesions, in vitro autoradiography was conducted using sections of AD brain. [{sup 18}F]THK-523 showed higher affinity for tau fibrils than for A{beta} fibrils, whereas the other probes showed a higher affinity for A{beta} fibrils. The autoradiographic analysis indicated that [{sup 18}F]THK-523 accumulated in the regions containing a high density of tau protein deposits. Conversely, PiB and BF-227 accumulated in the regions containing a high density of A{beta} plaques. These findings suggest that the unique binding profile of [{sup 18}F]THK-523 can be used to identify tau deposits in AD brain. (orig.)

Aggregation process of Aβ1-40 with non-Aβ amyloid component of α-synuclein

International Nuclear Information System (INIS)

Eugene, Cindie; Mousseau, Normand

2015-01-01

Many neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, are characterized by the presence of amyloid fibers. Recently, attention has turned from the fibers to the early stages of oligomerization where toxicity could be highest. Here, we focus on the interactions between non-Aβ amyloid component of a-synuclein (NAC) and Aβ 1-40 , two proteins found in amyloid fibrils associated with Alzheimer's disease. We combine the coarse-grained OPEP potential with a Hamiltonian and temperature replica exchange molecular dynamics simulation (HT-REMD) to identify mechanisms leading to the formation of secondary structures promoting fibrillation. We observe that the propensity to form beta-sheet remains the same for Aβ 1-40 whereas is decreases significantly for NAC. In particular, the 25-35 region of Aβ 1-40 is a significant area of secondary structure stabilization with NAC. The ionic interactions between salt-bridge D23 and K28 in Aβ 1-40 and K20 and E23 in NAC of the heterogeneous dimer are consistent with the salt-bridges found in NAC and Aβ 1-40 homogenous dimers and allow us to see that these interactions don't necessarily dominate the interchain stabilizations. Our numerical simulation also show the formation of interaction between the early oligomer of NAC and Aβ 1-40 . (paper)

In Vitro Restoration of an Amyloid-Beta Altered Network Circuitry in a 'Mutated Biomimetic Acetylcholinesterase' Memristor/Memcapacitor Neural Prosthesis

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John THORNTON

2015-08-01

Full Text Available Many diseases involve the ysregulation of acetylcholinesterase (ACHE causing inappropriate production of the neurotransmitter acetylcholine (ACH. Study of how the ACH actually restores a life threatening neural circuitry damage will provide valuable information for study Alzhermer’s disease. An artificial neuronal device was developed with nanostructured biomimetic mutated ACHE gorge membrane on gold chips having memristor/memcapacitor’s characteristics, served as a model for damaged brain circuitry prosthesis, compared before and after ACH treatments, for in vitro evaluation of the memory restoration in the presence of Amyloid-beta (Ab under the conditions of free from tracers and antibodies in NIST human serum. The results are presented in three categories in “Energy-Sensory” images. Before ACH treatments, images showed four stages of circuitry damages from non symptomatic to life threatening. After a 15 nM ACH treatment, the circuitry was restored due to the ACH removed Pathological High Frequency Oscillation (pHFO center during Slow- Waving Sleeping (SWS. After the prosthesis increased hydrophobicity, the High Frequency Oscillation (HFO was created. Results were compared between the recovered and the “normal brain”: 0.14 vs. 0.47 pJ/bit/µm3 for long-term and 14.0 vs.7.0 aJ/bit/µm3 for short-term memory restoration, respectively. The ratio of Rmax/Rmin value is 6.3-fold higher after the treatment of ACH compared without the treatment in the presence of Ab and the reentry sensitivity increased by 613.8- fold.

Analysis of the complex between amyloid beta peptides and mitochondrial enzyme 17beta-HSD in cerebrospinal fluid

Czech Academy of Sciences Publication Activity Database

Krištofíková, Z.; Hegnerová, Kateřina; Bocková, Markéta; Vaisocherová, Hana; Bartoš, A.; Říčný, J.; Řípová, D.; Homola, J.

