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Sample records for alzheimer amyloid peptide

  1. 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. PMID:25459121

  2. Tau/Amyloid Beta 42 Peptide Test (Alzheimer Biomarkers)

    Science.gov (United States)

    ... helpful? Also known as: Alzheimer Biomarkers Formal name: Tau Protein and Amyloid Beta 42 Peptide Related tests: Phosporylated ... should know? How is it used? Tests for Tau protein and Aß42 may be used as supplemental tests ...

  3. Plasma amyloid beta peptides and oligomers antibodies in Alzheimer's disease

    OpenAIRE

    Zhou, L.; Chu, LW; Kwan, JSC; Ho, JWM; Lam, KSL; Ho, PWL; Chan, KH

    2011-01-01

    INTRODUCTION: Various forms of amyloid beta (Aβ) including Aβ peptides, oligomers, protofibrils and fibrils are thought to be pathogenic in Alzheimer’s disease (AD). The exact pathophysiological role of endogenous Aβ autoantibodies (Ab) in healthy subjects and AD patients are uncertain. Potential protective role ...

  4. Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.

    Science.gov (United States)

    Di Scala, Coralie; Yahi, Nouara; Boutemeur, Sonia; Flores, Alessandra; Rodriguez, Léa; Chahinian, Henri; Fantini, Jacques

    2016-01-01

    Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer's and Parkinson's diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca(2+)-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined "membrane therapy") targeting amyloid pores formed by Aβ1-42 and α-synuclein. PMID:27352802

  5. Interactions of laminin with the amyloid ß peptide: Implications for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Morgan C.

    2001-01-01

    Full Text Available Extensive neuronal cell loss is observed in Alzheimer's disease. Laminin immunoreactivity colocalizes with senile plaques, the characteristic extracellular histopathological lesions of Alzheimer brain, which consist of the amyloid ß (Aß peptide polymerized into amyloid fibrils. These lesions have neurotoxic effects and have been proposed to be a main cause of neurodegeneration. In order to understand the pathological significance of the interaction between laminin and amyloid, we investigated the effect of laminin on amyloid structure and toxicity. We found that laminin interacts with the Aß1-40 peptide, blocking fibril formation and even inducing depolymerization of preformed fibrils. Protofilaments known to be intermediate species of Aß fibril formation were also detected as intermediate species of laminin-induced Aß fibril depolymerization. Moreover, laminin-amyloid interactions inhibited the toxic effects on rat primary hippocampal neurons. As a whole, our results indicate a putative anti-amyloidogenic role of laminin which may be of biological and therapeutic interest for controlling amyloidosis, such as those observed in cerebral angiopathy and Alzheimer's disease.

  6. Synthetic peptide homologous to β protein from Alzheimer's disease forms amyloid-like fibrils in vitro

    International Nuclear Information System (INIS)

    Progressive amyloid deposition in senile plaques and cortical blood vessels may play a central role in the pathogenesis of Alzheimer's disease. The authors have used x-ray diffraction and electron microscopy to study the molecular organization and morphology of macromolecular assemblies formed by three synthetic peptides homologous to β protein of brain amyloid: β-(1-28), residues 1-28 of the β protein; [Ala1-β-(1-28), β-(1-28) with alanine substituted for lysine at position 16; and β-(18-28), residues 18-28 of the β protein. β-(1-28) readily formed fibrils in vitro that were similar in ultrastructure to the in vivo amyloid and aggregated into large bundles resembling those of senile plaque cores. X-ray patterns from partially dried, oriented pellets showed a cross-β-conformation. [Ala16]β-(1-28) formed β-pleated sheet assemblies that were dissimilar to in vivo fibrils. The width of the 10-A spacing indicated stacks of about six sheets. Thus, substitution of the uncharged alanine for the positively charged lysine in the β-strand region enhances the packing of the sheets and dramatically alters the type of macromolecular aggregate formed. Β-(18-28) formed assemblies that had even a greater number of stacked sheets. The findings on these homologous synthetic assemblies help to define the specific sequence that is required to form Alzheimer's-type amyloid fibrils, thus providing an in vitro model of age-related cerebral amyloidogenesis

  7. High-affinity Anticalins with aggregation-blocking activity directed against the Alzheimer β-amyloid peptide

    OpenAIRE

    Rauth, Sabine; Hinz, Dominik; Börger, Michael; Uhrig, Markus; Mayhaus, Manuel; Riemenschneider, Matthias; Skerra, Arne

    2016-01-01

    Amyloid beta (Aβ) peptides, in particular Aβ42 and Aβ40, exert neurotoxic effects and their overproduction leads to amyloid deposits in the brain, thus constituting an important biomolecular target for treatments of Alzheimer's disease (AD). We describe the engineering of cognate Anticalins as a novel type of neutralizing protein reagent based on the human lipocalin scaffold. Phage display selection from a genetic random library comprising variants of the human lipocalin 2 (Lcn2) with mutatio...

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

    Science.gov (United States)

    Di Scala, Coralie; Yahi, Nouara; Flores, Alessandra; Boutemeur, Sonia; Kourdougli, Nazim; Chahinian, Henri; Fantini, Jacques

    2016-03-01

    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]. PMID:26909380

  9. In vitro fibrillization of Alzheimer's amyloidpeptide (1-42)

    Science.gov (United States)

    Tiiman, Ann; Krishtal, Jekaterina; Palumaa, Peep; Tõugu, Vello

    2015-09-01

    The amyloid deposition in the form of extracellular fibrillar aggregates of amyloid-β (Aβ) peptide is a critical pathological event in Alzheimer's disease. Here, we report a systematic investigation of the effects of environmental factors on the kinetics of Aβ fibrillization in vitro. The effects of Aβ42 peptide concentration, temperature, pH, added solvents and the ratio of Aβ40 and Aβ42 on the peptide fibrillization under agitated conditions was studied. The analysis show that the rate of fibril growth by monomer addition is not limited by diffusion but by rearrangement in the monomer structure, which is enhanced by low concentrations of fluorinated alcohols and characterized by the activation energy of 12 kcal/mol. Fibrillization rate decreases at pH values below 7.0 where simultaneous protonation of His 13 and 14 inhibits fibril formation. The lag period for Aβ42 was only twofold shorter and the fibril growth rate twofold faster than those of Aβ40. Lag period was shortened and the fibrillization rate was increased only at 90% content of Aβ42.

  10. Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease

    OpenAIRE

    Portelius, Erik; Andreasson, Ulf; Ringman, John M.; Buerger, Katharina; Daborg, Jonny; Buchhave, Peder; Hansson, Oskar; Harmsen, Andreas; Gustavsson, Mikael K; Hanse, Eric; Galasko, Douglas; Hampel, Harald; Blennow, Kaj; Zetterberg, Henrik

    2010-01-01

    Abstract Background Alzheimer's disease (AD) is associated with deposition of amyloid β (Aβ) in the brain, which is reflected by low concentration of the Aβ1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Aβ peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Aβ. Here, we test the hypothesis that AD is characterized by a specific CSF Aβ isoform pattern that is ...

  11. Broad neutralization of calcium-permeable amyloid pore channels with a chimeric Alzheimer/Parkinson peptide targeting brain gangliosides.

    Science.gov (United States)

    Di Scala, Coralie; Yahi, Nouara; Flores, Alessandra; Boutemeur, Sonia; Kourdougli, Nazim; Chahinian, Henri; Fantini, Jacques

    2016-02-01

    Growing evidence supports a role for brain gangliosides in the pathogenesis of neurodegenerative diseases including Alzheimer's and Parkinson's. Recently we deciphered the ganglioside-recognition code controlling specific ganglioside binding to Alzheimer's β-amyloid (Aβ1-42) peptide and Parkinson's disease-associated protein α-synuclein. Cracking this code allowed us to engineer a short chimeric Aβ/α-synuclein peptide that recognizes all brain gangliosides. Here we show that ganglioside-deprived neural cells do no longer sustain the formation of zinc-sensitive amyloid pore channels induced by either Aβ1-42 or α-synuclein, as assessed by single-cell Ca(2+) fluorescence microscopy. Thus, amyloid channel formation, now considered a key step in neurodegeneration, is a ganglioside-dependent process. Nanomolar concentrations of chimeric peptide competitively inhibited amyloid pore formation induced by Aβ1-42 or α-synuclein in cultured neural cells. Moreover, this peptide abrogated the intracellular calcium increases induced by Parkinson's-associated mutant forms of α-synuclein (A30P, E46K and A53T). The chimeric peptide also prevented the deleterious effects of Aβ1-42 on synaptic vesicle trafficking and decreased the Aβ1-42-induced impairment of spontaneous activity in rat hippocampal slices. Taken together, these data show that the chimeric peptide has broad anti-amyloid pore activity, suggesting that a common therapeutic strategy based on the prevention of amyloid-ganglioside interactions is a reachable goal for both Alzheimer's and Parkinson's diseases. PMID:26655601

  12. Amyloid properties of the leader peptide of variant B cystatin C: implications for Alzheimer and macular degeneration.

    Science.gov (United States)

    Sant'Anna, Ricardo; Navarro, Susanna; Ventura, Salvador; Paraoan, Luminita; Foguel, Debora

    2016-03-01

    Variant B (VB) of cystatin C has a mutation in its signal peptide (A25T), which interferes with its processing leading to reduced secretion and partial retention in the vicinity of the mitochondria. There are genetic evidences of the association of VB with Alzheimer's disease (AD) and age-related macular degeneration (AMD). Here, we investigated aggregation and amyloid propensities of unprocessed VB combining computational and in vitro studies. Aggregation predictors revealed the presence of four aggregation-prone regions, with a strong one at the level of the signal peptide, which indeed formed toxic aggregates and mature amyloid fibrils in solution. In light of these results, we propose for the first time the role of the signal peptide in pathogenesis of AD and AMD. PMID:26865059

  13. Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease

    OpenAIRE

    Portelius, Erik; Andreasson, Ulf; Ringman, John M.; Buerger, Katharina; Daborg, Jonny; Buchhave, Peder; Hansson, Oskar; Harmsen, Andreas; Gustavsson, Mikael K; Hanse, Eric; Galasko, Douglas; Hampel, Harald; Blennow, Kaj; Zetterberg, Henrik

    2010-01-01

    Background: Alzheimer's disease (AD) is associated with deposition of amyloid beta (A beta) in the brain, which is reflected by low concentration of the A beta 1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional A beta peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of A beta. Here, we test the hypothesis that AD is characterized by a specific CSF A beta isoform pattern that is distinct when comparing ...

  14. Distinct cerebrospinal fluid amyloid β peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease

    OpenAIRE

    Galasko Douglas; Hanse Eric; Gustavsson Mikael K; Harmsen Andreas; Hansson Oskar; Buchhave Peder; Daborg Jonny; Buerger Katharina; Ringman John M; Andreasson Ulf; Portelius Erik; Hampel Harald; Blennow Kaj; Zetterberg Henrik

    2010-01-01

    Abstract Background Alzheimer's disease (AD) is associated with deposition of amyloid β (Aβ) in the brain, which is reflected by low concentration of the Aβ1-42 peptide in the cerebrospinal fluid (CSF). There are at least 15 additional Aβ peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Aβ. Here, we test the hypothesis that AD is characterized by a specific CSF Aβ isoform pattern that is distinct when comparing sporadic AD (SAD...

  15. Metal-amyloidpeptide interactions: a preliminary investigation of molecular mechanisms for Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    JIAO Yong; YANG Pin

    2007-01-01

    Although humans have spent exactly 100 years combating Alzheimer's disease (AD), the molecular mechanisms of AD remain unclear. Owing to the rapid growth of the oldest age groups of the population and the continuous increase of the incidence of AD, it has become one of the crucial problems to modern sciences. It would be impossible to prevent or reverse AD at the root without elucidating its molecular mechanisms. From the point of view of metal-amyloidpeptide (Aβ) interactions, we review the molecular mechanisms of AD, mainly including Cu2+ and Zn2+ inducing the aggregation of Aβ, catalysing the production of active oxygen species from Aβ, as well as interacting with the ion-channel-like structures of Aβ. Moreover, the development of therapeutic drugs on the basis of metal-Aβ interactions is also briefly introduced. With the increasingly rapid progress of the molecular mechanisms of AD, we are now entering a new dawn that promises the delivery of revolutionary developments for the control of dementias.

  16. Lattice model for amyloid peptides: OPEP force field parametrization and applications to the nucleus size of Alzheimer's peptides

    Science.gov (United States)

    Tran, Thanh Thuy; Nguyen, Phuong H.; Derreumaux, Philippe

    2016-05-01

    Coarse-grained protein lattice models approximate atomistic details and keep the essential interactions. They are, therefore, suitable for capturing generic features of protein folding and amyloid formation at low computational cost. As our aim is to study the critical nucleus sizes of two experimentally well-characterized peptide fragments Aβ16-22 and Aβ37-42 of the full length Aβ1-42 Alzheimer's peptide, it is important that simulations with the lattice model reproduce all-atom simulations. In this study, we present a comprehensive force field parameterization based on the OPEP (Optimized Potential for Efficient protein structure Prediction) force field for an on-lattice protein model, which incorporates explicitly the formation of hydrogen bonds and directions of side-chains. Our bottom-up approach starts with the determination of the best lattice force parameters for the Aβ16-22 dimer by fitting its equilibrium parallel and anti-parallel β-sheet populations to all-atom simulation results. Surprisingly, the calibrated force field is transferable to the trimer of Aβ16-22 and the dimer and trimer of Aβ37-42. Encouraged by this finding, we characterized the free energy landscapes of the two decamers. The dominant structure of the Aβ16-22 decamer matches the microcrystal structure. Pushing the simulations for aggregates between 4-mer and 12-mer suggests a nucleus size for fibril formation of 10 chains. In contrast, the Aβ37-42 decamer is largely disordered with mixed by parallel and antiparallel chains, suggesting that the nucleus size is >10 peptides. Our refined force field coupled to this on-lattice model should provide useful insights into the critical nucleation number associated with neurodegenerative diseases.

  17. Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Ilaria Canobbio

    2015-03-01

    Full Text Available Alzheimer’s disease (AD is the most common neurodegenerative cause of dementia in the elderly. AD is accompanied by the accumulation of amyloid peptides in the brain parenchyma and in the cerebral vessels. The sporadic form of the AD accounts for about 95% of all cases. It is characterized by a late onset, typically after the age of 65, with a complex and still poorly understood aetiology. Several observations point towards a central role of cerebrovascular dysfunction in the onset of sporadic AD. According to the vascular hypothesis, AD may be initiated by vascular dysfunctions that precede and promote the neurodegenerative process. In accordance to this, AD patients show increased hemorragic or ischemic stroke risks. It is now clear that multiple bidirectional connections exist between AD and cerebrovascular disease, and in this new scenario, the effect of amyloid peptides on vascular cells and blood platelets appear to be central to AD. In this review we analyse the effect of amyloid peptides on vascular function and platelet activation and its contribution to the cerebrovascular pathology associated with AD and the progression of this disease.

  18. Recent progress in the study of intracellular toxicity of amyloid β peptide in Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yan; YU Longchuan

    2007-01-01

    Amyloid β (Aβ) deposition is one of the major pathological markers of Alzheimer's disease (AD). Extracellular Aβ toxicity has been studied for a long time in AD research field. However, controversial data show that extracellular Aβ load does not correlate with the dementia levels of AD patients and extracellular Aβ only induces significant cell death at non-physiological high concentrations.With the evolvement of Aβ hypothesis, considerable attention has been devoted to the study of intracellular Aβ toxicity recently. Intracellular Aβ induces dramatic cell loss in AD transgenic models and in human primary neurons (at pM concentrations) through p53, Bax and caspase-6 pathways. Here, we review the generation, toxicity and possible pathways of intracellular Aβ toxicity, and discuss the implication and current knowledge of intracellular Aβ in neuronal cell loss in neurodegenerative diseases.

  19. Proposal for an inhibitor of Alzheimer's disease blocking aggregation of amyloidpeptides: ab initio molecular simulations

    International Nuclear Information System (INIS)

    Aggregation of amyloid-β (Aβ) peptides is believed to play a key role in the mechanism of molecular pathogenesis of Alzheimer's disease (AD). To inhibit the aggregation and prevent AD, numerous compounds have been synthesized. A previous experimental study elucidated that a triazine derivative AA3E2 has anti-amyloidogenic ability, while a triazine derivative AA3D2 having a different substituent has no inhibitory effect. However, the reason for this remarkable difference in the ability cannot be explained by the chemical structures of these derivatives. In the present study, we present stable structures of the solvated complexes with Aβ and AA3E2/AA3D2 obtained by classical molecular mechanics method. The specific interactions between Aβ and AA3E2/AA3D2 in the complexes are investigated by ab initio fragment molecular orbital calculations. Based on the results obtained, we attempt to propose new potent inhibitors for the Aβ aggregation.