2008-01-01

Roč. 275, podzim (2008), s. 249-249 ISSN 1742-464X. [EUROPTRODE /9./. Dublin, 30.03.2008-02.04.2008] Institutional research plan: CEZ:AV0Z20670512 Keywords : surface plasmon resonance * alzheimer disease * 17beta-HSD10 Subject RIV: JB - Sensors, Measurment, Regulation Impact factor: 3.139, year: 2008

Chemical Methods to Knock Down the Amyloid Proteins

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Na Gao

2017-06-01

Full Text Available Amyloid proteins are closely related with amyloid diseases and do tremendous harm to human health. However, there is still a lack of effective strategies to treat these amyloid diseases, so it is important to develop novel methods. Accelerating the clearance of amyloid proteins is a favorable method for amyloid disease treatment. Recently, chemical methods for protein reduction have been developed and have attracted much attention. In this review, we focus on the latest progress of chemical methods that knock down amyloid proteins, including the proteolysis-targeting chimera (PROTAC strategy, the “recognition-cleavage” strategy, the chaperone-mediated autophagy (CMA strategy, the selectively light-activatable organic and inorganic molecules strategy and other chemical strategies.

Nuclear imaging of amyloid deposits based upon thioflavins

International Nuclear Information System (INIS)

Wang Yanming; Wu Chunying; Wei Jinjun

2005-01-01

Alzheimer's Disease (AD) is a chronic neurodegenerative disorders characterized by the presence of amyloid deposits and neurofibrillar tangles in the brain. Direct assessment of local changes of amyloid deposits in vivo would greatly facilitate the diagnosis and therapeutic treatments of AD. The goal of this study is to develop small-molecule probes that can be used to follow amyloid deposition in vivo in patients with neurodegenerative diseases. Over the past years, we set out to develop a series of small molecules based on thioflavins as radiotracers for use in nuclear imaging modalities such as positron emission tomography and single photon emission computed tomography. The potential of these amyloid-imaging agents for in vivo studies of amyloid deposition has been evaluated based on the following methods: 1) spectrophotometric binding. assays with synthetic amyloid-β (Aβ) fibrils and AD brain homogenates; 2) fluorescent staining of brain tissue sections to evaluate specificity of binding to amyloid deposits; 3) fluorescent microscopy in mouse models to determine the brain permeability and characterize the binding specificity in vivo, and 4) PET studies in human subjects diagnosed with AD and age-matched control subjects. To date, we have identified some lead compounds as molecular probes with specificity towards amyloid deposits. The in vitro and in vivo binding properties of these compounds have been demonstrated in the following ways: 1) they selectively binds to Aβ fibrils; 2) they selectively stains amyloid deposits in AD brain tissue sections; 3) they readily penetrates the blood-brain barrier, selectively detects amyloid deposits in vivo iri living mice; and 4) One of these compounds, termed PIB, has been successfully used in PET studies in human subjects. In conclusion, amyloid-imaging probes have been developed that could be used to monitor amyloid load in vivo. Applications of the probes are under investigation for potential pathophysiology studies

Dissociation between brain amyloid deposition and metabolism in early mild cognitive impairment.

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Liyong Wu

Full Text Available The hypothetical model of dynamic biomarkers for Alzheimer's disease (AD describes high amyloid deposition and hypometabolism at the mild cognitive impairment (MCI stage. However, it remains unknown whether brain amyloidosis and hypometabolism follow the same trajectories in MCI individuals. We used the concept of early MCI (EMCI and late MCI (LMCI as defined by the Alzheimer's disease Neuroimaging Initiative (ADNI-Go in order to compare the biomarker profile between EMCI and LMCI.To examine the global and voxel-based neocortical amyloid burden and metabolism among individuals who are cognitively normal (CN, as well as those with EMCI, LMCI and mild AD.In the present study, 354 participants, including CN (n = 109, EMCI (n = 157, LMCI (n = 39 and AD (n = 49, were enrolled between September 2009 and November 2011 through ADNI-GO and ADNI-2. Brain amyloid load and metabolism were estimated using [(18F]AV45 and [(18F]fluorodeoxyglucose ([(18F]FDG PET, respectively. Uptake ratio images of [(18F]AV45 and [(18F]FDG were calculated by dividing the summed PET image by the median counts of the grey matter of the cerebellum and pons, respectively. Group differences of global [(18F]AV45 and [(18F]FDG were analyzed using ANOVA, while the voxel-based group differences were estimated using statistic parametric mapping (SPM.EMCI patients showed higher global [(18F]AV45 retention compared to CN and lower uptake compared to LMCI. SPM detected higher [(18F]AV45 uptake in EMCI compared to CN in the precuneus, posterior cingulate, medial and dorsal lateral prefrontal cortices, bilaterally. EMCI showed lower [(18F]AV45 retention than LMCI in the superior temporal, inferior parietal, as well as dorsal lateral prefrontal cortices, bilaterally. Regarding to the global [(18F]FDG, EMCI patients showed no significant difference from CN and a higher uptake ratio compared to LMCI. At the voxel level, EMCI showed higher metabolism in precuneus, hippocampus, entorhinal and

Specific localization and imaging of amyloid deposits in vivo using 123I-labeled serum amyloid P component

International Nuclear Information System (INIS)

Hawkins, P.N.; Myers, M.J.; Epenetos, A.A.; Caspi, D.; Pepys, M.B.

1988-01-01

Highly specific, high-resolution scintigraphic images of amyloid-laden organs in mice with experimentally induced amyloid A protein (AA) amyloidosis were obtained after intravenous injection of 123 I-labeled serum amyloid P component (SAP). Interestingly, a much higher proportion (up to 40%) of the injected dose of heterologous human SAP localized to amyloid and was retained there than was the case with isologous mouse SAP, indicating that human SAP binds more avidly to mouse AA fibrils than does mouse SAP. Specificity of SAP localization was established by the failure of the related proteins, human C-reactive protein and Limulus C-reactive protein, to deposit significantly in amyloid and by the absence of human SAP deposition in nonamyloidotic organs. However, only partial correlations were observed between the quantity of SAP localized and two independent estimates, histology and RIA for AA of the amount of amyloid in particular organs. It is not clear which of the three methods used reflects better the extent or clinical significance of the amyloid deposits but in vivo localization of radiolabeled SAP, detectable and quantifiable by gamma camera imaging, is apparently extremely sensitive. These findings establish the use of labeled SAP as a noninvasive in vivo diagnostic probe in experimental amyloidosis, potentially capable of revealing the natural history of the condition, and suggest that it may also be applicable generally as a specific targeting agent for diagnostic and even therapeutic purposes in clinical amyloidosis

Pelargonidin Improves Passive Avoidance Task Performance in a Rat Amyloid Beta25-35 Model of Alzheimer’s Disease Via Estrogen Receptor Independent Pathways

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Hamid Sohanaki

2016-05-01

Full Text Available Alzheimer’s disease (AD is a disorder with multiple pathophysiological causes, destructive outcomes, and no available definitive cure. Pelargonidin (Pel, an anthocyanin derivative, is an estrogen receptor agonist with little estrogen side effects. This study was designed to assess Pel memory enhancing effects on the a rat Amyloid Beta25-35 (Aβ intrahippocampal microinjections model of AD in the passive avoidance task performance paradigm and further evaluate the potential estrogen receptor role on the memory-evoking compound. Equally divided rats were assigned to 5 groups of sham, Aβ intrahippocampal microinjected, Pel pretreated (10 mg/kg; P.O, α estrogen antagonist intra-cerebrovascular (i.c.v. microinjected, and β estrogen antagonist (i.c.v microinjected animals. Intrahippocampal microinjections of Aβ were adopted to provoke AD model. Passive avoidance task test was also used to assess memory performance. Pel pretreatment prior to Aβ microinjections significantly improved step-through latency (P<0.001 in passive avoidance test. In α and β estrogen, antagonists received animals, passive avoidance task performance was not statistically changed (P=0.11 & P=0.41 respectively compared to Pel pretreated and sham animals. Our results depicted that Pel improves Aβ induced memory dysfunction in passive avoidance test performance through estrogen receptor independently related pathways.