  20. High-affinity Anticalins with aggregation-blocking activity directed against the Alzheimer β-amyloid peptide

    Science.gov (United States)

    Rauth, Sabine; Hinz, Dominik; Börger, Michael; Uhrig, Markus; Mayhaus, Manuel; Riemenschneider, Matthias; Skerra, Arne

    2016-01-01

    Amyloid beta (Aβ) peptides, in particular Aβ42 and Aβ40, exert neurotoxic effects and their overproduction leads to amyloid deposits in the brain, thus constituting an important biomolecular target for treatments of Alzheimer's disease (AD). We describe the engineering of cognate Anticalins as a novel type of neutralizing protein reagent based on the human lipocalin scaffold. Phage display selection from a genetic random library comprising variants of the human lipocalin 2 (Lcn2) with mutations targeted at 20 exposed amino acid positions in the four loops that form the natural binding site was performed using both recombinant and synthetic target peptides and resulted in three different Anticalins. Biochemical characterization of the purified proteins produced by periplasmic secretion in Escherichia coli revealed high folding stability in a monomeric state, with Tm values ranging from 53.4°C to 74.5°C, as well as high affinities for Aβ40, between 95 pM and 563 pM, as measured by real-time surface plasmon resonance analysis. The central linear VFFAED epitope within the Aβ sequence was mapped using a synthetic peptide array on membranes and was shared by all three Anticalins, despite up to 13 mutual amino acid differences in their binding sites. All Anticalins had the ability–with varying extent–to inhibit Aβ aggregation in vitro according to the thioflavin-T fluorescence assay and, furthermore, they abolished Aβ42-mediated toxicity in neuronal cell culture. Thus, these Anticalins provide not only useful protein reagents to study the molecular pathology of AD but they also show potential as alternative drug candidates compared with antibodies. PMID:27029347

  1. High-affinity Anticalins with aggregation-blocking activity directed against the Alzheimer β-amyloid peptide.

    Science.gov (United States)

    Rauth, Sabine; Hinz, Dominik; Börger, Michael; Uhrig, Markus; Mayhaus, Manuel; Riemenschneider, Matthias; Skerra, Arne

    2016-06-01

    Amyloid beta (Aβ) peptides, in particular Aβ42 and Aβ40, exert neurotoxic effects and their overproduction leads to amyloid deposits in the brain, thus constituting an important biomolecular target for treatments of Alzheimer's disease (AD). We describe the engineering of cognate Anticalins as a novel type of neutralizing protein reagent based on the human lipocalin scaffold. Phage display selection from a genetic random library comprising variants of the human lipocalin 2 (Lcn2) with mutations targeted at 20 exposed amino acid positions in the four loops that form the natural binding site was performed using both recombinant and synthetic target peptides and resulted in three different Anticalins. Biochemical characterization of the purified proteins produced by periplasmic secretion in Escherichia coli revealed high folding stability in a monomeric state, with Tm values ranging from 53.4°C to 74.5°C, as well as high affinities for Aβ40, between 95 pM and 563 pM, as measured by real-time surface plasmon resonance analysis. The central linear VFFAED epitope within the Aβ sequence was mapped using a synthetic peptide array on membranes and was shared by all three Anticalins, despite up to 13 mutual amino acid differences in their binding sites. All Anticalins had the ability-with varying extent-to inhibit Aβ aggregation in vitro according to the thioflavin-T fluorescence assay and, furthermore, they abolished Aβ42-mediated toxicity in neuronal cell culture. Thus, these Anticalins provide not only useful protein reagents to study the molecular pathology of AD but they also show potential as alternative drug candidates compared with antibodies. PMID:27029347

  2. Silibinin inhibits acetylcholinesterase activity and amyloid β peptide aggregation: a dual-target drug for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Duan, Songwei; Guan, Xiaoyin; Lin, Runxuan; Liu, Xincheng; Yan, Ying; Lin, Ruibang; Zhang, Tianqi; Chen, Xueman; Huang, Jiaqi; Sun, Xicui; Li, Qingqing; Fang, Shaoliang; Xu, Jun; Yao, Zhibin; Gu, Huaiyu

    2015-05-01

    Alzheimer's disease (AD) is characterized by amyloid β (Aβ) peptide aggregation and cholinergic neurodegeneration. Therefore, in this paper, we examined silibinin, a flavonoid extracted from Silybum marianum, to determine its potential as a dual inhibitor of acetylcholinesterase (AChE) and Aβ peptide aggregation for AD treatment. To achieve this, we used molecular docking and molecular dynamics simulations to examine the affinity of silibinin with Aβ and AChE in silico. Next, we used circular dichroism and transmission electron microscopy to study the anti-Aβ aggregation capability of silibinin in vitro. Moreover, a Morris Water Maze test, enzyme-linked immunosorbent assay, immunohistochemistry, 5-bromo-2-deoxyuridine double labeling, and a gene gun experiment were performed on silibinin-treated APP/PS1 transgenic mice. In molecular dynamics simulations, silibinin interacted with Aβ and AChE to form different stable complexes. After the administration of silibinin, AChE activity and Aβ aggregations were down-regulated, and the quantity of AChE also decreased. In addition, silibinin-treated APP/PS1 transgenic mice had greater scores in the Morris Water Maze. Moreover, silibinin could increase the number of newly generated microglia, astrocytes, neurons, and neuronal precursor cells. Taken together, these data suggest that silibinin could act as a dual inhibitor of AChE and Aβ peptide aggregation, therefore suggesting a therapeutic strategy for AD treatment. PMID:25771396

  3. Molecular modeling on Zn(Ⅱ) binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes

    Institute of Scientific and Technical Information of China (English)

    HAN; Daxiong; YANG; Pin

    2004-01-01

    Aggregation of the amyloid β-peptide (A β) into insoluble fibrils is a key pathological event in Alzheimer's disease. Zn(Ⅱ) ion induces significant Aβ aggregation at nearly physiological concentrations in vitro. In order to explore the induce mechanism, the possible binding modes of Zn(Ⅱ) in Aβ peptide are studied by molecular modeling method. First, the Aβ species containing 1,2,4 and 12 peptides are established respectively. And next a Zn(Ⅱ) ion is manually hold the different sits of the Aβ species based on the experimental data and subsequently the coordinate atom and number are assigned. Finally, the optimum binding site is found by the system energy minimization. Modeling results show that in soluble Zn(Ⅱ) complex, Nτ of imidazole ring of His14, O of carbonyl of main-chain, and two O of water occupy the four ligand positions of the tetrahedral complex; in the aggregation of Aβ, the His13(Nτ)-Zn(Ⅱ)-His14(Nτ)bridges are formed by Zn(Ⅱ) cross-linking action. Therefore, the possible Zn(Ⅱ) binding mode obtained by the studies will be helpful to reveal the form mechanism of pathogenic aggregates in brain.

  4. Distinct cerebrospinal fluid amyloid β peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Galasko Douglas

    2010-01-01

    Full Text Available Abstract Background Alzheimer's disease (AD is associated with deposition of amyloid β (Aβ in the brain, which is reflected by low concentration of the Aβ1-42 peptide in the cerebrospinal fluid (CSF. There are at least 15 additional Aβ peptides in human CSF and their relative abundance pattern is thought to reflect the production and degradation of Aβ. Here, we test the hypothesis that AD is characterized by a specific CSF Aβ isoform pattern that is distinct when comparing sporadic AD (SAD and familial AD (FAD due to different mechanisms underlying brain amyloid pathology in the two disease groups. Results We measured Aβ isoform concentrations in CSF from 18 patients with SAD, 7 carriers of the FAD-associated presenilin 1 (PSEN1 A431E mutation, 17 healthy controls and 6 patients with depression using immunoprecipitation-mass spectrometry. Low CSF levels of Aβ1-42 and high levels of Aβ1-16 distinguished SAD patients and FAD mutation carriers from healthy controls and depressed patients. SAD and FAD were characterized by similar changes in Aβ1-42 and Aβ1-16, but FAD mutation carriers exhibited very low levels of Aβ1-37, Aβ1-38 and Aβ1-39. Conclusion SAD patients and PSEN1 A431E mutation carriers are characterized by aberrant CSF Aβ isoform patterns that hold clinically relevant diagnostic information. PSEN1 A431E mutation carriers exhibit low levels of Aβ1-37, Aβ1-38 and Aβ1-39; fragments that are normally produced by γ-secretase, suggesting that the PSEN1 A431E mutation modulates γ-secretase cleavage site preference in a disease-promoting manner.

  5. The Structure of the AmyloidPeptide High-Affinity Copper II Binding Site in Alzheimer Disease

    International Nuclear Information System (INIS)

    Neurodegeneration observed in Alzheimer disease (AD) is believed to be related to the toxicity from reactive oxygen species (ROS) produced in the brain by the amyloid-β (Aβ) protein bound primarily to copper ions. The evidence for an oxidative stress role of Aβ-Cu redox chemistry is still incomplete. Details of the copper binding site in Aβ may be critical to the etiology of AD. Here we present the structure determined by combining x-ray absorption spectroscopy (XAS) and density functional theory analysis of Aβ peptides complexed with Cu2+ in solution under a range of buffer conditions. Phosphate-buffered saline buffer salt (NaCl) concentration does not affect the high-affinity copper binding mode but alters the second coordination sphere. The XAS spectra for truncated and full-length Aβ-Cu2+ peptides are similar. The novel distorted six-coordinated (3N3O) geometry around copper in the Aβ-Cu2+ complexes include three histidines: glutamic, or/and aspartic acid, and axial water. The structure of the high-affinity Cu2+ binding site is consistent with the hypothesis that the redox activity of the metal ion bound to Aβ can lead to the formation of dityrosine-linked dimers found in AD.

  6. 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

    -Abeta antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interleukin-10, and tumor growth factor-beta. Our results demonstrate that chronic nasal administration of Abeta peptide can induce an immune response to Abeta that decreases...

  7. In vivo amyloid imaging in Alzheimer's disease

    International Nuclear Information System (INIS)

    Targeted approaches to therapy for Alzheimer's disease have evolved based on detailed understanding of the genetic, molecular biologic, and neuropathologic basis of the disease. Given the potential for greater treatment efficacy in the earlier stages of the disease, the notion of early diagnosis has become more relevant. Current clinical and imaging diagnostic approaches lack reliability in the preclinical and prodromal phases of the disease. We review emerging studies on imaging of the molecular substrate of the disease, most notably the amyloid peptide, which hope to increase early diagnostic efficacy. We offer a brief overview of the demographics, diagnostic criteria, and current imaging tests, followed by a review of amyloid biology and developments in cerebral amyloid imaging yielded by recent in vitro, in vivo and human studies. (orig.)

  8. Accumulation of murine amyloid-β mimics early Alzheimer's disease.

    Science.gov (United States)

    Krohn, Markus; Bracke, Alexander; Avchalumov, Yosef; Schumacher, Toni; Hofrichter, Jacqueline; Paarmann, Kristin; Fröhlich, Christina; Lange, Cathleen; Brüning, Thomas; von Bohlen Und Halbach, Oliver; Pahnke, Jens

    2015-08-01

    Amyloidosis mouse models of Alzheimer's disease are generally established by transgenic approaches leading to an overexpression of mutated human genes that are known to be involved in the generation of amyloid-β in Alzheimer's families. Although these models made substantial contributions to the current knowledge about the 'amyloid hypothesis' of Alzheimer's disease, the overproduction of amyloidpeptides mimics only inherited (familiar) Alzheimer's disease, which accounts for mild cognitive impairment. Using behavioural tests, electrophysiology and morphological analyses, we compared different ABC transporter-deficient animals and found that alterations are most prominent in neprilysin × ABCC1 double-deficient mice. We show that these mice have a reduced probability to survive, show increased anxiety in new environments, and have a reduced working memory performance. Furthermore, we detected morphological changes in the hippocampus and amygdala, e.g. astrogliosis and reduced numbers of synapses, leading to defective long-term potentiation in functional measurements. Compared to human, murine amyloid-β is poorly aggregating, due to changes in three amino acids at N-terminal positions 5, 10, and 13. Interestingly, our findings account for the action of early occurring amyloid-β species/aggregates, i.e. monomers and small amyloid-β oligomers. Thus, neprilysin × ABCC1 double-deficient mice present a new model for early effects of amyloid-β-related mild cognitive impairment that allows investigations without artificial overexpression of inherited Alzheimer's disease genes. PMID:25991605

  9. 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

  10. Amyloid imaging in Alzheimer's disease: a literature review.

    Science.gov (United States)

    Saidlitz, P; Voisin, T; Vellas, B; Payoux, P; Gabelle, A; Formaglio, M; Delrieu, J

    2014-07-01

    Therapies targeting amyloidpeptide currently represent approximately 50% of drugs now being developed for Alzheimer's disease. Some, including active and passive anti-Aβ immunotherapy, directly target the amyloid plaques. The new amyloid tracers are increasingly being included in the proposed updated diagnostic criteria, and may allow earlier diagnosis. Those targeting amyloidpeptide allow identification of amyloid plaques in vivo. We need to gain insight into all aspects of their application. As florbetapir (Amyvid™) and flutemetamol (Vizamyl™) have received marketing authorization, clinicians require deeper knowledge to be rationally used in diagnosis. In this paper, we review both completed and ongoing observational, longitudinal and interventional studies of these tracers, our main objective being to show the performance of the four most commonly used tracers and their validation. PMID:25226113

  11. Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome.

    Science.gov (United States)

    Schupf, Nicole; Lee, Annie; Park, Naeun; Dang, Lam-Ha; Pang, Deborah; Yale, Alexander; Oh, David Kyung-Taek; Krinsky-McHale, Sharon J; Jenkins, Edmund C; Luchsinger, José A; Zigman, Warren B; Silverman, Wayne; Tycko, Benjamin; Kisselev, Sergey; Clark, Lorraine; Lee, Joseph H

    2015-10-01

    We examined the contribution of candidates genes for Alzheimer's disease (AD) to individual differences in levels of beta amyloid peptides in adults with Down syndrom, a population at high risk for AD. Participants were 254 non-demented adults with Down syndrome, 30-78 years of age. Genomic deoxyribonucleic acid was genotyped using an Illumina GoldenGate custom array. We used linear regression to examine differences in levels of Aβ peptides associated with the number of risk alleles, adjusting for age, sex, level of intellectual disability, race and/or ethnicity, and the presence of the APOE ε4 allele. For Aβ42 levels, the strongest gene-wise association was found for a single nucleotide polymorphism (SNP) on CAHLM1; for Aβ40 levels, the strongest gene-wise associations were found for SNPs in IDE and SOD1, while the strongest gene-wise associations with levels of the Aβ42/Aβ40 ratio were found for SNPs in SORCS1. Broadly classified, variants in these genes may influence amyloid precursor protein processing (CALHM1, IDE), vesicular trafficking (SORCS1), and response to oxidative stress (SOD1). PMID:26166206

  12. Take five—BACE and the γ-secretase quartet conduct Alzheimer's amyloid β-peptide generation

    OpenAIRE

    Haass, Christian

    2004-01-01

    In 1959, Dave Brubeck and Paul Desmond revolutionized modern jazz music by composing their unforgettable Take Five in 5/4, one of the most defiant time signatures in all music. Of similar revolutionary importance for biomedical and basic biochemical research is the identification of the minimal set of genes required to obtain a deadly time bomb ticking in all of us: Alzheimer's disease. It now appears that one needs to Take Five genes to produce a deadly peptide by a proteolytic mechanism, wh...

  13. Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer's Disease AmyloidPeptide Which Exhibit Reduced Neurotoxicity.

    Science.gov (United States)

    Prade, Elke; Barucker, Christian; Sarkar, Riddhiman; Althoff-Ospelt, Gerhard; Lopez del Amo, Juan Miguel; Hossain, Shireen; Zhong, Yifei; Multhaup, Gerd; Reif, Bernd

    2016-03-29

    Alzheimer's disease is characterized by deposition of the amyloid β-peptide (Aβ) in brain tissue of affected individuals. In recent years, many potential lead structures have been suggested that can potentially be used for diagnosis and therapy. However, the mode of action of these compounds is so far not understood. Among these small molecules, the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide received a lot of attention. In this manuscript, we characterize the interaction between the monomeric Aβ peptide and the NSAID sulindac sulfide. We find that sulindac sulfide efficiently depletes the pool of toxic oligomers by enhancing the rate of fibril formation. In vitro, sulindac sulfide forms colloidal particles which catalyze the formation of fibrils. Aggregation is immediate, presumably by perturbing the supersaturated Aβ solution. We find that sulindac sulfide induced Aβ aggregates are structurally homogeneous. The C-terminal part of the peptide adopts a β-sheet structure, whereas the N-terminus is disordered. The salt bridge between D23 and K28 is present, similar as in wild type fibril structures. (13)C-(19)F transferred echo double resonance experiments suggest that sulindac sulfide colocalizes with the Aβ peptide in the aggregate. PMID:26900939

  14. Beta-amyloid peptides enhance the proliferative response of activated CD4CD28 lymphocytes from Alzheimer disease patients and from healthy elderly.

    Directory of Open Access Journals (Sweden)

    Agnieszka Jóźwik

    Full Text Available Alzheimer's disease (AD is the most frequent form of dementia among elderly. Despite the vast amount of literature on non-specific immune mechanisms in AD there is still little information about the potential antigen-specific immune response in this pathology. It is known that early stages of AD include β-amyloid (Aβ- reactive antibodies production and inflammatory response. Despite some evidence gathered proving cellular immune response background in AD pathology, the specific reactions of CD4(+ and CD8(+ cells remain unknown as the previous investigations yielded conflicting results. Here we investigated the CD4(+CD28(+ population of human peripheral blood T cells and showed that soluble β-amyloids alone were unable to stimulate these cells to proliferate significantly, resulting only in minor, probably antigen-specific, proliferative response. On the other hand, the exposure of in vitro pre-stimulated lymphocytes to soluble Aβ peptides significantly enhanced the proliferative response of these cells which had also lead to increased levels of TNF, IL-10 and IL-6. We also proved that Aβ peptide-enhanced proliferative response of CD4(+CD28(+ cells is autonomous and independent from disease status while being associated with the initial, ex vivo activation status of the CD4(+ cells. In conclusion, we suggest that the effect of Aβ peptides on the immune system of AD patients does not depend on the specific reactivity to Aβ epitope(s, but is rather a consequence of an unspecific modulation of the cell cycle dynamics and cytokine production by T cells, occurring simultaneously in a huge proportion of Aβ peptide-exposed T lymphocytes and affecting the immune system performance.

  15. A potential amyloid-imaging probe for Alzheimer's disease

    International Nuclear Information System (INIS)

    Purpose: To screen out the human single-chain fragment variable (scFv) against amyloid β peptide 40 from a human synthetic antibody library, sub-clone its gene into E. coli expression system, and express and purify it for amyloid peptide imaging research. The overload of amyloid β peptide and the appearance of senile plaques in the human brain tissue is one of the hallmark of the Alzheimer's disease, and in vivo imaging of amyloidβ peptide is valuable for the earlier diagnosis of Alzheimer's disease. Methods: Amyloid β peptide 40 was bound on the solid surface of Nunc plates as antigen and a human antibody library constructed with human antibody heavy and light chain variable gene and nucleotides sequence coded (Gly4Ser)3 linker and displayed on the protein surface of filamentous phage was used to screen the binding clones. After five rounds of bio-panning, the host E. coli TG1 was infected with eluted filamentous phage from the last turn of selection. 55 well-separated colonies were picked randomly from the plates and several specific positive clones were identified by ELISA testing, and their binding sites were determined by competitive ELISA with amyloid 13 peptide 40, 1-16, 25-35. The single-chain Fv antibody gene was sequenced and their amino acids sequence was deduced. The scFv antibody gene was sub-cloned into a protokayotic expression vector pET-22b(+) and transformed into bacteria strain BL21 to express the His6-tagged single-chain antibody and the whole cell culture was subjected to SDS-PAGE analysis. The antibody was expressed in inclusion bodies and purified with serial buffers and verified with western blotting and their activity was tested by ELISA against amyloid β peptide 40. Results: ELISA testing showed that 33 clones could bind amyloid β peptide 40 and 10 of these clones could be inhibited by amyloid β peptide 40 itself to below 50% of its original binding activities. Five clones could also be inhibited by amyloid β peptide 1-16. DNA

  16. The effect of HIV protease inhibitors on amyloidpeptide degradation and synthesis in human cells and Alzheimer's disease animal model.