How cholesterol constrains glycolipid conformation for optimal recognition of Alzheimer's beta amyloid peptide (Abeta1-40).

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Yahi, Nouara; Aulas, Anaïs; Fantini, Jacques

2010-02-05

Membrane lipids play a pivotal role in the pathogenesis of Alzheimer's disease, which is associated with conformational changes, oligomerization and/or aggregation of Alzheimer's beta-amyloid (Abeta) peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs) on the supramolecular assembly of Abeta peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Abeta(1-40) and chemically defined GSLs (GalCer, LacCer, GM1, GM3). Using the Langmuir monolayer technique, we show that Abeta(1-40) selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs). In contrast, Abeta(1-40) did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs). Cholesterol inhibited the interaction of Abeta(1-40) with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Abeta(1-40) binding. Both crystallographic data and molecular dynamics simulations suggested that the active conformation of HFA-GSL involves a H-bond network that restricts the orientation of the sugar group of GSLs in a parallel orientation with respect to the membrane. This particular conformation is stabilized by the 2-OH group of the GSL. Correspondingly, the interaction of Abeta(1-40) with HFA-GSLs is strongly inhibited by NaF, an efficient competitor of H-bond formation. For NFA-GSLs, this is the OH group of cholesterol that constrains the glycolipid to adopt the active L-shape conformation compatible with sugar-aromatic CH-pi stacking interactions involving residue Y10 of Abeta(1-40). We conclude that cholesterol can either inhibit or facilitate membrane-Abeta interactions through fine tuning of glycosphingolipid conformation. These data shed some light on the complex molecular interplay between cell surface GSLs, cholesterol and Abeta peptides, and on the influence

How cholesterol constrains glycolipid conformation for optimal recognition of Alzheimer's beta amyloid peptide (Abeta1-40.

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Nouara Yahi

Full Text Available Membrane lipids play a pivotal role in the pathogenesis of Alzheimer's disease, which is associated with conformational changes, oligomerization and/or aggregation of Alzheimer's beta-amyloid (Abeta peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs on the supramolecular assembly of Abeta peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Abeta(1-40 and chemically defined GSLs (GalCer, LacCer, GM1, GM3. Using the Langmuir monolayer technique, we show that Abeta(1-40 selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs. In contrast, Abeta(1-40 did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs. Cholesterol inhibited the interaction of Abeta(1-40 with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Abeta(1-40 binding. Both crystallographic data and molecular dynamics simulations suggested that the active conformation of HFA-GSL involves a H-bond network that restricts the orientation of the sugar group of GSLs in a parallel orientation with respect to the membrane. This particular conformation is stabilized by the 2-OH group of the GSL. Correspondingly, the interaction of Abeta(1-40 with HFA-GSLs is strongly inhibited by NaF, an efficient competitor of H-bond formation. For NFA-GSLs, this is the OH group of cholesterol that constrains the glycolipid to adopt the active L-shape conformation compatible with sugar-aromatic CH-pi stacking interactions involving residue Y10 of Abeta(1-40. We conclude that cholesterol can either inhibit or facilitate membrane-Abeta interactions through fine tuning of glycosphingolipid conformation. These data shed some light on the complex molecular interplay between cell surface GSLs, cholesterol and Abeta peptides, and on the

Human Islet Amyloid Polypeptide

DEFF Research Database (Denmark)

Kosicka, Iga

2014-01-01

Diabetes mellitus type II is a metabolic disease affecting millions of people worldwide. The disease is associated with occurence of insoluble, fibrillar, protein aggregates in islets of Langerhans in the pancreas - islet amyloid. The main constituent of these protein fibers is the human islet...... of diabetes type II, while revealing the structure(s) of islet amyloid fibrils is necessary for potential design of therapeutic agents....

Chronic cladribine administration increases amyloid beta peptide generation and plaque burden in mice.

Directory of Open Access Journals (Sweden)

Crystal D Hayes

Full Text Available The clinical uses of 2-chloro-2'-deoxyadenosine (2-CDA or cladribine which was initially prescribed to patients with hematological and lymphoid cancers is now extended to treat patients with multiple sclerosis (MS. Previous data has shown that 2-CDA has high affinity to the brain and readily passes through the blood brain barrier reaching CSF concentrations 25% of that found in plasma. However, whether long-term administration of 2-CDA can lead to any adverse effects in patients or animal models is not yet clearly known.Here we show that exposure of 2-CDA to CHO cells stably expressing wild-type APP751 increased generation and secretion of amyloid β peptide (Aβ in to the conditioned medium. Interestingly, increased Aβ levels were noticed even at non-toxic concentrations of 2-CDA. Remarkably, chronic treatment of APdE9 mice, a model of Alzheimer's disease with 2-CDA for 60 days increased amyloid plaque burden by more than 1-fold. Increased Aβ generation appears to result from increased turnover of APP as revealed by cycloheximide-chase experiments. Additionally, surface labeling of APP with biotin and immunoprecipitation of surface labeled proteins with anti-biotin antibody also indicated increased APP at the cell surface in 2-CDA treated cells compared to controls. Increased turnover of APP by 2-CDA in turn might be a consequence of decreased protein levels of PIN 1, which is known to regulate cis-trans isomerization and phosphorylation of APP. Most importantly, like many other oncology drugs, 2-CDA administration led to significant delay in acquiring a reward-based learning task in a T maze paradigm.Taken together, these data provide compelling evidence for the first time that chronic 2-CDA administration can increase amyloidogenic processing of APP leading to robustly increased plaque burden which may be responsible for the observed deficits in learning skills. Thus chronic treatment of mice with 2-CDA can have deleterious effects in vivo.

Strong transthyretin immunostaining: potential pitfall in cardiac amyloid typing.

Science.gov (United States)

Satoskar, Anjali A; Efebera, Yvonne; Hasan, Ayesha; Brodsky, Sergey; Nadasdy, Gyongyi; Dogan, Ahmet; Nadasdy, Tibor

2011-11-01

Although systemic amyloidosis commonly presents with renal disease, cardiac involvement usually determines the patient's prognosis. Cardiac involvement is seen in light chain amyloid and transthyretin amyloidosis. Distinguishing between these two is critical because prognosis and treatment differ. Our study demonstrates the unreliability of transthyretin immunostaining in subtyping cardiac amyloid. Between January 2003 and August 2010, we retrieved 229 native endomyocardial biopsies, of which 24 had amyloid. Immunohistochemistry for κ, λ, transthyretin, and serum amyloid A protein was performed on formalin-fixed, paraffin-embedded sections. Staining was graded as weak (trace to 1+) or strong (2 to 3+). Mass spectrometry (MS)-based proteomic typing of microdissected amyloid material was performed on selected cases. Fifteen patients had monoclonal gammopathy/plasma cell dyscrasia with cardiac amyloid. Eight of them (53%) showed strong transthyretin staining in the cardiac amyloid deposits. MS was performed in 5 of these 8 biopsies, and all 5 biopsies revealed light chain amyloid-type amyloid. Two of these 5 light chain amyloid biopsies did not even have concomitant strong staining for the appropriate light chain. Among the 15 cases with plasma cell dyscrasia, only 7 biopsies showed strong staining for the corresponding monoclonal light chain. Strong, false-positive immunostaining for transthyretin in cardiac amyloid is a potential pitfall, augmented by the frequent lack of staining for immunoglobulin light chains. Therefore, the presence of amyloid in the cardiac biopsy should prompt a search for plasma cell dyscrasia irrespective of transthyretin staining. Confirmation with MS should be sought, particularly if there is any discrepancy between κ/λ staining and serum immunofixation results.