    Science.gov (United States)

    Lan, Xiqian; Kiyota, Tomomi; Hanamsagar, Richa; Huang, Yunlong; Andrews, Scott; Peng, Hui; Zheng, Jialin C; Swindells, Susan; Carlson, George A; Ikezu, Tsuneya

    2012-06-01

    Combined antiretroviral therapy (ART) tremendously improved the lifespan and symptoms associated with AIDS-defining illness in affected individuals. However, chronic ART-treated patients frequently develop age-dependent complications, including dementia, diabetes, and hyperlipidemia: all risk factors of Alzheimer's disease. Importantly, the effect of ART compounds on amyloid generation and clearance has never been systematically examined. Nine prescribed HIV protease inhibitors were tested for their effect on amyloidpeptide (Aβ) clearance in primary cultured human monocyte-derived macrophages. Atazanavir, ritonavir, and saquinavir modestly inhibited of Aβ degradation, while lopinavir, nelfinavir, and ritonavir enhanced secretion of undigested Aβ after phagocytosis. Lopinavir, nelfinavir, ritonavir, and saquinavir inhibited endogenous Aβ40 production from primary cultured human cortical neurons, which were associated with reduction in Beta-site APP Converting Enzyme 1 (BACE1) and γ-secretase enzyme activities. However, ART compounds showed little inhibition of purified BACE1 activity in vitro, suggesting the indirect effect of ART compounds on BACE1 activity in neurons. Finally, nefinavir or lopinavir/ritonavir (Kaletra) were orally administered for 30 days into APP SCID mice expressing a double mutant form of APP 695 (KM670/671NL + V717F) in homozygosity for the scid allele of Prkdc. There was no difference in beta-amyloidosis by ART drug administration as determined by both immunohistochemistry and ELISA measurements although the therapeutic doses of the ART compounds was present in the brain. These data demonstrated that ART drugs can inhibit Aβ clearance in macrophages and Aβ production in neurons, but these effects did not significantly alter Aβ accumulation in the mouse brain. PMID:21826404

  17. Oligomer Formation of Toxic and Functional Amyloid Peptides Studied with Atomistic Simulations.

    Science.gov (United States)

    Carballo-Pacheco, Martín; Ismail, Ahmed E; Strodel, Birgit

    2015-07-30

    Amyloids are associated with diseases, including Alzheimer's, as well as functional roles such as storage of peptide hormones. It is still unclear what differences exist between aberrant and functional amyloids. However, it is known that soluble oligomers formed during amyloid aggregation are more toxic than the final fibrils. Here, we perform molecular dynamics simulations to study the aggregation of the amyloidpeptide Aβ25-35, associated with Alzheimer's disease, and two functional amyloid-forming tachykinin peptides: kassinin and neuromedin K. Although the three peptides have similar primary sequences, tachykinin peptides, in contrast to Aβ25-35, form nontoxic amyloids. Our simulations reveal that the charge of the C-terminus is essential to controlling the aggregation process. In particular, when the kassinin C-terminus is not amidated, the aggregation kinetics decreases considerably. In addition, we observe that the monomeric peptides in extended conformations aggregate faster than those in collapsed hairpin-like conformations. PMID:26130191

  18. Neuroprotective approaches in experimental models of beta-amyloid neurotoxicity : Relevance to Alzheimer's disease

    NARCIS (Netherlands)

    Harkany, T; Hortobagyi, T; Sasvari, M; Konya, C; Penke, B; Luiten, PGM; Nyakas, C

    1999-01-01

    1. beta-Amyloid peptides (A beta s) accumulate abundantly in the Alzheimer's disease (AD) brain in areas subserving information acquisition arid processing, and memory formation. A beta fragments are producedin a process of abnormal proteolytic cleavage of their precursor, the amyloid precursor prot

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

    NARCIS (Netherlands)

    Giacomelli, CE; 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 dena

  20. In vivo amyloid imaging in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Sair, H.I.; Doraiswamy, P.M.; Petrella, J.R. [Department of Radiology, Box 3808, Duke University Medical Center, NC 27710, Durham (United States)

    2004-02-01

    Targeted approaches to therapy for Alzheimer's disease have evolved based on detailed understanding of the genetic, molecular biologic, and neuropathologic basis of the disease. Given the potential for greater treatment efficacy in the earlier stages of the disease, the notion of early diagnosis has become more relevant. Current clinical and imaging diagnostic approaches lack reliability in the preclinical and prodromal phases of the disease. We review emerging studies on imaging of the molecular substrate of the disease, most notably the amyloid peptide, which hope to increase early diagnostic efficacy. We offer a brief overview of the demographics, diagnostic criteria, and current imaging tests, followed by a review of amyloid biology and developments in cerebral amyloid imaging yielded by recent in vitro, in vivo and human studies. (orig.)

  1. 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, L.; 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 was to ...

  2. Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent

    OpenAIRE

    Greig, Nigel H.; Utsuki, Tadanobu; Ingram, Donald K.; Wang, Yue; Pepeu, Giancarlo; Scali, Carla; Yu, Qian-sheng; Mamczarz, Jacek; Holloway, Harold W.; Giordano, Tony; Chen, DeMao; Furukawa, Katsutoshi; Sambamurti, Kumar; Brossi, Arnold; Lahiri, Debomoy K.

    2005-01-01

    Like acetylcholinesterase, butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused long-term inhibition of brain BChE and ele...

  3. β-淀粉样肽对线粒体的损伤及其在阿尔茨海默病中的作用%Mitochondria injury by amyloidpeptide and it's function in Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    杨秀明

    2012-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, which characterized by extracellular amyloidpeptide (Aβ) plaques and intracellular neurofibrillary tangles(NFTs). The etiological factors and pathogenesis are still unclear. Amyloidpeptide locates in mitochondria and it can induce a series of disorders in mitochondrial function, such as decreasing in ATP production, promoting oxidative stress, brokening the balance of mitochondrial fission/fusion and enhancing cellular apoptosis, and so on.%阿尔茨海默病(Alzheimer′s disease,AD)是以老年斑(senile plaque,SP)和神经纤维缠结(neurofibrillary tangles,NFTs)为主要病理特征的中枢神经系统退行性疾病,其病因及发病机制至今仍不明确.AD的病变产物β-淀粉样肽(amyloidpeptide,Aβ)在线粒体内沉积导致线粒体功能障碍,如ATP产生减少、氧化应激增强、细胞凋亡增强以及线粒体分裂/融合异常等,进而引起AD的一系列病理变化.

  4. Amyloid β protein and Alzheimer disease

    OpenAIRE

    Square, D

    1997-01-01

    Amyloid beta protein is predominant in senile plaques, the neuropathologic hallmarks of Alzheimer disease. Researchers in Winnipeg have shown that this protein can overstimulate certain hydrolytic enzymes to break down the phospholipid building blocks of the brain-cell wall. They speculate that the abnormal destruction of phospholipids gradually drains the energy resources a neuron uses to rebuild its membrane. As neurons "burn out," the brain loses its ability to function normally. In view o...

  5. Polymorphic structures of Alzheimer's β-amyloid globulomers.

    Directory of Open Access Journals (Sweden)

    Xiang Yu

    Full Text Available BACKGROUND: Misfolding and self-assembly of Amyloid-β (Aβ peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic Aβ structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these Aβ species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation. METHODS AND FINDINGS: Here, we model a series of molecular structures of Aβ globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD simulations. Structural and energetic analysis shows that although Aβ globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated β-structure in Aβ globulomers make them difficult to convert into other high-order Aβ aggregates and fibrils with dominant β-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These Aβ globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR. CONCLUSIONS: Our computationally modeled Aβ globulomers provide useful

  6. NNanomechanical characteristics of proteins and peptides in amyloid

    OpenAIRE

    Boayue, Nya Mehnwolo

    2012-01-01

    ......The understanding of the aggregation of amyloid fibrils is essential as they are linked to a number of diseases such as Alzheimer and Parkston’s disease. Amy- loids from different proteins or peptides have common characteristics such as core β-sheet structure, green birefringence upon binding to Congo red, and fibrillar mor- phology. In this thesis, I report single molecule analysis of TTR105−115 a fragment of transthyretin, a serum and cerebrospinal fluid carrier of ...

  7. Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation.

    Science.gov (United States)

    Kurnellas, Michael P; Adams, Chris M; Sobel, Raymond A; Steinman, Lawrence; Rothbard, Jonathan B

    2013-04-01

    The amyloid-forming proteins tau, αB crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein αB crystallin (HspB5) and from amyloid β fibrils, characteristic of Alzheimer's disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, we showed a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid β A4, major prion protein (PrP), HspB5, amylin, serum amyloid P, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-6 and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of tau 623-628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders. PMID:23552370

  8. Seeded growth of β-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure

    OpenAIRE

    Paravastu, Anant K.; Qahwash, Isam; Leapman, Richard D.; Meredith, Stephen C.; Tycko, Robert

    2009-01-01

    Studies by solid-state nuclear magnetic resonance (NMR) of amyloid fibrils prepared in vitro from synthetic 40-residue β-amyloid (Aβ1–40) peptides have shown that the molecular structure of Aβ1–40 fibrils is not uniquely determined by amino acid sequence. Instead, the fibril structure depends on the precise details of growth conditions. The molecular structures of β-amyloid fibrils that develop in Alzheimer's disease (AD) are therefore uncertain. We demonstrate through thioflavin T fluorescen...

  9. 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.

  10. The novel amyloid-beta peptide aptamer inhibits intracellular amyloid-beta peptide toxicity

    Institute of Scientific and Technical Information of China (English)

    Xu Wang; Yi Yang; Mingyue Jia; Chi Ma; Mingyu Wang; Lihe Che; Yu Yang; Jiang Wu

    2013-01-01

    Amyloid β peptide binding alcohol dehydrogenase (ABAD) decoy peptide (DP) can competitively antagonize binding of amyloid β peptide to ABAD and inhibit the cytotoxic effects of amyloid β peptide. Based on peptide aptamers, the present study inserted ABAD-DP into the disulfide bond of human thioredoxin (TRX) using molecular cloning technique to construct a fusion gene that can express the TRX1-ABAD-DP-TRX2 aptamer. Moreover, adeno-associated virus was used to allow its stable expression. Immunofluorescent staining revealed the co-expression of the transduced fusion gene TRX1-ABAD-DP-TRX2 and amyloid β peptide in NIH-3T3 cells, indicating that the TRX1-ABAD-DP-TRX2 aptamer can bind amyloid β peptide within cells. In addition, cell morphology and MTT results suggested that TRX1-ABAD-DP-TRX2 attenuated amyloid β peptide-induced SH-SY5Y cell injury and improved cell viability. These findings confirmed the possibility of constructing TRX-based peptide aptamer using ABAD-DP. Moreover, TRX1-ABAD-DP-TRX2 inhibited the cytotoxic effect of amyloid β peptide.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Validation of assays for measurement of amyloidpeptides in cerebrospinal fluid and plasma specimens from patients with Alzheimer's disease treated with solanezumab.

    Science.gov (United States)

    Lachno, D Richard; Evert, Barbara A; Vanderstichele, Hugo; Robertson, Michael; Demattos, Ronald B; Konrad, Robert J; Talbot, Jayne A; Racke, Margaret M; Dean, Robert A

    2013-01-01

    The aim of this study was to validate new assays for measurement of amyloid-β (Aβ) peptides in cerebrospinal fluid (CSF) and plasma specimens in clinical studies of solanezumab according to current regulatory recommendations. Four assays based on the INNOTEST® β-AMYLOID(1-42) and prototype INNOTEST β-AMYLOID(1-40) kits were developed and validated. To render these assays 'solanezumab-tolerant', excess drug was added to calibrators, quality control, and test samples via a 2-fold dilution with kit diluent. Validation parameters were evaluated by repeated testing of human CSF and EDTA-plasma pools containing solanezumab. Calibration curve correlation coefficients for the four assays were ≥0.9985. Intra- and inter-assay coefficients of variation for Aβ1-40 and Aβ1-42 were ≤13 and ≤15%, respectively for both matrices. Dilutional linearity, within and between assays, was demonstrated for both analytes in CSF and plasma at clinically relevant dilution factors. This dilution regimen was successfully applied during Phase 3 clinical sample analysis. Aβ1-40 and Aβ1-42 were stable in CSF and plasma containing solanezumab at 2-8°C and room temperature for up to 8 h and during 5 additional freeze-thaw cycles from ≤-20 and ≤-70°C. Results of parallel tests on stored clinical samples using INNOTEST methods and proprietary ELISA methods were closely correlated (r2 > 0.9), although bias in reported concentrations was observed between assays. In conclusion, the modified INNOTEST assays provided (relatively) accurate and precise quantification of Aβ1-40 and Aβ1-42 in CSF and plasma containing solanezumab according to established consensus validation criteria. The clinical experience with these assays post validation has shown them to be robust and reliable. PMID:23302661

  13. Atomic force microscopy and MD simulations reveal pore-like structures of all-D-enantiomer of Alzheimer's β-amyloid peptide: relevance to the ion channel mechanism of AD pathology.

    Science.gov (United States)

    Connelly, Laura; Jang, Hyunbum; Arce, Fernando Teran; Capone, Ricardo; Kotler, Samuel A; Ramachandran, Srinivasan; Kagan, Bruce L; Nussinov, Ruth; Lal, Ratnesh

    2012-02-01

    Alzheimer's disease (AD) is a protein misfolding disease characterized by a buildup of β-amyloid (Aβ) peptide as senile plaques, uncontrolled neurodegeneration, and memory loss. AD pathology is linked to the destabilization of cellular ionic homeostasis and involves Aβ peptide-plasma membrane interactions. In principle, there are two possible ways through which disturbance of the ionic homeostasis can take place: directly, where the Aβ peptide either inserts into the membrane and creates ion-conductive pores or destabilizes the membrane organization, or, indirectly, where the Aβ peptide interacts with existing cell membrane receptors. To distinguish between these two possible types of Aβ-membrane interactions, we took advantage of the biochemical tenet that ligand-receptor interactions are stereospecific; L-amino acid peptides, but not their D-counterparts, bind to cell membrane receptors. However, with respect to the ion channel-mediated mechanism, like L-amino acids, D-amino acid peptides will also form ion channel-like structures. Using atomic force microscopy (AFM), we imaged the structures of both D- and L-enantiomers of the full length Aβ(1-42) when reconstituted in lipid bilayers. AFM imaging shows that both L- and D-Aβ isomers form similar channel-like structures. Molecular dynamics (MD) simulations support the AFM imaged 3D structures. Previously, we have shown that D-Aβ(1-42) channels conduct ions similarly to their L- counterparts. Taken together, our results support the direct mechanism of Aβ ion channel-mediated destabilization of ionic homeostasis rather than the indirect mechanism through Aβ interaction with membrane receptors. PMID:22217000

  14. Imaging β-amyloid fibrils in Alzheimer's disease: a critical analysis through simulation of amyloid fibril polymerization

    International Nuclear Information System (INIS)

    The polymerization of β-amyloid (Aβ) peptides into fibrillary plaques is implicated, in part, in the pathogenesis of Alzheimer's disease. Aβ molecular imaging probes (Aβ-MIPs) have been introduced in an effort to quantify amyloid burden or load, in subjects afflicted with AD by invoking the classic PET receptor model for the quantitation of neuronal receptor density. In this communication, we explore conceptual differences between imaging the density of amyloid fibril polymers and neuronal receptors. We formulate a mathematical model for the polymerization of Aβ with parameters that are mapped to biological modulators of fibrillogenesis and introduce a universal measure for amyloid load to accommodate various interactions of Aβ-MIPs with fibrils. Subsequently, we hypothesize four Aβ-MIPs and utilize the fibrillogenesis model to simulate PET tissue time activity curves (TACs). Given the unique nature of polymer growth and resulting PET TAC, the four probes report differing amyloid burdens for a given brain pathology, thus complicating the interpretation of PET images. In addition, we introduce the notion of an MIP's resolution, apparent maximal binding site concentration, optimal kinetic topology and its resolving power in characterizing the pathological progression of AD and the effectiveness of drug therapy. The concepts introduced in this work call for a new paradigm that goes beyond the classic parameters B max and K D to include binding characteristics to polymeric peptide aggregates such as amyloid fibrils, neurofibrillary tangles and prions

  15. The CCAAT/enhancer binding protein (C/EBP δ is differently regulated by fibrillar and oligomeric forms of the Alzheimer amyloidpeptide

    Directory of Open Access Journals (Sweden)

    Nilsson Lars NG

    2011-04-01

    Full Text Available Abstract Background The transcription factors CCAAT/enhancer binding proteins (C/EBP α, β and δ have been shown to be expressed in brain and to be involved in regulation of inflammatory genes in concert with nuclear factor κB (NF-κB. In general, C/EBPα is down-regulated, whereas both C/EBPβ and δ are up-regulated in response to inflammatory stimuli. In Alzheimer's disease (AD one of the hallmarks is chronic neuroinflammation mediated by astrocytes and microglial cells, most likely induced by the formation of amyloid-β (Aβ deposits. The inflammatory response in AD has been ascribed both beneficial and detrimental roles. It is therefore important to delineate the inflammatory mediators and signaling pathways affected by Aβ deposits with the aim of defining new therapeutic targets. Methods Here we have investigated the effects of Aβ on expression of C/EBP family members with a focus on C/EBPδ in rat primary astro-microglial cultures and in a transgenic mouse model with high levels of fibrillar Aβ deposits (tg-ArcSwe by western blot analysis. Effects on DNA binding activity were analyzed by electrophoretic mobility shift assay. Cross-talk between C/EBPδ and NF-κB was investigated by analyzing binding to a κB site using a biotin streptavidin-agarose pull-down assay. Results We show that exposure to fibril-enriched, but not oligomer-enriched, preparations of Aβ inhibit up-regulation of C/EBPδ expression in interleukin-1β-activated glial cultures. Furthermore, we observed that, in aged transgenic mice, C/EBPα was significantly down-regulated and C/EBPβ was significantly up-regulated. C/EBPδ, on the other hand, was selectively down-regulated in the forebrain, a part of the brain showing high levels of fibrillar Aβ deposits. In contrast, no difference in expression levels of C/EBPδ between wild type and transgenic mice was detected in the relatively spared hindbrain. Finally, we show that interleukin-1β-induced C/EBPδ DNA

  16. Antiaggregation Potential of Padina gymnospora against the Toxic Alzheimer's Beta-Amyloid Peptide 25-35 and Cholinesterase Inhibitory Property of Its Bioactive Compounds.

    Directory of Open Access Journals (Sweden)

    Balakrishnan Shanmuganathan

    Full Text Available Inhibition of β-amyloid (Aβ aggregation in the cerebral cortex of the brain is a promising therapeutic and defensive strategy in identification of disease modifying agents for Alzheimer's disease (AD. Since natural products are considered as the current alternative trend for the discovery of AD drugs, the present study aims at the evaluation of anti-amyloidogenic potential of the marine seaweed Padina gymnospora. Prevention of aggregation and disaggregation of the mature fibril formation of Aβ 25-35 by acetone extracts of P. gymnospora (ACTPG was evaluated in two phases by Thioflavin T assay. The results were further confirmed by confocal laser scanning microscopy (CLSM analysis and Fourier transform infrared (FTIR spectroscopic analysis. The results of antiaggregation and disaggregation assay showed that the increase in fluorescence intensity of aggregated Aβ and the co-treatment of ACTPG (250 μg/ml with Aβ 25-35, an extensive decrease in the fluorescence intensity was observed in both phases, which suggests that ACTPG prevents the oligomers formation and disaggregation of mature fibrils. In addition, ACTPG was subjected to column chromatography and the bioactivity was screened based on the cholinesterase inhibitory activity. Finally, the active fraction was subjected to LC-MS/MS analysis for the identification of bioactive compounds. Overall, the results suggest that the bioactive compound alpha bisabolol present in the alga might be responsible for the observed cholinesterase inhibition with the IC50 value < 10 μg/ml for both AChE and BuChE when compared to standard drug donepezil (IC50 value < 6 μg/ml and support its use for the treatment of neurological disorders.

  17. Neuroprotective peptides related to Alzheimer's disease

    Czech Academy of Sciences Publication Activity Database

    Slaninová, Jiřina; Borovičková, Lenka; Krejčová, G.; Patočka, J.

    2004-01-01

    Roč. 10, S (2004), s. H33. ISSN 1075-2617. [Hellenic Forum on Bioactive Peptides /4./. 22.04.2004-24.04.2004, Patras-Hellas] Keywords : neuroprotective peptides * Alzheimer's disease Subject RIV: CE - Biochemistry

  18. Specific interactions between amyloidpeptide and curcumin derivatives: Ab initio molecular simulations

    Science.gov (United States)

    Ishimura, Hiromi; Kadoya, Ryushi; Suzuki, Tomoya; Murakawa, Takeru; Shulga, Sergiy; Kurita, Noriyuki

    2015-07-01

    Alzheimer's disease is caused by accumulation of amyloid-β (Aβ) peptides in a brain. To suppress the production of Aβ peptides, it is effective to inhibit the cleavage of amyloid precursor protein (APP) by secretases. However, because the secretases also play important roles to produce vital proteins for human body, inhibitors for the secretases may have side effects. To propose new agents for protecting the cleavage site of APP from the attacking of the γ-secretase, we have investigated here the specific interactions between a short APP peptide and curcumin derivatives, using protein-ligand docking as well as ab initio molecular simulations.

  19. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Science.gov (United States)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  20. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1 Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Henrik H Hansen

    Full Text Available One of the major histopathological hallmarks of Alzheimer's disease (AD is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1 receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP and presenilin-1 (PS1 are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9 of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c., or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.. In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

  1. Modeling Amyloid Beta Peptide Insertion into Lipid Bilayers

    CERN Document Server

    Mobley, D L; Singh, R R P; Maddox, M W; Longo, M J; Mobley, David L.; Cox, Daniel L.; Singh, Rajiv R. P.; Maddox, Michael W.; Longo, Marjorie L.

    2003-01-01

    Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (A-beta), can insert into cell membranes and form harmful ion channels, we model insertion of the peptide into cell membranes using a Monte Carlo code which is specific at the amino acid level. We examine insertion of the regular A-beta peptide as well as mutants causing familial Alzheimer's disease. We present our results and develop the hypothesis that partial insertion into the membrane, leaving the peptide in one leaflet, increases the probability of harmful channel formation. This hypothesis can partly explain why these mutations are neurotoxic simply due to peptide insertion behavior, and also explains why, normally, A-beta 42 is more toxic to some cultured cells than A-beta 40, but the E22Q mutation reverses this effect. We further apply this model to various artificial A-beta mutants which have been examined experimentally, and offer testable experimental predictions contrasting the roles of aggregation and insertion with regard ...

  2. Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein

    Directory of Open Access Journals (Sweden)

    Saoussen Ben Halima

    2016-03-01

    Full Text Available Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD. AD is characterized by toxic β-amyloid (Aβ peptides produced by β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP. β-secretase inhibitors reduce Aβ levels, but mechanism-based side effects arise because they also inhibit β-cleavage of non-amyloid substrates like Neuregulin. We report that β-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of β-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by β-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal β-secretase by an endosomally targeted β-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC-derived neurons. β-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects.

  3. Inhibition of Alzheimer amyloid β aggregation by polyvalent trehalose

    International Nuclear Information System (INIS)

    A glycopolymer carrying trehalose was found to suppress the formation of amyloid fibrils from the amyloid β peptide (1-42) (Aβ), as evaluated by thioflavin T assay and atomic force microscopy. Glycopolymers carrying sugar alcohols also changed the aggregation properties of Aβ, and the inhibitory effect depended on the type of sugar and alkyl side chain. Neutralization activity was confirmed by in vitro assay using HeLa cells. The glycopolymer carrying trehalose strongly inhibited amyloid formation and neutralized cytotoxicity.

  4. Amyloid cascade in Alzheimer's disease: Recent advances in medicinal chemistry.

    Science.gov (United States)

    Mohamed, Tarek; Shakeri, Arash; Rao, Praveen P N

    2016-05-01

    Alzheimer's disease is of major concern all over the world due to a number of factors including (i) an aging population (ii) increasing life span and (iii) lack of effective pharmacotherapy options. The past decade has seen intense research in discovering disease-modifying multitargeting small molecules as therapeutic options. The pathophysiology of Alzheimer's disease is attributed to a number of factors such as the cholinergic dysfunction, amyloid/tau toxicity and oxidative stress/mitochondrial dysfunction. In recent years, targeting the amyloid cascade has emerged as an attractive strategy to discover novel neurotherapeutics. Formation of beta-amyloid species, with different degrees of solubility and neurotoxicity is associated with the gradual decline in cognition leading to dementia. The two commonly used approaches to prevent beta-amyloid accumulation in the brain include (i) development of beta-secretase inhibitors and (ii) designing direct inhibitors of beta-amyloid (self-induced) aggregation. This review highlights the amyloid cascade hypothesis and the key chemical features required to design small molecules that inhibit lower and higher order beta-amyloid aggregates. Several recent examples of small synthetic molecules with disease-modifying properties were considered and their molecular docking studies were conducted using either a dimer or steric-zipper assembly of beta-amyloid. These investigations provide a mechanistic understanding on the structural requirements needed to design novel small molecules with anti-amyloid aggregation properties. Significantly, this work also demonstrates that the structural requirements to prevent aggregation of various amyloid species differs considerably, which explains the fact that many small molecules do not exhibit similar inhibition profile toward diverse amyloid species such as dimers, trimers, tetramers, oligomers, protofibrils and fibrils. PMID:26945113

  5. Cytochrome c peroxidase activity of heme bound amyloid β peptides.

    Science.gov (United States)

    Seal, Manas; Ghosh, Chandradeep; Basu, Olivia; Dey, Somdatta Ghosh

    2016-09-01

    Heme bound amyloid β (Aβ) peptides, which have been associated with Alzheimer's disease (AD), can catalytically oxidize ferrocytochrome c (Cyt c(II)) in the presence of hydrogen peroxide (H2O2). The rate of catalytic oxidation of Cyt(II) c has been found to be dependent on several factors, such as concentration of heme(III)-Aβ, Cyt(II) c, H2O2, pH, ionic strength of the solution, and peptide chain length of Aβ. The above features resemble the naturally occurring enzyme cytochrome c peroxidase (CCP) which is known to catalytically oxidize Cyt(II) c in the presence of H2O2. In the absence of heme(III)-Aβ, the oxidation of Cyt(II) c is not catalytic. Thus, heme-Aβ complex behaves as CCP. PMID:27270708

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

    OpenAIRE

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

    2013-01-01

    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, an...

  7. Amyloid Beta Peptides Differentially Affect Hippocampal Theta Rhythms In Vitro

    Directory of Open Access Journals (Sweden)

    Armando I. Gutiérrez-Lerma

    2013-01-01

    Full Text Available Soluble amyloid beta peptide (Aβ is responsible for the early cognitive dysfunction observed in Alzheimer's disease. Both cholinergically and glutamatergically induced hippocampal theta rhythms are related to learning and memory, spatial navigation, and spatial memory. However, these two types of theta rhythms are not identical; they are associated with different behaviors and can be differentially modulated by diverse experimental conditions. Therefore, in this study, we aimed to investigate whether or not application of soluble Aβ alters the two types of theta frequency oscillatory network activity generated in rat hippocampal slices by application of the cholinergic and glutamatergic agonists carbachol or DHPG, respectively. Due to previous evidence that oscillatory activity can be differentially affected by different Aβ peptides, we also compared Aβ25−35 and Aβ1−42 for their effects on theta rhythms in vitro at similar concentrations (0.5 to 1.0 μM. We found that Aβ25−35 reduces, with less potency than Aβ1−42, carbachol-induced population theta oscillatory activity. In contrast, DHPG-induced oscillatory activity was not affected by a high concentration of Aβ25−35 but was reduced by Aβ1−42. Our results support the idea that different amyloid peptides might alter specific cellular mechanisms related to the generation of specific neuronal network activities, instead of exerting a generalized inhibitory effect on neuronal network function.

  8. Common molecular mechanism of amyloid pore formation by Alzheimer’s β-amyloid peptide and α-synuclein

    Science.gov (United States)

    Di Scala, Coralie; Yahi, Nouara; Boutemeur, Sonia; Flores, Alessandra; Rodriguez, Léa; Chahinian, Henri; Fantini, Jacques

    2016-01-01

    Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer’s and Parkinson’s diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca2+-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined “membrane therapy”) targeting amyloid pores formed by Aβ1-42 and α-synuclein. PMID:27352802

  9. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect

    KAUST Repository

    Demetrius, Lloyd A.

    2015-01-14

    Epidemiological and biochemical studies show that the sporadic forms of Alzheimer\\'s disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

  10. Differences between amyloid-β aggregation in solution and on the membrane: insights into elucidation of the mechanistic details of Alzheimer's disease.

    Science.gov (United States)

    Kotler, Samuel A; Walsh, Patrick; Brender, Jeffrey R; Ramamoorthy, Ayyalusamy

    2014-10-01

    The association of the amyloid-β (Aβ) peptide with cellular membranes is hypothesized to be the underlying phenomenon of neurotoxicity in Alzheimer's disease. Misfolding of proteins and peptides, as is the case with Aβ, follows a progression from a monomeric state, through intermediates, ending at long, unbranched amyloid fibers. This tutorial review offers a perspective on the association of toxic Aβ structures with membranes as well as details of membrane-associated mechanisms of toxicity. PMID:24464312

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

    Science.gov (United States)

    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

  12. Laser-Induced In-Source Decay Applied to the Determination of Amyloid-Beta in Alzheimer's Brains.

    Science.gov (United States)

    Kelley, Andrea R; Perry, George; Castellani, Rudolph J; Bach, Stephan B H

    2016-03-16

    A method for the analysis of amyloid-beta peptides in isolated plaques and intact tissue sections affected by Alzheimer's disease (AD) is presented. This method employs matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry and the inherent laser-induced in-source decay (ISD) that occurs coupled with imaging mass spectrometry (IMS) to investigate the composition of these samples eliminating the need for other confirmational MS/MS techniques. These results demonstrate this technique's usefulness for the identification of amyloid-beta peptides in tissue and isolated senile plaques from AD patients using the reproducible fragmentation pattern demonstrated via the laser-induced ISD of synthetic amyloid-beta peptide clips (1-40, 1-42). Clear differences between the hippocampal AD tissue and the control hippocampal tissue regarding the presence of amyloid-beta have been identified. These are based on laser-induced ISD of standard amyloid-beta clips as controls as well as the analysis of isolated senile plaques as a confirmation before tissue analysis. Using the resulting observed peptide clip masses from the control data, we present mass spectrometry based identification of the amyloid-beta peptides in both isolated plaques and hippocampal regions of those patients diagnosed with AD. PMID:26720297

  13. Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid-beta pores.

    Science.gov (United States)

    Arbor, Sage C; LaFontaine, Mike; Cumbay, Medhane

    2016-03-01

    Amyloid beta (Aβ), the hallmark of Alzheimer's Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review. PMID:27505013

  14. Methionine oxidation of amyloid peptides by peroxovanadium complexes: inhibition of fibril formation through a distinct mechanism.

    Science.gov (United States)

    He, Lei; Wang, Xuesong; Zhu, Dengsen; Zhao, Cong; Du, Weihong

    2015-12-01

    Fibril formation of amyloid peptides is linked to a number of pathological states. The prion protein (PrP) and amyloid-β (Aβ) are two remarkable examples that are correlated with prion disorders and Alzheimer's disease, respectively. Metal complexes, such as those formed by platinum and ruthenium compounds, can act as inhibitors against peptide aggregation primarily through metal coordination. This study revealed the inhibitory effect of two peroxovanadium complexes, (NH4)[VO(O2)2(bipy)]·4H2O (1) and (NH4)[VO(O2)2(phen)]·2H2O (2), on amyloid fibril formation of PrP106-126 and Aβ1-42via site-specific oxidation of methionine residues, besides direct binding of the complexes with the peptides. Complexes 1 and 2 showed higher anti-amyloidogenic activity on PrP106-126 aggregation than on Aβ1-42, though their regulation on the cytotoxicity induced by the two peptides could not be differentiated. The action efficacy may be attributed to the different molecular structures of the vanadium complex and the peptide sequence. Results reflected that methionine oxidation may be a crucial action mode in inhibiting amyloid fibril formation. This study offers a possible application value for peroxovanadium complexes against amyloid proteins. PMID:26444976

  15. Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer's Disease

    OpenAIRE

    Ryan, N. S.; Lashley, T.; Revesz, T; Dantu, K.; Fox, N.C.; Morris, H R

    2014-01-01

    Amyloid-related imaging abnormalities (ARIA), thought to reflect immune responses to vascular amyloid, have been detected in several amyloid-modifying therapy trials for Alzheimer's disease (AD). We report a case of ARIA developing spontaneously during the course of Presenilin 1 (PSEN1)-associated familial AD (FAD), in an APOE4 homozygous patient. Severe cerebral amyloid angiopathy with associated inflammation was subsequently found at autopsy. Recognition that ARIA may arise spontaneously du...

  16. Modeling an Anti-Amyloid Combination Therapy for Alzheimer's Disease

    OpenAIRE

    Chow, Vivian W.; Savonenko, Alena V; Melnikova, Tatiana; Kim, Hyunsu; Price, Donald L.; Li, Tong; Wong, Philip C.

    2010-01-01

    As only symptomatic treatments are now available for Alzheimer's disease (AD), safe and effective mechanism-based therapies remain a great unmet need for patients with this neurodegenerative disease. Although γ-secretase and BACE1 [β-site β-amyloid (Aβ) precursor protein (APP) cleaving enzyme 1] are well-recognized therapeutic targets for AD, untoward side effects associated with strong inhibition or reductions in amounts of these aspartyl proteases have raised concerns regarding their therap...

  17. Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect.

    Science.gov (United States)

    Demetrius, Lloyd A; Magistretti, Pierre J; Pellerin, Luc

    2014-01-01

    Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events-mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model. PMID:25642192

  18. Action of Caffeine as an Amyloid Inhibitor in the Aggregation of Aβ16-22 Peptides.

    Science.gov (United States)

    Sharma, Bhanita; Paul, Sandip

    2016-09-01

    Alzheimer's disease (AD) is a neurodegenerative disease caused due to aggregation of Aβ peptides in the brain tissues. Recently, several studies on AD transgenic mice have shown the effect of caffeine in significantly reducing the Aβ amyloid level in their brains. However, the mechanism and mode of caffeine action on amyloid aggregation are not known. Therefore, in this study, we have carried out molecular dynamics simulations of five amyloid-forming Aβ16-22 peptides in pure water and in a regime of caffeine solutions, with different caffeine/peptide stoichiometric ratios. The secondary structure analyses of peptides in pure water show the formation of β-sheet conformations, whereas on addition of caffeine, these ordered conformations become negligible. The radial distribution function, contact map, nonbonding interaction energy, hydrogen bonding, potential of mean force, and hydration analyses show that there is less interpeptide interaction in the presence of caffeine, and the effect is greater with an increasing caffeine ratio. The interaction of aromatic phenylalanine residues of peptides with caffeine restricts the interpeptide interaction tendency. Upon increasing the number of caffeine molecules, interaction of caffeine with other hydrophobic residues also increases. Thus, the hydrophobic core-recognition motif of amyloid formation of peptides is physically blocked by caffeine, thereby abolishing the self-assembly formation. PMID:27487451

  19. Beta-amyloid peptide blocks the fast-inactivating K+ current in rat hippocampal neurons.

    OpenAIRE

    Good, T A; Smith, D. O.; Murphy, R M

    1996-01-01

    Deposition of beta-amyloid peptide (A beta) in senile plaques is a hallmark of Alzheimer disease neuropathology. Chronic exposure of neuronal cultures to synthetic A beta is directly toxic, or enhances neuronal susceptibility to excitotoxins. Exposure to A beta may cause a loss of cellular calcium homeostasis, but the mechanism by which this occurs is uncertain. In this work, the acute response of rat hippocampal neurons to applications of synthetic A beta was measured using whole-cell voltag...

  20. 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...

  1. Characterization of D-enatiomeric peptides derived from D3 for treatment of Alzheimer`s disease

    OpenAIRE

    Klein, Antonia Nicole; Tusche, Markus; Schlosser, Christine; Bartnik, Dirk; Kutzsche, Janine; Willbold, Dieter

    2014-01-01

    Alzheimer's disease (AD) is the most prominent neurodegenerative disease affecting more than 24 million people worldwide. Currently, it is the sixth-leading cause of death, but until now there is no causal therapy available. The amyloid-beta (Aβ) peptide plays an important role in the pathology of the disease. Especially the soluble, most harmful neurotoxic oligomers of Aβ are discussed to be responsible for the development and progression of the disease. In our group we identified the D-enan...

  2. Validation of a multiplex assay for simultaneous quantification of amyloidpeptide species in human plasma with utility for measurements in studies of Alzheimer's disease therapeutics.

    Science.gov (United States)

    Lachno, D Richard; Emerson, Julie K; Vanderstichele, Hugo; Gonzales, Celedon; Martényi, Ferenc; Konrad, Robert J; Talbot, Jayne A; Lowe, Stephen L; Oefinger, Paul E; Dean, Robert A

    2012-01-01

    The aim of this study was to validate the INNO-BIA plasma amyloid-β (Aβ) forms assay for quantification of Aβ1-40 and Aβ1-42 according to regulatory guidance for bioanalysis and demonstrate its fitness for clinical trial applications. Validation parameters were evaluated by repeated testing of human EDTA-plasma pools. In 6 separate estimates, intra-assay coefficients of variation (CV) for repeated testing of 5 plasma pools were ≤9% and relative error (RE) varied between -35% and +22%. Inter-assay CV (n = 36) ranged from 5% to 17% and RE varied from -17% to +8%. Dilutional linearity was not demonstrated for either analyte using diluent buffer, but dilution with immuno-depleted plasma by 1.67-fold gave results within 20% of target. Analyte stability was demonstrated in plasma at 2-8 °C for up to 6 h. Stability during frozen storage up to 12 months and through 3 freeze-thaw cycles at ≤ -70 °C was also demonstrated in 5 of 6 individuals but deteriorated thereafter. Neither semagacestat nor LY2811376 interfered with the assay but solanezumab at 500 mg/L reduced recovery of Aβ1-42 by 53%. Specimens from a Phase I human volunteer study of the β-secretase inhibitor LY2811376 were tested at baseline and at intervals up to 12 h after single oral doses, demonstrating a clear treatment effect. During 1,041 clinical assay runs from semagacestat studies over 10 months, the CV for plasma quality control pools at three levels were ≤15% and RE were <10%. In conclusion, the INNO-BIA plasma assay was successfully validated and qualified for use in clinical research. PMID:22886018

  3. A binding-site barrier affects imaging efficiency of high affinity amyloid-reactive peptide radiotracers in vivo.

    Directory of Open Access Journals (Sweden)

    Jonathan S Wall

    Full Text Available Amyloid is a complex pathology associated with a growing number of diseases including Alzheimer's disease, type 2 diabetes, rheumatoid arthritis, and myeloma. The distribution and extent of amyloid deposition in body organs establishes the prognosis and can define treatment options; therefore, determining the amyloid load by using non-invasive molecular imaging is clinically important. We have identified a heparin-binding peptide designated p5 that, when radioiodinated, was capable of selectively imaging systemic visceral AA amyloidosis in a murine model of the disease. The p5 peptide was posited to bind effectively to amyloid deposits, relative to similarly charged polybasic heparin-reactive peptides, because it adopted a polar α helix secondary structure. We have now synthesized a variant, p5R, in which the 8 lysine amino acids of p5 have been replaced with arginine residues predisposing the peptide toward the α helical conformation in an effort to enhance the reactivity of the peptide with the amyloid substrate. The p5R peptide had higher affinity for amyloid and visualized AA amyloid in mice by using SPECT/CT imaging; however, the microdistribution, as evidenced in micro-autoradiographs, was dramatically altered relative to the p5 peptide due to its increased affinity and a resultant "binding site barrier" effect. These data suggest that radioiodinated peptide p5R may be optimal for the in vivo detection of discreet, perivascular amyloid, as found in the brain and pancreatic vasculature, by using molecular imaging techniques; however, peptide p5, due to its increased penetration, may yield more quantitative imaging of expansive tissue amyloid deposits.