Florbetapir F18 PET Amyloid Neuroimaging and Characteristics in Patients With Mild and Moderate Alzheimer Dementia.

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Degenhardt, Elisabeth K; Witte, Michael M; Case, Michael G; Yu, Peng; Henley, David B; Hochstetler, Helen M; D'Souza, Deborah N; Trzepacz, Paula T

2016-01-01

Clinical diagnosis of Alzheimer disease (AD) is challenging, with a 70.9%-87.3% sensitivity and 44.3%-70.8% specificity, compared with autopsy diagnosis. Florbetapir F18 positron emission tomography (FBP-PET) estimates beta-amyloid plaque density antemortem. Of 2052 patients (≥55 years old) clinically diagnosed with mild or moderate AD dementia from 2 solanezumab clinical trials, 390 opted to participate in a FBP-PET study addendum. We analyzed baseline prerandomization characteristics. A total of 22.4% had negative FBP-PET scans, whereas 72.5% of mild and 86.9% of moderate AD patients had positive results. No baseline clinical variable reliably differentiated negative from positive FBP-PET scan groups. These data confirm the challenges of correctly diagnosing AD without using biomarkers. FBP-PET can aid AD dementia differential diagnosis by detecting amyloid pathology antemortem, even when the diagnosis of AD is made by expert clinicians. Copyright © 2016 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Memantine, a Low-Affinity NMDA Receptor Antagonist, Protects against Methylmercury-Induced Cytotoxicity of Rat Primary Cultured Cortical Neurons, Involvement of Ca2+ Dyshomeostasis Antagonism, and Indirect Antioxidation Effects.

Science.gov (United States)

Liu, Wei; Xu, Zhaofa; Yang, Tianyao; Xu, Bin; Deng, Yu; Feng, Shu

2017-09-01

Methylmercury (MeHg) is an extremely dangerous environmental pollutant that induces severe toxic effects in the central nervous system. Neuronal damage plays critical roles mediating MeHg-induced loss of brain function and neurotoxicity. The molecular mechanisms of MeHg neurotoxicity are incompletely understood. The objective of the study is to explore mechanisms that contribute to MeHg-induced neurocyte injuries focusing on neuronal Ca 2+ dyshomeostasis and alteration of N-methyl-D-aspartate receptors (NMDARs) expression, as well as oxidative stress in primary cultured cortical neurons. In addition, the neuroprotective effects of memantine against MeHg cytotoxicity were also investigated. The cortical neurons were exposed to 0, 0.01, 0.1, 1, or 2 μM methylmercury chloride (MeHgCl) for 0.5-12 h, or pre-treated with 2.5, 5, 10, or 20 μM memantine for 0.5-6 h, respectively; cell viability and LDH release were then quantified. For further experiments, 2.5, 5, and 10 μM of memantine pre-treatment for 3 h followed by 1 μM MeHgCl for 6 h were performed for evaluation of neuronal injuries, specifically addressing apoptosis; intracellular free Ca 2+ concentrations; ATPase activities; calpain activities; expressions of NMDAR subunits (NR1, NR2A, NR2B); NPSH levels; and ROS formation. Exposure of MeHgCl resulted in toxicity of cortical neurons, which were shown as a loss of cell viability, high levels of LDH release, morphological changes, and cell apoptosis. Moreover, intracellular Ca 2+ dyshomeostasis, ATPase activities inhibition, calpain activities, and NMDARs expression alteration were observed with 1 μM MeHgCl administration. Last but not least, NPSH depletion and reactive oxygen species (ROS) overproduction showed an obvious oxidative stress in neurons. However, memantine pre-treatment dose-dependently antagonized MeHg-induced neuronal toxic effects, apoptosis, Ca 2+ dyshomeostasis, NMDARs expression alteration, and oxidative stress. In conclusion, the