  4. MR Microimaging of amyloid plaques in Alzheimer's disease transgenic mice

    International Nuclear Information System (INIS)

    Alzheimer's disease (AD) is the most prevalent neurological condition affecting industrialized nations and will rapidly become a healthcare crisis as the population ages. Currently, the post-mortem histological observation of amyloid plaques and neurofibrillary tangles is the only definitive diagnosis available for AD. A pre-mortem biological or physiological marker specific for AD used in conjunction with current neurological and memory testing could add a great deal of confidence to the diagnosis of AD and potentially allow therapeutic intervention much earlier in the disease process. Our group has developed MRI techniques to detect individual amyloid plaques in AD transgenic mouse brain in vivo. We are also developing contrast-enhancing agents to increase the specificity of detection of amyloid plaques. Such in vivo imaging of amyloid plaques will also allow the evaluation of anti-amyloid therapies being developed by the pharmaceutical industry in pre-clinical trials of AD transgenic mice. This short review briefly discusses our progress in these areas. (orig.)

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

    International Nuclear Information System (INIS)

    Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Aβ 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 Aβ 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 Aβ 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 Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials

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

    Directory of Open Access Journals (Sweden)

    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].

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

    Science.gov (United States)

    Di Scala, Coralie; Yahi, Nouara; Flores, Alessandra; Boutemeur, Sonia; Kourdougli, Nazim; Chahinian, Henri; Fantini, Jacques

    2016-01-01

    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]. PMID:26909380

  8. Amyloid-beta Alzheimer targets — protein processing, lipid rafts, and amyloid-beta pores

    Science.gov (United States)

    Arbor, Sage C.; LaFontaine, Mike; Cumbay, Medhane

    2016-01-01

    Amyloid beta (Aβ), the hallmark of Alzheimer’s Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review.

  9. Neuroprotective peptides related to Alzheimer's disease

    Czech Academy of Sciences Publication Activity Database

    Slaninová, Jiřina; Borovičková, Lenka; Bláha, I.; Hlaváček, Jan; Krejčová, G.; Patočka, J.

    Patras : Typorama, 2005 - (Cordopatis, P.; Manessi-Zoupa, E.; Pairas, G.), 147-154 ISBN 960-7620-31-3. [Hellenic Forum on Bioactive Peptides /4./. Patras (GR), 22.04.2004-24.04.2004] R&D Projects: GA ČR(CZ) GA305/03/1100 Institutional research plan: CEZ:AV0Z40550506 Keywords : peptides * Alzheimer's disease * humanin Subject RIV: CE - Biochemistry

  10. Neurotrophic effects of amyloid precursor protein peptide 165 in vitro.

    Science.gov (United States)

    Yao, Jie; Ma, Lina; Wang, Rong; Sheng, Shuli; Ji, Zhijuan; Zhang, Jingyan

    2016-01-01

    Diabetic encephalopathy is one of the risk factors for Alzheimer's disease. Our previous findings indicated that animals with diabetic encephalopathy exhibit learning and memory impairment in addition to hippocampal neurodegeneration, both of which are ameliorated with amyloid precursor protein (APP) 17-mer (APP17) peptide treatment. Although APP17 is neuroprotective, it is susceptible to enzymatic degradation. Derived from the active sequence structure of APP17, we have previously structurally transformed and modified several APP5-mer peptides (APP328-332 [RERMS], APP 5). We have developed seven different derivatives of APP5, including several analogs. Results from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on human neuroblastoma SH-SY5Y cells in the present study showed that P165 was the most neuroprotective APP5 derivative. Furthermore, we tested the effects of APP5 and P165 on the number of cells and the release of lactate dehydrogenase. Western immunoblot analyses were also performed. The digestion rates of P165 and APP5 were determined by the pepsin digestion test. P165 resisted pepsin digestion significantly more than APP5. Therefore, P165 may be optimal for oral administration. Overall, these findings suggest that P165 may be a potential drug for the treatment of diabetic encephalopathy. PMID:26551064

  11. Cholesterol Depletion Reduces the Internalization of β-Amyloid Peptide in SH-SY5Y Cells

    Institute of Scientific and Technical Information of China (English)

    ZHOU Qinghua; HE Li; SUI Senfang

    2006-01-01

    Deposition of amyloid in the brain is a critical step in the pathogenesis of Alzheimer's disease. The endocytosis of β-amyloid peptide (Aβ) is an important factor among the many factors that contribute to the genesis of amyloid deposits. Since cholesterol participates in many important physiological processes, the present work investigated the relationship between the cellular cholesterol content and the endocytosis of the exogenic Aβ, and found that reduction of the cholesterol content by methyl-β-cyclodextrin could reduce the endocytosis of Aβ. The study indicates that the endocytosis of Aβ is partly mediated by cholesterol.

  12. Reexamining Alzheimer's Disease: Evidence for a Protective Role for Amyloid-β Protein Precursor and Amyloid

    OpenAIRE

    Castellani, Rudy J.; Lee, Hyoung-gon; Siedlak, Sandra L.; Nunomura, Akihiko; Hayashi, Takaaki; Nakamura, Masao; Zhu, Xiongwei; Perry, George; Smith, Mark A.

    2009-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-β-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused on amyloid-β as the major pathogenic mechanisms with the ultimate goal of using amyloid-β lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectac...

  13. Tackling amyloidogenesis in Alzheimer's disease with A2V variants of Amyloid-β.

    Science.gov (United States)

    Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Morbin, Michela; Moda, Fabio; Colombo, Laura; Rossi, Alessandro; Cagnotto, Alfredo; Virgilio, Tommaso; Palamara, Luisa; Ruggerone, Margherita; Giaccone, Giorgio; Campagnani, Ilaria; Costanza, Massimo; Pedotti, Rosetta; Salvalaglio, Matteo; Salmona, Mario; Tagliavini, Fabrizio

    2016-01-01

    We developed a novel therapeutic strategy for Alzheimer's disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics. PMID:26864599

  14. Preparation of Amyloid Immuno-Nanoparticles as Potential MRI Contrast Agents for Alzheimer's Disease Diagnosis.

    Science.gov (United States)

    Yin, Zhenyu; Yul, Tingting; Xu, Yun

    2015-09-01

    Alzheimer's disease (AD) is the most common form of dementia which is caused by accumulation in the brain of plaques made up of amyloid beta-peptide (Abeta). Research on nanosized systems indicated that nanoparticles (NPs) could pass across the blood-brain barrier (BBB) and improve the visibility of internal body structures in magnetic resonance imaging (MRI), which made it possible to aid the early diagnosis of AD. In this research study we synthesized magnetite nanoparticles by high-temperature solution-phase reaction, transferred into water based on a ligand exchange process and coated with meso-2,3-dimercaptosuccinic (DMSA). Subsequently, the anti-amyloid Abeta immunomagnetic nanoparticles (IMNPs) were prepared by grafting anti-amyloid antibodies on the surface of the DMSA-coated magnetic nanoparticles (MNPs). The enzyme linked immunosorbent assay (ELISA) method was introduced to evaluate the IMNPs activity and conjugation amount of antibodies. The biocompatibility of the IMNPs was tested by colony-forming assay. The results showed that the anti-amyloid Abeta IMNPs were biocompatible and biologically active, as well as effective in enhancing MRI solution, indicating that the IMNPs could be used as potential MRI contrast agents and targeted carriers for AD early diagnosis and therapy. PMID:26716196

  15. The Alzheimer's Amyloid-Degrading Peptidase, Neprilysin: Can We Control It?

    Directory of Open Access Journals (Sweden)

    N. N. Nalivaeva

    2012-01-01

    Full Text Available The amyloid cascade hypothesis of Alzheimer's disease (AD postulates that accumulation in the brain of amyloid β-peptide (Aβ is the primary trigger for neuronal loss specific to this pathology. In healthy brain, Aβ levels are regulated by a dynamic equilibrium between Aβ release from the amyloid precursor protein (APP and its removal by perivascular drainage or by amyloid-degrading enzymes (ADEs. During the last decade, the ADE family was fast growing, and currently it embraces more than 20 members. There are solid data supporting involvement of each of them in Aβ clearance but a zinc metallopeptidase neprilysin (NEP is considered as a major ADE. NEP plays an important role in brain function due to its role in terminating neuropeptide signalling and its decrease during ageing or after such pathologies as hypoxia or ischemia contribute significantly to the development of AD pathology. The recently discovered mechanism of epigenetic regulation of NEP by the APP intracellular domain (AICD opens new avenues for its therapeutic manipulation and raises hope for developing preventive strategies in AD. However, consideration needs to be given to the diverse physiological roles of NEP. This paper critically evaluates general biochemical and physiological functions of NEP and their therapeutic relevance.

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

    Directory of Open Access Journals (Sweden)

    Juliet A Moncaster

    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

  17. Nanoparticulate Radiolabelled Quinolines Detect Amyloid Plaques in Mouse Models of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Frederick J. Bonte

    2009-01-01

    Full Text Available Detecting aggregated amyloid peptides (Aβ plaques presents targets for developing biomarkers of Alzheimer's disease (AD. Polymeric n-butyl-2-cyanoacrylate (PBCA nanoparticles (NPs were encapsulated with radiolabelled amyloid affinity I125-clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline as in vivo probes. I125-CQ-PBCA NPs crossed the BBB (2.3±0.9 ID/g (P<.05 in the WT mouse (N = 210, compared to I125-CQ (1.0±0.4 ID/g. I125-CQ-PBCA NP brain uptake increased in AD transgenic mice (APP/PS1 versus WT (N = 38; 2.54×105±5.31×104 DLU/mm2; versus 1.98×105±2.22×104 DLU/mm2 and in APP/PS1/Tau. Brain increases were in mice intracranially injected with aggregated Aβ42 peptide (N = 17; 7.19×105±1.25×105 DLU/mm2, versus WT (6.07×105±7.47×104 DLU/mm2. Storage phosphor imaging and histopathological staining of the plaques, Fe2+ and Cu2+, validated results. I125-CQ-PBCA NPs have specificity for Aβ in vitro and in vivo and are promising as in vivo SPECT (I123, or PET (I124 amyloid imaging agents.

  18. Amyloidβ Peptides in interaction with raft-mime model membranes: a neutron reflectivity insight.

    Science.gov (United States)

    Rondelli, Valeria; Brocca, Paola; Motta, Simona; Messa, Massimo; Colombo, Laura; Salmona, Mario; Fragneto, Giovanna; Cantù, Laura; Del Favero, Elena

    2016-01-01

    The role of first-stage β-amyloid aggregation in the development of the Alzheimer disease, is widely accepted but still unclear. Intimate interaction with the cell membrane is invoked. We designed Neutron Reflectometry experiments to reveal the existence and extent of the interaction between β-amyloid (Aβ) peptides and a lone customized biomimetic membrane, and their dependence on the aggregation state of the peptide. The membrane, asymmetrically containing phospholipids, GM1 and cholesterol in biosimilar proportion, is a model for a raft, a putative site for amyloid-cell membrane interaction. We found that the structured-oligomer of Aβ(1-42), its most acknowledged membrane-active state, is embedded as such into the external leaflet of the membrane. Conversely, the Aβ(1-42) unstructured early-oligomers deeply penetrate the membrane, likely mimicking the interaction at neuronal cell surfaces, when the Aβ(1-42) is cleaved from APP protein and the membrane constitutes a template for its further structural evolution. Moreover, the smaller Aβ(1-6) fragment, the N-terminal portion of Aβ, was also used. Aβ N-terminal is usually considered as involved in oligomer stabilization but not in the peptide-membrane interaction. Instead, it was seen to remove lipids from the bilayer, thus suggesting its role, once in the whole peptide, in membrane leakage, favouring peptide recruitment. PMID:26880066

  19. Evidence for Inhibition of Lysozyme Amyloid Fibrillization by Peptide Fragments from Human Lysozyme: A Combined Spectroscopy, Microscopy, and Docking Study.

    Science.gov (United States)

    Kar, Rajiv K; Gazova, Zuzana; Bednarikova, Zuzana; Mroue, Kamal H; Ghosh, Anirban; Zhang, Ruiyan; Ulicna, Katarina; Siebert, Hans-Christian; Nifantiev, Nikolay E; Bhunia, Anirban

    2016-06-13

    Degenerative diseases, such as Alzheimer's and prion diseases, as well as type II diabetes, have a pathogenesis associated with protein misfolding, which routes with amyloid formation. Recent strategies for designing small-molecule and polypeptide antiamyloid inhibitors are mainly based on mature fibril structures containing cross β-sheet structures. In the present study, we have tackled the hypothesis that the rational design of antiamyloid agents that can target native proteins might offer advantageous prospect to design effective therapeutics. Lysozyme amyloid fibrillization was treated with three different peptide fragments derived from lysozyme protein sequence R(107)-R(115). Using low-resolution spectroscopic, high-resolution NMR, and STD NMR-restrained docking methods such as HADDOCK, we have found that these peptide fragments have the capability to affect lysozyme fibril formation. The present study implicates the prospect that these peptides can also be tested against other amyloid-prone proteins to develop novel therapeutic agents. PMID:27116396

  20. Alzheimer's disease cybrids replicate beta-amyloid abnormalities through cell death pathways.

    Science.gov (United States)

    Khan, S M; Cassarino, D S; Abramova, N N; Keeney, P M; Borland, M K; Trimmer, P A; Krebs, C T; Bennett, J C; Parks, J K; Swerdlow, R H; Parker, W D; Bennett, J P

    2000-08-01

    Alzheimer's disease (AD) is characterized by the deposition in brain of beta-amyloid (Abeta) peptides, elevated brain caspase-3, and systemic deficiency of cytochrome c oxidase. Although increased Abeta deposition can result from mutations in amyloid precursor protein or presenilin genes, the cause of increased Abeta deposition in sporadic AD is unknown. Cytoplasmic hybrid ("cybrid") cells made from mitochondrial DNA of nonfamilial AD subjects show antioxidant-reversible lowering of mitochondrial membrane potential (delta(gYm), secrete twice as much Abeta(1-40) and Abeta(1-42), have increased intracellular Abeta(1-40) (1.7-fold), and develop Congo red-positive Abeta deposits. Also elevated are cytoplasmic cytochrome c (threefold) and caspase-3 activity (twofold). Increased AD cybrid Abeta(1-40) secretion was normalized by inhibition of caspase-3 or secretase and reduced by treatment with the antioxidant S(-)pramipexole. Expression of AD mitochondrial genes in cybrid cells depresses cytochrome c oxidase activity and increases oxidative stress, which, in turn, lowers delta(psi)m. Under stress, cells with AD mitochondrial genes are more likely to activate cell death pathways, which drive caspase 3-mediated Abeta peptide secretion and may account for increased Abeta deposition in the AD brain. Therapeutic strategies for reducing neurodegeneration in sporadic AD can address restoration of delta(psi)m and reduction of elevated Abeta secretion. PMID:10939564

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

    Directory of Open Access Journals (Sweden)

    Létitia Jean

    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

  2. Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide

    OpenAIRE

    de Melo, Joana Barbosa; Agostinho, Paula; Oliveira, Catarina Resende

    2003-01-01

    Acetylcholinesterase (AChE) activity is increased within and around amyloid plaques, which are present in Alzheimer's disease (AD) patient's brain. In this study, using cultured retinal cells as a neuronal model, we analyzed the effect of the synthetic peptide A[beta]25-35 on the activity of AChE, the degradation enzyme of acetylcholine, as well as the involvement of oxidative stress in this process. The activity of AChE was increased when retinal cells were incubated with A[beta]25-35 (25 [m...

  3. Probing amyloid-β pathology in transgenic Alzheimer's disease (tgArcSwe) mice using MALDI imaging mass spectrometry.

    Science.gov (United States)

    Carlred, Louise; Michno, Wojciech; Kaya, Ibrahim; Sjövall, Peter; Syvänen, Stina; Hanrieder, Jörg

    2016-08-01

    The pathological mechanisms underlying Alzheimer's disease (AD) are still not understood. The disease pathology is characterized by the accumulation and aggregation of amyloid-β (Aβ) peptides into extracellular plaques, however the factors that promote neurotoxic Aβ aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides and proteins in biological tissues. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS)-based imaging was used to study Aβ deposition in transgenic mouse brain tissue and to elucidate the plaque-associated chemical microenvironment. The imaging experiments were performed in brain sections of transgenic Alzheimer's disease mice carrying the Arctic and Swedish mutation of amyloid-beta precursor protein (tgArcSwe). Multivariate image analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their chemical identity. This include cortical and hippocampal Aβ deposits, whose amyloid peptide content was further verified using immunohistochemistry and laser microdissection followed by MALDI MS analysis. Subsequent statistical analysis on spectral data of regions of interest revealed brain region-specific differences in Aβ peptide aggregation. Moreover, other plaque-associated protein species were identified including macrophage migration inhibitory factor suggesting neuroinflammatory processes and glial cell reactivity to be involved in AD pathology. The presented data further highlight the potential of IMS as a powerful approach in neuropathology. Hanrieder et al. described an imaging mass spectrometry based study on comprehensive spatial profiling of C-terminally truncated Aβ species within individual plaques in tgArcSwe mice. Here, brain region-dependent differences in Aβ truncation and other plaque-associated proteins, such as

  4. Fibrillation of β amyloid peptides in the presence of phospholipid bilayers and the consequent membrane disruption.

    Science.gov (United States)

    Qiang, Wei; Yau, Wai-Ming; Schulte, Jürgen

    2015-01-01

    Fibrillation of β amyloid (Aβ) peptides and the accumulation of amyloid plaques are considered as an important clinical hallmark to identify Alzheimer's disease (AD). The physiological connection between Aβ plaques and the disruption of neuronal cells has not been clearly understood. One hypothesis to explain the Aβ neurotoxicity is that the fibrillation process induces disruption to the cellular membrane. We studied the Aβ fibrillation process in two biologically relevant conditions with the peptide either pre-incorporated into or externally added to the synthetic phospholipid bilayers. These two sample preparation conditions mimic the physiological membrane proximities of Aβ peptides before and after the enzymatic cleavage of amyloid precursor protein (APP). Using thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM), we were able to monitor the kinetics and morphological evolution of fibril formation, which was highly sensitive to the two sample preparation protocols. While the external addition protocol generates long and mature fibrils through normal fibrillation process, the pre-incubation protocol was found to stabilize the immature protofibrils. Fluorescence spectroscopy studies with doubly-labeled phospholipids indicated that there may be a lipid uptake process associated with the fibril formation. Solid state nuclear magnetic resonance (NMR) spectroscopy provided evidence for high resolution structural variations in fibrils formed with different protocols, and in particular the stabilization of long-range contact between N- and C-terminal β strands. In addition, disruption of phospholipid bilayers was supported by measurements with ³¹P chemical shifts and relaxation time constants. PMID:24769158

  5. Inhibition of Cu-amyloid-β by using bifunctional peptides with β-sheet breaker and chelator moieties.

    Science.gov (United States)

    Jensen, Madeleine; Canning, Anne; Chiha, Sabri; Bouquerel, Pierre; Pedersen, Jeppe Trudslev; Østergaard, Jesper; Cuvillier, Olivier; Sasaki, Isabelle; Hureau, Christelle; Faller, Peter

    2012-04-16

    Breaking the mold: Inhibition of toxic amyloid-β (Aβ) aggregates and disruption of Cu-Aβ with subsequent redox-silencing of Cu have been considered promising strategies against Alzheimer's disease. The design and proof of concept of simple peptides containing a Cu-chelating/redox-silencing unit and an Aβ-aggregation inhibition unit (β-sheet breaker) is described (see scheme). PMID:22422637

  6. The mechanism of the low-density lipoprotein receptor- related protein (LRP) in the production of amyloid-[Beta] peptide

    OpenAIRE

    Chen, Eunice Chungyu

    2008-01-01

    Alzheimer's disease (AD) is the most common form of neurodegenerative disorder affecting the elderly, presenting symptoms such as memory impairment and dementia. AD is pathologically characterized by the development of extracellular senile plaques and intracellular neurofibrillary tangles (NFT). The plaques are composed of amyloid-[Beta] peptide (A[Beta]) and the NFTs are composed of a hyperphosphorylated form of the tau protein. A[Beta] is formed by sequential proteolytic processing of the a...

  7. Aliphatic peptides show similar self-assembly to amyloid core sequences, challenging the importance of aromatic interactions in amyloidosis.

    Science.gov (United States)

    Lakshmanan, Anupama; Cheong, Daniel W; Accardo, Angelo; Di Fabrizio, Enzo; Riekel, Christian; Hauser, Charlotte A E

    2013-01-01

    The self-assembly of abnormally folded proteins into amyloid fibrils is a hallmark of many debilitating diseases, from Alzheimer's and Parkinson diseases to prion-related disorders and diabetes type II. However, the fundamental mechanism of amyloid aggregation remains poorly understood. Core sequences of four to seven amino acids within natural amyloid proteins that form toxic fibrils have been used to study amyloidogenesis. We recently reported a class of systematically designed ultrasmall peptides that self-assemble in water into cross-β-type fibers. Here we compare the self-assembly of these peptides with natural core sequences. These include core segments from Alzheimer's amyloid-β, human amylin, and calcitonin. We analyzed the self-assembly process using circular dichroism, electron microscopy, X-ray diffraction, rheology, and molecular dynamics simulations. We found that the designed aliphatic peptides exhibited a similar self-assembly mechanism to several natural sequences, with formation of α-helical intermediates being a common feature. Interestingly, the self-assembly of a second core sequence from amyloid-β, containing the diphenylalanine motif, was distinctly different from all other examined sequences. The diphenylalanine-containing sequence formed β-sheet aggregates without going through the α-helical intermediate step, giving a unique fiber-diffraction pattern and simulation structure. Based on these results, we propose a simplified aliphatic model system to study amyloidosis. Our results provide vital insight into the nature of early intermediates formed and suggest that aromatic interactions are not as important in amyloid formation as previously postulated. This information is necessary for developing therapeutic drugs that inhibit and control amyloid formation. PMID:23267112

  8. Proteólisis cerebral del péptido amiloide-ß: Relevancia de la enzima degradadora de insulina en la enfermedad de Alzheimer Cerebral proteolysis of amyloidpeptide: Relevance of insulin-degrading enzyme in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    María Celeste Leal

    2009-10-01

    Full Text Available El aumento global de la expectativa de vida convierte a la enfermedad de Alzheimer (EA en un problema creciente. Una de las características distintivas de EA es la acumulación excesiva del péptido amiloide ß (Aß en el cerebro. En los últimos años se ha fortalecido el concepto de que la degradación de Aß por proteasas in situ es un mecanismo importante que previene su acumulación cerebral. Datos bioquímicos y genéticos mostraron que la enzima degradadora de insulina (IDE participa en la homeostasis de Aß e insulina. La expresión y la actividad de IDE están significativamente disminuidas en cerebros con EA comparados con controles de igual edad. Además, IDE se deposita con Aß en placas seniles y vasos, indicando un grosero cambio conformacional producto de distintos mecanismos post-traduccionales. Estas alteraciones en la distribución y actividad de IDE resultan en una insuficiente degradación de Aß e insulina y promueven la formación de oligómeros de Aß y la resistencia a la hormona, procesos que convergen hacia la neurodegeneración. El estudio de los mecanismos de eliminación de Aß cerebral no sólo ayudará a comprender la patogenia de EA sino que permitirá una mejor interpretación de los ensayos clínicos en curso y el desarrollo de nuevas estrategias terapéuticas.The global increase in life expectancy turns Alzheimer's disease (AD into a growing problem. One of the distinctive features of AD is the excessive accumulation of amyloid-ß (Aß peptide in the brain. In recent years, a concept that has gained strength is that degradation of Aß by proteases in situ is an important mechanism that prevents cerebral peptide accumulation. Biochemical and genetic data have shown that insulin-degrading enzyme (IDE participates in Aß and insulin homeostasis. IDE expression and activity are significantly decreased in AD brains compared to age-matched controls. Also, IDE is deposited with Aß in senile plaques and blood vessels

  9. Cu(II) mediates kinetically distinct, non-amyloidogenic aggregation of amyloidpeptides

    DEFF Research Database (Denmark)

    Pedersen, Jeppe T.; Østergaard, Jesper; Rozlosnik, Noemi; Gammelgaard, Bente; Heegaard, Niels H. H.

    2011-01-01

    aggregates, which shifted from fibrillar to non-fibrillar at increasing Cu(II):Aβ ratios. We observed dynamic morphological changes of the aggregates, and that the formation of spherical aggregates appeared to be a common morphological end point independent on the Cu(II) concentration. Experiments with Aβ1......Cu(II) ions are implicated in the pathogenesis of Alzheimer disease by influencing the aggregation of the amyloid-β (Aβ) peptide. Elucidating the underlying Cu(II)-induced Aβ aggregation is paramount for understanding the role of Cu(II) in the pathology of Alzheimer disease. The aim of this study...... was to characterize the qualitative and quantitative influence of Cu(II) on the extracellular aggregation mechanism and aggregate morphology of Aβ1-40 using spectroscopic, microelectrophoretic, mass spectrometric, and ultrastructural techniques. We found that the Cu(II):Aβ ratio in solution has a...

  10. 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

  11. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Goldgaber, D.; Lerman, M.I.; McBride, O.W.; Saffiotti, U.; Gajdusek, D.C.

    1987-02-20

    Four clones were isolated from an adult human brain complementary DNA library with an oligonucleotide probe corresponding to the first 20 amino acids of the ..beta.. peptide of brain amyloid from Alzheimer's disease. The open reading frame of the sequenced clone coded for 97 amino acids, including the known amino acid sequence of this polypeptide. The 3.5-kilobase messenger RNA was detected in mammalian brains and human thymus. The gene is highly conserved in evolution and has been mapped to human chromosome 21.

  12. Effect of osmolytes on the conformation and aggregation of some amyloid peptides: CD spectroscopic data.

    Science.gov (United States)

    Inayathullah, Mohammed; Rajadas, Jayakumar

    2016-06-01

    Protein misfolding and aggregation are responsible for a large number of diseases called protein conformational diseases or disorders that include Alzheimer׳s disease, Huntington׳s diseases, Prion related encephalopathies and type-II diabetes (http://dx.doi.org/10.1038/35041139) (Kopito and Ron, 2000) [1]. A variety of studies have shown that some small organic molecules, known as osmolytes have the ability to stabilize native conformation of proteins and prevent misfolding and aggregation (http://www.la-press.com/article.php?article_id=447) (Zhao et al., 2008) [2]. It has been shown that certain short segment or fragment of respective proteins can also form amyloids, and the segments also promote the aggregation in the full-length protein (http://dx.doi.org/10.2174/0929867023369187) (Gazit, 2002) [3]. This article presents circular dichroism spectroscopic data on conformational analysis and effect of osmolytes on Aβ peptide fragments, different lengths of polyglutamine peptide and the amyloidogenic segment of islet amyloid polypeptide. PMID:27222868

  13. Estrogen has anti-amyloidogenic effects on Alzheimer's β-amyloid fibrils in vitro

    International Nuclear Information System (INIS)

    Inhibition of the assembly of amyloid β-peptide (Aβ) as well as the destabilization of preformed β-amyloid fibrils (fAβ) in the central nervous system could be valuable therapeutics of patients with Alzheimer's disease (AD). Epidemiological studies have indicated that estrogen therapy reduced the risk of developing AD in women. Here, we examined the effects of estrogen (estrone (E1), estradiol (E2), and estriol (E3)) and related sexual steroids (androstenedione (AND) and testosterone (TES)) on the polymerization, extension and destabilization of fAβ(1-42) and fAβ(1-40) at pH 7.5 at 37 oC in vitro, using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies. E1, E2, and E3 dose-dependently inhibited the formation, as well as destabilization of fAβs. The overall anti-amyloidogenic activity of these molecules was in the order of: E3 > E2 = E1 >>AND = TES. Estrogen could be a potential therapeutic agent to prevent or delay AD progression

  14. Protective effects of BAY 73-6691, a selective inhibitor of phosphodiesterase 9, on amyloidpeptides-induced oxidative stress in in-vivo and in-vitro models of Alzheimer's disease.

    Science.gov (United States)

    Li, Jian; Liu, Chun-Na; Wei, Ning; Li, Xi-Dong; Liu, Yuan-Yuan; Yang, Rui; Jia, Yu-Jie

    2016-07-01

    Alzheimer's disease (AD) is accompanied by enhanced oxidative stress and excess free radicals. Phosphodiesterase 9 inhibitors (PDE-9Is) showed memory improving effects in many pharmacological deficit models. However, whether BAY 73-6691 (a selective PDE-9I) may attenuate the oxidative stress during the development of AD is still unclear. For this purpose, primary cultures of SH-SY5Y cells were incubated with 20μM beta-amyloid25-35 (Aβ25-35), followed by exposure to different concentrations (50, 100, 150 and 200μg/ml) of BAY 73-6691. Furthermore, the antioxidant effect of BAY 73-6691 was evaluated in mice subjected to intracerebroventricular injection of Aβ25-35 (day 0) and treatment with BAY 73-6691 by intraperitoneal injection once daily (days 1-10). Our results elucidated that treatment with BAY 73-6691 attenuated the Aβ25-35-induced cytotoxicity and oxidative stress in SH-SY5Y cells. In vivo, BAY 73-6691 protected Aβ25-35-induced oxidative damage in hippocampus, associated with the attenuation of impairments in hippocampal neurons. Administration of BAY 73-6691 improved learning and memory in the Morris water maze test, and restored several hippocampal memory-associated proteins. Our study identified a neuroprotective role for BAY 73-6691 against Aβ25-35-induced oxidative stress in vivo and in vitro, harboring therapeutic potential for the treatment of AD by alleviating the impairments in spatial memory and hippocampal neurons. PMID:27071547

  15. Successful adjuvant-free vaccination of BALB/c mice with mutated amyloid β peptides

    Directory of Open Access Journals (Sweden)

    Wahi Monika M

    2008-02-01

    Full Text Available Abstract Background A recent human clinical trial of an Alzheimer's disease (AD vaccine using amyloid beta (Aβ 1–42 plus QS-21 adjuvant produced some positive results, but was halted due to meningoencephalitis in some participants. The development of a vaccine with mutant Aβ peptides that avoids the use of an adjuvant may result in an effective and safer human vaccine. Results All peptides tested showed high antibody responses, were long-lasting, and demonstrated good memory response. Epitope mapping indicated that peptide mutation did not lead to epitope switching. Mutant peptides induced different inflammation responses as evidenced by cytokine profiles. Ig isotyping indicated that adjuvant-free vaccination with peptides drove an adequate Th2 response. All anti-sera from vaccinated mice cross-reacted with human Aβ in APP/PS1 transgenic mouse brain tissue. Conclusion Our study demonstrated that an adjuvant-free vaccine with different Aβ peptides can be an effective and safe vaccination approach against AD. This study represents the first report of adjuvant-free vaccines utilizing Aβ peptides carrying diverse mutations in the T-cell epitope. These largely positive results provide encouragement for the future of the development of human vaccinations for AD.

  16. Anti-amyloid-beta to tau-based immunization: developments in immunotherapy for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Lambracht-Washington D

    2013-08-01

    Full Text Available Doris Lambracht-Washington, Roger N Rosenberg Department of Neurology and Neurotherapeutics, Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA Abstract: Immunotherapy might provide an effective treatment for Alzheimer's disease (AD. A unique feature of AD immunotherapies is that an immune response against a self-antigen needs to be elicited without causing adverse autoimmune reactions. Current research is focused on two possible targets in this regard. One is the inhibition of accumulation and deposition of amyloid beta 1–42 (Aβ42, which is one of the major peptides found in senile plaques, and the second target is hyperphosphorylated tau, which forms neurofibrillary tangles inside the nerve cell and shows association with the progression of dementia. Mouse models have shown that immunotherapy targeting Aβ42 as well as tau with the respective anti-Aβ or anti-tau antibodies can provide significant improvements in these mice. While anti-Aβ immunotherapy (active and passive immunizations is already in several stages of clinical trials, tau-based immunizations have been analyzed only in mouse models. Recently, as a significant correlation of progression of dementia and levels of phosphorylated tau have been found, high interest has again focused on further development of tau-based therapies. While Aβ immunotherapy might delay the onset of AD, immunotherapy targeting tau might provide benefits in later stages of this disease. Last but not least, targeting Aβ and tau simultaneously with immunotherapy might provide additional therapeutic effects, as these two pathologies are likely synergistic; this is an approach that has not been tested yet. In this review, we will summarize animal models used to test possible therapies for AD, some of the facts about Aβ42 and tau biology, and present an overview on halted, ongoing, and upcoming clinical trials together with ongoing preclinical studies targeting tau

  17. Drugs and drug delivery systems targeting amyloid-β in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Morgan Robinson

    2015-07-01

    Full Text Available Alzheimer's disease (AD is a devastating neurodegenerative disorder with no cure and limited treatment solutions that are unable to target any of the suspected causes. Increasing evidence suggests that one of the causes of neurodegeneration is the overproduction of amyloid beta (Aβ and the inability of Aβ peptides to be cleared from the brain, resulting in self-aggregation to form toxic oligomers, fibrils and plaques. One of the potential treatment options is to target Aβ and prevent self-aggregation to allow for a natural clearing of the brain. In this paper, we review the drugs and drug delivery systems that target Aβ in relation to Alzheimer's disease. Many attempts have been made to use anti-Aβ targeting molecules capable of targeting Aβ (with much success in vitro and in vivo animal models, but the major obstacle to this technique is the challenge posed by the blood brain barrier (BBB. This highly selective barrier protects the brain from toxic molecules and pathogens and prevents the delivery of most drugs. Therefore novel Aβ aggregation inhibitor drugs will require well thought-out drug delivery systems to deliver sufficient concentrations to the brain.

  18. Amyloid-beta: a crucial factor in Alzheimer's disease.

    Science.gov (United States)

    Sadigh-Eteghad, Saeed; Sabermarouf, Babak; Majdi, Alireza; Talebi, Mahnaz; Farhoudi, Mehdi; Mahmoudi, Javad

    2015-01-01

    Alzheimer's disease (AD) is the most prevalent form of dementia which affects people older than 60 years of age. In AD, the dysregulation of the amyloid-beta (Aβ) level leads to the appearance of senile plaques which contain Aβ depositions. Aβ is a complex biological molecule which interacts with many types of receptors and/or forms insoluble assemblies and, eventually, its nonphysiological depositions alternate with the normal neuronal conditions. In this situation, AD signs appear and the patients experience marked cognitional disabilities. In general, intellect, social skills, personality, and memory are influenced by this disease and, in the long run, it leads to a reduction in quality of life and life expectancy. Due to the pivotal role of Aβ in the pathobiology of AD, a great deal of effort has been made to reveal its exact role in neuronal dysfunctions and to finding efficacious therapeutic strategies against its adverse neuronal outcomes. Hence, the determination of its different molecular assemblies and the mechanisms underlying its pathological effects are of interest. In the present paper, some of the well-established structural forms of Aβ, its interactions with various receptors and possible molecular and cellular mechanisms underlying its neurotoxicity are discussed. In addition, several Aβ-based rodent models of AD are reviewed. PMID:25471398

  19. A peptide study of the relationship between the collagen triple-helix and amyloid

    OpenAIRE

    Parmar, Avanish S.; Nunes, Ana Monica; Baum, Jean; Brodsky, Barbara

    2012-01-01

    Type XXV collagen, or Collagen-Like Amyloidogenic Component (CLAC), is a component of amyloid plaques, and recent studies suggest this collagen affects amyloid fibril elongation and has a genetic association with Alzheimer’s disease. The relationship between the collagen triple helix and amyloid fibrils was investigated by studying peptide models, including a very stable triple helical peptide (Pro-Hyp-Gly)10; an amyloidogenic peptide GNNQQNY; and a hybrid peptide where the GNNQQNY sequence w...

  20. The amyloid hypothesis of Alzheimer's disease at 25 years.

    Science.gov (United States)

    Selkoe, Dennis J; Hardy, John

    2016-01-01

    Despite continuing debate about the amyloid β-protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ-secretase has provided a linchpin: all dominant mutations causing early-onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild-type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long-term potentiation, and enhance long-term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD-relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau-positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid-PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target. PMID:27025652

  1. Immunotherapy for the treatment of Alzheimer's disease: amyloid-β or tau, which is the right target?

    Directory of Open Access Journals (Sweden)

    Castillo-Carranza DL

    2013-12-01

    Full Text Available Diana L Castillo-Carranza,1,2 Marcos J Guerrero-Muñoz,1,2 Rakez Kayed1–31Mitchell Center for Neurodegenerative Diseases, 2Departments of Neurology, Neuroscience, and Cell Biology, 3Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, USAAbstract: Alzheimer's disease (AD is characterized by the presence of amyloid plaques composed mainly of amyloid-β (Aβ protein. Overproduction or slow clearance of Aβ initiates a cascade of pathologic events that may lead to formation of neurofibrillary tangles, neuronal cell death, and dementia. Although immunotherapy in animal models has been demonstrated to be successful at removing plaques or prefibrillar forms of Aβ, clinical trials have yielded disappointing results. The lack of substantial cognitive improvement obtained by targeting Aβ raises the question of whether or not this is the correct target. Another important pathologic process in the AD brain is tau aggregation, which seems to become independent once initiated. Recent studies targeting tau in AD mouse models have displayed evidence of cognitive improvement, providing a novel therapeutic approach for the treatment of AD. In this review, we describe new advances in immunotherapy targeting Aβ peptide and tau protein, as well as future directions.Keywords: immunotherapy, Alzheimer's disease, β-amyloid, tau

  2. Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

    OpenAIRE

    Frenkel, Dan; Maron, Ruth; Burt, David S.; Weiner, Howard L.

    2005-01-01

    Amyloid β-peptide (Aβ) appears to play a key pathogenic role in Alzheimer disease (AD). Immune therapy in mouse models of AD via Aβ immunization or passive administration of Aβ antibodies markedly reduces Aβ levels and reverses behavioral impairment. However, a human trial of Aβ immunization led to meningoencephalitis in some patients and was discontinued. Here we show that nasal vaccination with a proteosome-based adjuvant that is well tolerated in humans plus glatiramer acetate, an FDA-appr...

  3. In situ hybridization of nucleus basalis neurons shows increased β-amyloid mRNA in Alzheimer disease

    International Nuclear Information System (INIS)

    To determine which cells within the brain produce β-amyloid mRNA and to assess expression of the β-amyloid gene in Alzheimer disease, the authors analyzed brain tissue from Alzheimer and control patients by in situ hybridization. The results demonstrate that β-amyloid mRNA is produced by neurons in the nucleus basalis of Meynert and cerebral cortex and that nuclues basalis perikarya from Alzheimer patients consistently hybridize more β-amyloid probe than those from controls. These observations support the hypothesis that increased expression of the β-amyloid gene plays an important role in the deposition of amyloid in the brains of patients with Alzheimer disease

  4. The immunotherapy of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Weksler Marc E

    2004-11-01

    Full Text Available Abstract Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's disease. The single trial of active immunization with the amyloid beta peptide provided suggestive evidence of a reduction in cerebral amyloid plaques and of stabilization in cognitive function of half the patients who developed good antibody responses to the amyloid beta peptide. However, 6% of actively immunized Alzheimer patients developed sterile meningoencephalitis that forced the cessation of the clinical trial. Passive immunotherapy in animal models of Alzheimer's disease has provided similar benefits comparable to those seen with active immunotherapy and has the potential of being effective in the half of Alzheimer's disease patients who do not make a significant anti-amyloid beta peptide antibody response and without inducing T-cell-mediated encephalitis. Published studies of 5 patients with sporadic Alzheimer disease treated with intravenous immunoglobulin containing anti-amyloid beta peptide antibodies showed that amyloid beta peptide was mobilized from the brain and cognitive decline was interrupted. Further studies of passive immunotherapy are urgently required to confirm these observations.

  5. Atrophy, hypometabolism and clinical trajectories in patients with amyloid-negative Alzheimer's disease.

    Science.gov (United States)

    Chételat, Gaël; Ossenkoppele, Rik; Villemagne, Victor L; Perrotin, Audrey; Landeau, Brigitte; Mézenge, Florence; Jagust, William J; Dore, Vincent; Miller, Bruce L; Egret, Stéphanie; Seeley, William W; van der Flier, Wiesje M; La Joie, Renaud; Ames, David; van Berckel, Bart N M; Scheltens, Philip; Barkhof, Frederik; Rowe, Christopher C; Masters, Colin L; de La Sayette, Vincent; Bouwman, Femke; Rabinovici, Gil D

    2016-09-01

    See O'Sullivan and Vann (doi:10.1093/aww166) for a scientific commentary on this article.About 15% of patients clinically diagnosed with Alzheimer's disease do not show high tracer retention on amyloid positon emission tomography imaging. The present study investigates clinical and demographic features, patterns of brain atrophy and hypometabolism and longitudinal clinical trajectories of these patients. Forty amyloid-negative patients carrying a pre-scan diagnosis of Alzheimer's disease dementia from four centres were included (11/29 females/males; mean age = 67 ± 9). Detailed clinical histories, including the clinical diagnoses before and after the amyloid scan and at follow-up, were collected. Patients were classified according to their pre-scan clinical phenotype as amnestic (memory predominant), non-amnestic (predominant language, visuospatial or frontal symptoms), or non-specific (diffuse cognitive deficits). Demographic, clinical, neuropsychological, magnetic resonance imaging and (18)F-fluorodeoxyglucose positon emission tomography data were compared to 27 amyloid-positive typical Alzheimer's disease cases (14/13 females/males; mean age = 71 ± 10) and 29 amyloid-negative controls (15/14 females/males; mean age = 69 ± 12) matched for age, gender and education. There were 21 amnestic, 12 non-amnestic, and seven non-specific amyloid-negative Alzheimer's disease cases. Amyloid-negative subgroups did not differ in age, gender or education. After the amyloid scan, clinicians altered the diagnosis in 68% of amyloid-negative patients including 48% of amnestic versus 94% of non-amnestic and non-specific cases. Amnestic amyloid-negative cases were most often reclassified as frontotemporal dementia, non-amnestic as frontotemporal dementia or corticobasal degeneration, and non-specific as dementia with Lewy bodies or unknown diagnosis. The longer-term clinical follow-up was consistent with the post-scan diagnosis in most cases (90%), including in amnestic amyloid

  6. Neuroprotective Approaches in Experimental Models of β-Amyloid Neurotoxicity : Relevance to Alzheimer's Disease

    NARCIS (Netherlands)

    Harkany, Tibor; Hortobágyi, Tibor; Sasvári, Maria; Kónya, Csaba; Penke, Botond; Luiten, Paul G.M.; Nyakas, Csaba

    1999-01-01

    1. β-Amyloid peptides (Aβs) accumulate abundantly in the Alzheimer’s disease (AD) brain in areas subserving information acquisition and processing, and memory formation. Aβ fragments are produced in a process of abnormal proteolytic cleavage of their precursor, the amyloid precursor protein (APP). W

  7. The relationship between complement factor C3, APOE ε4, amyloid and tau in Alzheimer's disease.

    Science.gov (United States)

    Bonham, Luke W; Desikan, Rahul S; Yokoyama, Jennifer S

    2016-01-01

    Inflammation is becoming increasingly recognized as an important contributor to Alzheimer's disease (AD) pathogenesis. As a part of the innate immune system, the complement cascade enhances the body's ability to destroy and remove pathogens and has recently been shown to influence Alzheimer's associated amyloid and tau pathology. However, little is known in humans about the effects of the complement system and genetic modifiers of AD risk like the ε4 allele of apolioprotein E (APOE ε4) on AD pathobiology. We evaluated cerebrospinal fluid (CSF) protein levels from 267 individuals clinically diagnosed as cognitively normal, mild cognitive impairment, and AD. Using linear models, we assessed the relationship between APOE ε4 genotype, CSF Complement 3 (C3), CSF amyloid-β (amyloid) and CSF hyperphosphorylated tau (ptau). We found a significant interaction between APOE ε4 and CSF C3 on both CSF amyloid and CSF ptau. We also found that CSF C3 is only associated with CSF ptau after accounting for CSF amyloid. Our results support a conceptual model of the AD pathogenic cascade where a synergistic relationship between the complement cascade (C3) and APOE ε4 results in elevated Alzheimer's neurodegeneration and in turn, amyloid further regulates the effect of the complement cascade on downstream tau pathology. PMID:27357286

  8. Designing peptidic inhibitors of serum amyloid A aggregation process.

    Science.gov (United States)

    Sosnowska, Marta; Skibiszewska, Sandra; Kamińska, Emilia; Wieczerzak, Ewa; Jankowska, Elżbieta

    2016-04-01

    Amyloid A amyloidosis is a life-threatening complication of a wide range of chronic inflammatory, infectious and neoplastic diseases, and the most common form of systemic amyloidosis worldwide. It is characterized by extracellular tissue deposition of fibrils that are composed of fragments of serum amyloid A protein (SAA), a major acute-phase reactant protein, produced predominantly by hepatocytes. Currently, there are no approved therapeutic agents directed against the formation of fibrillar SAA assemblies. We attempted to develop peptidic inhibitors based on their similarity and complementarity to the regions critical for SAA self-association, which they should interact with and block their assembly into amyloid fibrils. Inh1 and inh4 which are comprised of the residues from the amyloidogenic region of SAA1.1 protein and Aβ peptide, respectively, were found by us as capable to significantly suppress aggregation of the SAA1-12 peptide. It was chosen as an aggregation model that mimicks the amyloidogenic nucleus of SAA protein. We suppose that aromatic interactions may be responsible for inhibitory activity of both compounds. We also recognized that aromatic residues are involved in self-association of SAA1-12. PMID:26759015

  9. Neuroprotective peptides as drug candidates against Alzheimer's diasease

    Czech Academy of Sciences Publication Activity Database

    Patočka, J.; Slaninová, Jiřina; Kunešová, G.

    2005-01-01

    Roč. 3, - (2005), 67-73. ISSN 1214-021X R&D Projects: GA ČR(CZ) GA305/03/1100 Institutional research plan: CEZ:AV0Z40550506 Keywords : Alzheimers's disease * neuroprotective peptide * Abeta peptide Subject RIV: CE - Biochemistry

  10. 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

  11. The Alzheimer Structural Connectome: Changes in Cortical Network Topology with Increased Amyloid Plaque Burden

    OpenAIRE

    Prescott, Jeffrey W.; Guidon, Arnaud; Doraiswamy, P. Murali; Roy Choudhury, Kingshuk; Liu, Chunlei; Petrella, Jeffrey R.

    2014-01-01

    Our cross-sectional study of baseline data from a national cohort of patients with Alzheimer disease, mild cognitive impairment, or normal cognition shows that increased cortical amyloid deposition is significantly associated with alterations in the topology of the structural connectome.

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

    DEFF Research Database (Denmark)

    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 positron...

  13. Molecular modeling of the ion channel-like nanotube structure of amyloid β-peptide

    Institute of Scientific and Technical Information of China (English)

    JIAO Yong; YANG Pin

    2007-01-01

    The ion channel-like nanotube structure of the oligomers of amyloid β-peptide (Aβ) was first investigated by molecular modeling. The results reveal that the hydrogen bond net is one of the key factors to stabilize the structure. The hydrophobicity distribution mode of the side chains is in favor of the structure inserting into the bilayers and forming a hydrophilic pore. The lumen space is under the control of the negative potential, weaker but spreading continuously, to which the cation selectivity attributes; meanwhile, the alternate distribution of the stronger positive and negative potentials makes the electrostatic distribution of the structure framework balance, which is also one of the key factors stabilizing the structure. The results lay the theoretical foundation for illuminating the structure stability and the ion permeability, and give a clue to elucidating the molecular mechanism of Alzheimer's disease (AD) and designing novel drugs to prevent or reverse AD at the root.

  14. Designed amyloid beta peptide fibril - a tool for high-throughput screening of fibril inhibitors.

    Science.gov (United States)

    Dolphin, Gunnar T; Ouberai, Myriam; Dumy, Pascal; Garcia, Julian

    2007-11-01

    Amyloid beta peptide (Abeta) fibril formation is widely believed to be the causative event of Alzheimer's disease pathogenesis. Therapeutic approaches are therefore in development that target various sites in the production and aggregation of Abeta. Herein we present a high-throughput screening tool to generate novel hit compounds that block Abeta fibril formation. This tool is an application for our fibril model (Abeta(16-37)Y(20)K(22)K(24))(4), which is a covalent assembly of four Abeta fragments. With this tool, screening studies are complete within one hour, as opposed to days with native Abeta(1-40). A Z' factor of 0.84+/-0.03 was determined for fibril formation and inhibition, followed by the reporter molecule thioflavin T. Herein we also describe the analysis of a broad range of reported inhibitors and non-inhibitors of Abeta fibril formation to test the validity of the system. PMID:17876751

  15. Nano-biosensors to detect beta-amyloid for Alzheimer's disease management.

    Science.gov (United States)

    Kaushik, Ajeet; Jayant, Rahul Dev; Tiwari, Sneham; Vashist, Arti; Nair, Madhavan

    2016-06-15

    Beta-amyloid (β-A) peptides are potential biomarkers to monitor Alzheimer's diseases (AD) for diagnostic purposes. Increased β-A level is neurotoxic and induces oxidative stress in brain resulting in neurodegeneration and causes dementia. As of now, no sensitive and inexpensive method is available for β-A detection under physiological and pathological conditions. Although, available methods such as neuroimaging, enzyme-linked immunosorbent assay (ELISA), and polymerase chain reaction (PCR) detect β-A, but they are not yet extended at point-of-care (POC) due to sophisticated equipments, need of high expertize, complicated operations, and challenge of low detection limit. Recently, β-A antibody based electrochemical immuno-sensing approach has been explored to detect β-A at pM levels within 30-40min compared to 6-8h of ELISA test. The introduction of nano-enabling electrochemical sensing technology could enable rapid detection of β-A at POC and may facilitate fast personalized health care delivery. This review explores recent advancements in nano-enabling electrochemical β-A sensing technologies towards POC application to AD management. These analytical tools can serve as an analytical tool for AD management program to obtain bio-informatics needed to optimize therapeutics for neurodegenerative diseases diagnosis management. PMID:26851586

  16. Seeded growth of beta-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure.

    Science.gov (United States)

    Paravastu, Anant K; Qahwash, Isam; Leapman, Richard D; Meredith, Stephen C; Tycko, Robert

    2009-05-01

    Studies by solid-state nuclear magnetic resonance (NMR) of amyloid fibrils prepared in vitro from synthetic 40-residue beta-amyloid (Abeta(1-40)) peptides have shown that the molecular structure of Abeta(1-40) fibrils is not uniquely determined by amino acid sequence. Instead, the fibril structure depends on the precise details of growth conditions. The molecular structures of beta-amyloid fibrils that develop in Alzheimer's disease (AD) are therefore uncertain. We demonstrate through thioflavin T fluorescence and electron microscopy that fibrils extracted from brain tissue of deceased AD patients can be used to seed the growth of synthetic Abeta(1-40) fibrils, allowing preparation of fibrils with isotopic labeling and in sufficient quantities for solid-state NMR and other measurements. Because amyloid structures propagate themselves in seeded growth, as shown in previous studies, the molecular structures of brain-seeded synthetic Abeta(1-40) fibrils most likely reflect structures that are present in AD brain. Solid-state (13)C NMR spectra of fibril samples seeded with brain material from two AD patients were found to be nearly identical, indicating the same molecular structures. Spectra of an unseeded control sample indicate greater structural heterogeneity. (13)C chemical shifts and other NMR data indicate that the predominant molecular structure in brain-seeded fibrils differs from the structures of purely synthetic Abeta(1-40) fibrils that have been characterized in detail previously. These results demonstrate a new approach to detailed structural characterization of amyloid fibrils that develop in human tissue, and to investigations of possible correlations between fibril structure and the degree of cognitive impairment and neurodegeneration in AD. PMID:19376973

  17. Optimal parameters for near infrared fluorescence imaging of amyloid plaques in Alzheimer's disease mouse models

    International Nuclear Information System (INIS)

    Amyloid-β plaques are an Alzheimer's disease biomarker which present unique challenges for near-infrared fluorescence tomography because of size (<50 μm diameter) and distribution. We used high-resolution simulations of fluorescence in a digital Alzheimer's disease mouse model to investigate the optimal fluorophore and imaging parameters for near-infrared fluorescence tomography of amyloid plaques. Fluorescence was simulated for amyloid-targeted probes with emission at 630 and 800 nm, plaque-to-background ratios from 1-1000, amyloid burden from 0-10%, and for transmission and reflection measurement geometries. Fluorophores with high plaque-to-background contrast ratios and 800 nm emission performed significantly better than current amyloid imaging probes. We tested idealized fluorophores in transmission and full-angle tomographic measurement schemes (900 source-detector pairs), with and without anatomical priors. Transmission reconstructions demonstrated strong linear correlation with increasing amyloid burden, but underestimated fluorescence yield and suffered from localization artifacts. Full-angle measurements did not improve upon the transmission reconstruction qualitatively or in semi-quantitative measures of accuracy; anatomical and initial-value priors did improve reconstruction localization and accuracy for both transmission and full-angle schemes. Region-based reconstructions, in which the unknowns were reduced to a few distinct anatomical regions, produced highly accurate yield estimates for cortex, hippocampus and brain regions, even with a reduced number of measurements (144 source-detector pairs).

  18. ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing.

    Science.gov (United States)

    Satoh, Kanayo; Abe-Dohmae, Sumiko; Yokoyama, Shinji; St George-Hyslop, Peter; Fraser, Paul E

    2015-10-01

    The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late onset Alzheimer disease in genome-wide association studies. ABCA7 has been shown to mediate phagocytosis and affect membrane trafficking. The current study examined the impact of ABCA7 loss of function on amyloid precursor protein (APP) processing and generation of amyloid-β (Aβ). Suppression of endogenous ABCA7 in several different cell lines resulted in increased β-secretase cleavage and elevated Aβ. ABCA7 knock-out mice displayed an increased production of endogenous murine amyloid Aβ42 species. Crossing ABCA7-deficient animals to an APP transgenic model resulted in significant increases in the soluble Aβ as compared with mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble Aβ and amyloid plaque densities were observed once the amyloid pathology was well developed, whereas Aβ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knock-out cells that is mechanistically consistent with the increased Aβ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing that may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to Alzheimer disease that in some instances have a greater impact than apoE allelic variants have recently been identified. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated Alzheimer disease susceptibility. PMID:26260791

  19. Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group.

    Directory of Open Access Journals (Sweden)

    Yi Su

    Full Text Available Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer's Network (DIAN, an autosomal dominant Alzheimer's disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer's disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted.

  20. Alzheimer disease: presenilin springs a leak

    OpenAIRE

    Gandy, S; Doeven, M.K.; Poolman, B.

    2006-01-01

    Presenilins are thought to contribute to Alzheimer disease through a protein cleavage reaction that produces neurotoxic amyloid-beta peptides. A new function for presenilins now comes to light - controlling the leakage of calcium out of the endoplasmic reticulum. Is this a serious challenge to the 'amyloid hypothesis' of Alzheimer disease?

  1. Down's Syndrome with Alzheimer's Disease-Like Pathology: What Can It Teach Us about the Amyloid Cascade Hypothesis?

    Directory of Open Access Journals (Sweden)

    Gabrielle M. de Courten-Myers

    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 ε3/3 genotypes, a similar age at death, and comparable amyloid-beta 42 peptide (Aβ42 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 Aβ42 could relate to the cases' similar life-time accumulation of Aβ 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 Aβ42, 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.

  2. Transcranial laser therapy alters amyloid precursor protein processing and improves mitochondrial function in a mouse model of Alzheimer's disease

    Science.gov (United States)

    McCarthy, Thomas; Yu, Jin; El-Amouri, Salim; Gattoni-Celli, Sebastiano; Richieri, Steve; De Taboada, Luis; Streeter, Jackson; Kindy, Mark S.

    2011-03-01

    Transcranial laser therapy (TLT) using a near-infrared energy laser system was tested in the 2x Tg amyloid precursor protein (APP) mouse model of Alzheimer's Disease (AD). TLT was administered 3 times/week at escalating doses, starting at 3 months of age, and was compared to a control group which received no laser treatment. Treatment sessions were continued for a total of six months. The brains were examined for amyloid plaque burden, Aβ peptides (Aβ1-40 and Aβ1-42 ), APP cleavage products (sAPPα, CTFβ) and mitochondrial activity. Administration of TLT was associated with a significant, dose-dependent reduction in amyloid load as indicated by the numbers of Aβ plaques. Levels of Aβ1-40 and Aβ1-42 levels were likewise reduced in a dose-dependent fashion. All TLT doses produced an increase in brain sAPPα and a decrease in CTFβ levels consistent with an increase in α-secretase activity and a decrease in β-secretase activity. In addition, TLT increased ATP levels and oxygen utilization in treated animals suggesting improved mitochondrial function. These studies suggest that TLT is a potential candidate for treatment of AD.

  3. Manipulation of self-assembly amyloid peptide nanotubes by dielectrophoresis.

    Science.gov (United States)

    Castillo, Jaime; Tanzi, Simone; Dimaki, Maria; Svendsen, Winnie

    2008-12-01

    Self-assembled amyloid peptide nanotubes (SAPNT) were manipulated and immobilized using dielectrophoresis. Micro-patterned electrodes of Au were fabricated by photolithography and lifted off on a silicon dioxide layer. SAPNT were manipulated by adjusting the amplitude and frequency of the applied voltage. The immobilized SAPNT were evaluated by SEM and atomic force microscopy. The conductivity of the immobilized SAPNT was studied by I-V characterization, for both single SAPNT and bundles. This work illustrates a way to manipulate and integrate biological nanostructures into novel bio-nanoassemblies with concrete applications, such as field-effect transistors, microprobes, microarrays, and biosensing devices. PMID:19130587

  4. Dimensionality of carbon nanomaterial impacting on the modulation of amyloid peptide assembly

    Science.gov (United States)

    Wang, J.; Zhu, Z.; Bortolini, C.; Hoffmann, S. V.; Amari, A.; Zhang, H. X.; Liu, L.; Dong, M. D.

    2016-07-01

    A wide variety of inorganic nanomaterials have been exploited so far for their great potential for biological applications. Some of these materials could be valid candidates to modulate the assembly of amyloid peptides, which is relevant to amyloid-related diseases. In this work, we reveal that a carbon nanomaterial can indeed modulate the assembly of amyloid peptides and, additionally, we show that this modulating effect is closely related to the dimensionality of the nanomaterials.

  5. Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta.

    Science.gov (United States)

    Castellani, Rudy J; Lee, Hyoung-gon; Siedlak, Sandra L; Nunomura, Akihiko; Hayashi, Takaaki; Nakamura, Masao; Zhu, Xiongwei; Perry, George; Smith, Mark A

    2009-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-beta-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-beta as the major pathogenic mechanism with the ultimate goal of using amyloid-beta lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on "proteinopathies'' and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition. PMID:19584435

  6. Beta-protein deposition: a pathogenetic link between Alzheimer's disease and cerebral amyloid angiopathies.

    Science.gov (United States)

    Coria, F; Prelli, F; Castaño, E M; Larrondo-Lillo, M; Fernandez-Gonzalez, J; van Duinen, S G; Bots, G T; Luyendijk, W; Shelanski, M L; Frangione, B

    1988-10-25

    Cerebral amyloid angiopathy (CAA) refers to a group of hereditary (hereditary cerebral hemorrhage with amyloidosis, HCHWA and sporadic (SCAA) disorders characterized by amyloid fibril deposition restricted to the leptomeningeal and cortical vasculature leading to recurrent hemorrhagic and/or ischemic accidents. On clinical and biochemical grounds, two forms of HCHWA can be distinguished. The amyloid subunit of the HCHWA of Icelandic origin is related to Cystatin C, while amyloid from patients of Dutch origin (HCHWA-D) is related to the beta-protein (or A4), the main component of vascular and plaque core amyloid in Alzheimer's disease (AD) and Down's syndrome (DS) [corrected]. SCAA is an increasingly recognized cause of stroke in normotensive individual amounting to 5-10% of all cerebrovascular accidents. We now report the isolation and partial amino acid sequence of the amyloid subunit from a case of SCAA and a new case of HCHWA-D. The recognition that a heterogeneous group of diseases are linked by similar pathological and chemical features suggests that diversity of etiological factors may promote a common pathogenetic mechanism leading to amyloid-beta (A beta) deposition, and open new ways of research in AD and CAA as they are related to dementia and stroke. PMID:3058268

  7. Midlife adiposity predicts earlier onset of Alzheimer's dementia, neuropathology and presymptomatic cerebral amyloid accumulation.

    Science.gov (United States)

    Chuang, Y-F; An, Y; Bilgel, M; Wong, D F; Troncoso, J C; O'Brien, R J; Breitner, J C; Ferruci, L; Resnick, S M; Thambisetty, M

    2016-07-01

    Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD. PMID:26324099

  8. PARP-1 modulates amyloid beta peptide-induced neuronal damage.

    Directory of Open Access Journals (Sweden)

    Sara Martire

    Full Text Available Amyloid beta peptide (Aβ causes neurodegeneration by several mechanisms including oxidative stress, which is known to induce DNA damage with the consequent activation of poly (ADP-ribose polymerase (PARP-1. To elucidate the role of PARP-1 in the neurodegenerative process, SH-SY5Y neuroblastoma cells were treated with Aβ25-35 fragment in the presence or absence of MC2050, a new PARP-1 inhibitor. Aβ25-35 induces an enhancement of PARP activity which is prevented by cell pre-treatment with MC2050. These data were confirmed by measuring PARP-1 activity in CHO cells transfected with amylod precursor protein and in vivo in brains specimens of TgCRND8 transgenic mice overproducing the amyloid peptide. Following Aβ25-35 exposure a significant increase in intracellular ROS was observed. These data were supported by the finding that Aβ25-35 induces DNA damage which in turn activates PARP-1. Challenge with Aβ25-35 is also able to activate NF-kB via PARP-1, as demonstrated by NF-kB impairment upon MC2050 treatment. Moreover, Aβ25-35 via PARP-1 induces a significant increase in the p53 protein level and a parallel decrease in the anti-apoptotic Bcl-2 protein. These overall data support the hypothesis of PARP-1 involvment in cellular responses induced by Aβ and hence a possible rationale for the implication of PARP-1 in neurodegeneration is discussed.

  9. Effects of ketone bodies in Alzheimer's disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function

    DEFF Research Database (Denmark)

    Hertz, Leif; Chen, Ye; Waagepetersen, Helle S

    2015-01-01

    impaired glucose metabolism may be early destruction of the noradrenergic brain stem nucleus, locus coeruleus, which stimulates glucose metabolism, at least in astrocytes. These glial cells are essential in Alzheimer pathogenesis. The β-amyloid peptide Aβ interferes with their cholinergic innervation......, which impairs synaptic function because of diminished astrocytic glutamate release. Aβ also reduces glucose metabolism and causes hyperexcitability. Ketone bodies are similarly used against seizures, but the effectively used concentrations are so high that they must interfere with glucose metabolism and...... panglial-neuronal disorder with long-standing brain hypometabolism, aberrations in both neuronal and astrocytic glucose metabolism, inflammation, hyperexcitability, and dementia. Relatively low doses of β-hydroxybutyrate can have an ameliorating effect on cognitive function. This could be because of...

  10. Physiopathological modulators of amyloid aggregation and novel pharmacological approaches in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    DEFELICE FERNANDA G.

    2002-01-01

    Full Text Available The biological mechanisms underlying the neuropathology of Alzheimer's disease (AD are complex, as several factors likely contribute to the development of the disease. Therefore, it is not surprising that a number of different possible therapeutic approaches addressing distinct aspects of this disease are currently being investigated. Among these are ways to prevent amyloid aggregation and/or deposition, to prevent neuronal degeneration, and to increase brain neurotransmitter levels. Here, we discuss possible roles of endogenous modulators of Abeta aggregation in the physiopathology of AD and some of the strategies currently under consideration to interfere with brain levels of beta-amyloid, its aggregation and neurotoxicity.

  11. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Rodriguez-Vieitez, Elena; Saint-Aubert, Laure; Carter, Stephen F; Almkvist, Ove; Farid, Karim; Schöll, Michael; Chiotis, Konstantinos; Thordardottir, Steinunn; Graff, Caroline; Wall, Anders; Långström, Bengt; Nordberg, Agneta

    2016-03-01

    See Schott and Fox (doi:10.1093/brain/awv405) for a scientific commentary on this article.Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants

  12. Small molecule agents that target amyloid-β aggregation in Alzheimer's disease

    OpenAIRE

    Jones, Michael Roy

    2015-01-01

    Alzheimer’s disease (AD) is the most common form of dementia and currently there is no cure. AD is characterized by the formation of two pathological hallmarks; aggregated forms of the amyloid-β (Aβ) peptide called Aβ plaques and hyperphosphorylated tau proteins, called neurofibrillary tangles (NFT). Aβ is enzymatically cleaved from the amyloid precursor protein (APP) to afford a 38-43 amino acid residue peptide with Aβ1-40 and Aβ1-42 being the most common. Plaque deposits have been shown to ...

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

    DEFF Research Database (Denmark)

    Sennvik, Kristina; Bogdanovic, N; Volkmann, Inga; Fastbom, J; Benedikz, Eirikur

    2004-01-01

    (beta-sAPP) in brain tissue sections from the frontal, temporal and occipital lobe. Strong granular beta-sAPP staining was found throughout the gray matter of all three areas, while white matter staining was considerably weaker. beta-sAPP was found to be localized in astrocytes and in axons. We found...... 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 and......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...

  14. Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease

    OpenAIRE

    Basi, Guriqbal S; Hemphill, Susanna; Brigham, Elizabeth F.; Liao, Anna; Aubele, Danielle L; Baker, Jeanne; Barbour, Robin; Bova, Michael; Chen, Xiao-Hua; Dappen, Michael S; Eichenbaum, Tovah; Goldbach, Erich; Hawkinson, Jon; Lawler-Herbold, Rose; Hu, Kang

    2010-01-01

    Introduction Inhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a ...

  15. Molecular basis for mid-region amyloid-β capture by leading Alzheimer's disease immunotherapies

    OpenAIRE

    Crespi, Gabriela A. N.; Hermans, Stefan J.; Parker, Michael W.; Luke A. Miles

    2015-01-01

    Solanezumab (Eli Lilly) and crenezumab (Genentech) are the leading clinical antibodies targeting Amyloid-β (Aβ) to be tested in multiple Phase III clinical trials for the prevention of Alzheimer's disease in at-risk individuals. Aβ capture by these clinical antibodies is explained here with the first reported mid-region Aβ-anti-Aβ complex crystal structure. Solanezumab accommodates a large Aβ epitope (960 Å2 buried interface over residues 16 to 26) that forms extensive contacts and hydrogen b...

  16. Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine

    OpenAIRE

    Hayes, Crystal D.; Dey, Debleena; Palavicini, Juan Pablo; Wang, Hongjie; Patkar, Kshitij A; Minond, Dimitriy; Nefzi, Adel; Lakshmana, Madepalli K.

    2013-01-01

    Background Currently available therapies for Alzheimer's disease (AD) do not treat the underlying cause of AD. Anecdotal observations in nursing homes from multiple studies strongly suggest an inverse relationship between cancer and AD. Therefore, we reasoned that oncology drugs may be effective against AD. Methods We screened a library of all the FDA-approved oncology drugs and identified bis-chloroethylnitrosourea (BCNU or carmustine) as an effective amyloid beta (Aβ) reducing compound. To ...

  17. Preclinical studies of potential amyloid binding PET/SPECT ligands in Alzheimer's disease

    International Nuclear Information System (INIS)

    Visualizing the neuropathological hallmarks amyloid plaques and neurofibrillary tangles of Alzheimer's disease in vivo using positron emission tomography (PET) or single photon emission computed tomography will be of great value in diagnosing the individual patient and will also help in our understanding of the disease. The successful introduction of [11C]PIB as a PET tracer for the amyloid plaques less than 10 years ago started an intensive research, and numerous new compounds for use in molecular imaging of the amyloid plaques have been developed. The candidates are based on dyes like thioflavin T, Congo red and chrysamine G, but also on other types such as benzoxazoles, curcumin and stilbenes. In the present review, we present methods of the radiochemistry and preclinical evaluation as well as the main properties of some of these compounds.

  18. Beta-Amyloid Deposition and Alzheimer's Type Changes Induced by Borrelia Spirochetes

    Energy Technology Data Exchange (ETDEWEB)

    Miklossy,J.; Kis, A.; Radenovic, A.; Miller, L.; Forro, L.; Martins, R.; Reiss, K.; Darbinian, N.; Darekar, P.; et al.

    2006-01-01

    The pathological hallmarks of Alzheimer's disease (AD) consist of {beta}-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes, which drive this host reaction are unknown. To determine whether an analogous host reaction to that occurring in AD could be induced by infectious agents, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes and to the inflammatory bacterial lipopolysaccharide (LPS). Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to the spirochetes. Increased levels of {beta}-amyloid presursor protein (A{beta}PP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes or LPS. These observations indicate that, by exposure to bacteria or to their toxic products, host responses similar in nature to those observed in AD may be induced.

  19. Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies.

    Science.gov (United States)

    Panza, Francesco; Frisardi, Vincenza; Solfrizzi, Vincenzo; Imbimbo, Bruno P; Logroscino, Giancarlo; Santamato, Andrea; Greco, Antonio; Seripa, Davide; Pilotto, Alberto

    2012-02-01

    The exact mechanisms leading to Alzheimer's disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of Aβ. The most innovative of the pharmacological approaches was the stimulation of Aβ clearance from the brain of AD patients via the administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive vaccination). Several active and passive anti-Aβ vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate Aβ and an immune adjuvant, QS-21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4 carriers), has raised concerns on the safety of these antibodies directed against the N-terminus of the Aβ peptide. Solanezumab, a humanized anti-Aβ monoclonal antibody directed against the midregion of the Aβ peptide, was shown to neutralize soluble Aβ species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III

  20. 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

  1. Membrane Incorporation, Channel Formation, and Disruption of Calcium Homeostasis by Alzheimer's β-Amyloid Protein

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    Masahiro Kawahara

    2011-01-01

    Full Text Available Oligomerization, conformational changes, and the consequent neurodegeneration of Alzheimer's β-amyloid protein (AβP play crucial roles in the pathogenesis of Alzheimer's disease (AD. Mounting evidence suggests that oligomeric AβPs cause the disruption of calcium homeostasis, eventually leading to neuronal death. We have demonstrated that oligomeric AβPs directly incorporate into neuronal membranes, form cation-sensitive ion channels (“amyloid channels”, and cause the disruption of calcium homeostasis via the amyloid channels. Other disease-related amyloidogenic proteins, such as prion protein in prion diseases or α-synuclein in dementia with Lewy bodies, exhibit similarities in the incorporation into membranes and the formation of calcium-permeable channels. Here, based on our experimental results and those of numerous other studies, we review the current understanding of the direct binding of AβP into membrane surfaces and the formation of calcium-permeable channels. The implication of composition of membrane lipids and the possible development of new drugs by influencing membrane properties and attenuating amyloid channels for the treatment and prevention of AD is also discussed.

  2. Differential regulation of amyloid-β-protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease

    International Nuclear Information System (INIS)

    The authors have mapped the neuroanatomical distribution of amyloid-β-protein mRNA within neuronal subpopulations of the hippocampal formation in the cynomolgus monkey (Macaca fascicularis), normal aged human, and patients with Alzheimer disease. Amyloid-β-protein mRNA appears to be expressed in all hippocampal neurons, but at different levels of abundance. In the central nervous system of monkey and normal aged human, image analysis shows that neurons of the dentate gyrus and cornu Ammonis fields contain a 2.5-times-greater hybridization signal than is present in neurons of the subiculum and entorhinal cortex. In contrast, in the Alzheimer disease hippocampal formation, the levels of amyloid-β-protein mRNA in the cornu Ammonis field 3 and parasubiculum are equivalent. These findings suggest that within certain neuronal subpopulations cell type-specific regulation of amyloid-β-protein gene expression may be altered in Alzheimer disease

  3. Familial Alzheimer's Disease Mutations in Presenilin Generate Amyloidogenic Aβ Peptide Seeds.

    Science.gov (United States)

    Veugelen, Sarah; Saito, Takashi; Saido, Takaomi C; Chávez-Gutiérrez, Lucía; De Strooper, Bart

    2016-04-20

    Recently it was proposed that the familial Alzheimer's disease (FAD) causing presenilin (PSEN) mutations PSEN1-L435F and PSEN1-C410Y do not support the generation of Aβ-peptides from the amyloid precursor protein (APP). This challenges the amyloid hypothesis and disagrees with previous work showing that PSEN1 FAD causing mutations generate invariably long Aβ and seed amyloid. We contrast here the proteolytic activities of these mutant PSEN alleles with the complete loss-of-function PSEN1-D257A allele. We find residual carboxy- and endo-peptidase γ-secretase activities, similar to the formerly characterized PSEN1-R278I. We conclude that the PSEN1-L435F and -C410Y mutations are extreme examples of the previously proposed "dysfunction" of γ-secretase that characterizes FAD-associated PSEN. This Matters Arising paper is in response to Xia et al. (2015), published in Neuron. See also the response by Xia et al. (2016), published in this issue. PMID:27100199

  4. All-d-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers.

    Science.gov (United States)

    Capone, Ricardo; Jang, Hyunbum; Kotler, Samuel A; Connelly, Laura; Teran Arce, Fernando; Ramachandran, Srinivasan; Kagan, Bruce L; Nussinov, Ruth; Lal, Ratnesh

    2012-03-13

    Alzheimer's disease (AD) is the most common type of senile dementia in aging populations. Amyloid β (Aβ)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. Aβ-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via Aβ binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an Aβ peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels can directly mediate Aβ effects even in the absence of receptor-peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we show that the d-Aβ isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the l-Aβ isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance similar to the l-Aβ isomer channels, and the d-isomer channel conductance is blocked by Zn(2+), a known blocker of l-Aβ isomer channels. MD simulations further verify formation of β-barrel-like Aβ channels with d- and l-isomers, illustrating that both d- and l-Aβ barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca(2+) leaking, unregulated channels in AD, and suggest that Aβ toxicity is mediated through a receptor-independent, nonstereoselective mechanism. PMID:22423218

  5. Green tea aroma fraction reduces β-amyloid peptide-induced toxicity in Caenorhabditis elegans transfected with human β-amyloid minigene.

    Science.gov (United States)

    Takahashi, Atsushi; Watanabe, Tatsuro; Fujita, Takashi; Hasegawa, Toshio; Saito, Michio; Suganuma, Masami

    2014-01-01

    Green tea is a popular world-wide beverage with health benefits that include preventive effects on cancer as well as cardiovascular, liver and Alzheimer's diseases (AD). This study will examine the preventive effects on AD of a unique aroma of Japanese green tea. First, a transgenic Caenorhabditis elegans (C. elegans) CL4176 expressing human β-amyloid peptide (Aβ) was used as a model of AD. A hexane extract of processed green tea was further fractionated into volatile and non-volatile fractions, named roasty aroma and green tea aroma fractions depending on their aroma, by microscale distillation. Both hexane extract and green tea aroma fraction were found to inhibit Aβ-induced paralysis, while only green tea aroma fraction extended lifespan in CL4176. We also found that green tea aroma fraction has antioxidant activity. This paper indicates that the green tea aroma fraction is an additional component for prevention of AD. PMID:25229860

  6. Perspectives on future Alzheimer therapies: amyloid-β protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease.

    Science.gov (United States)

    Lannfelt, Lars; Möller, Christer; Basun, Hans; Osswald, Gunilla; Sehlin, Dag; Satlin, Andrew; Logovinsky, Veronika; Gellerfors, Pär

    2014-01-01

    The symptomatic drugs currently on the market for Alzheimer's disease (AD) have no effect on disease progression, and this creates a large unmet medical need. The type of drug that has developed most rapidly in the last decade is immunotherapy: vaccines and, especially, passive vaccination with monoclonal antibodies. Antibodies are attractive drugs as they can be made highly specific for their target and often with few side effects. Data from recent clinical AD trials indicate that a treatment effect by immunotherapy is possible, providing hope for a new generation of drugs. The first anti-amyloid-beta (anti-Aβ) vaccine developed by Elan, AN1792, was halted in phase 2 because of aseptic meningoencephalitis. However, in a follow-up study, patients with antibody response to the vaccine demonstrated reduced cognitive decline, supporting the hypothesis that Aβ immunotherapy may have clinically relevant effects. Bapineuzumab (Elan/Pfizer Inc./Johnson & Johnson), a monoclonal antibody targeting fibrillar Aβ, was stopped because the desired clinical effect was not seen. Solanezumab (Eli Lilly and Company) was developed to target soluble, monomeric Aβ. In two phase 3 studies, Solanezumab did not meet primary endpoints. When data from the two studies were pooled, a positive pattern emerged, revealing a significant slowing of cognitive decline in the subgroup of mild AD. The Arctic mutation has been shown to specifically increase the formation of soluble Aβ protofibrils, an Aβ species shown to be toxic to neurons and likely to be present in all cases of AD. A monoclonal antibody, mAb158, was developed to target Aβ protofibrils with high selectivity. It has at least a 1,000-fold higher selectivity for protofibrils as compared with monomers of Aβ, thus targeting the toxic species of the peptide. A humanized version of mAb158, BAN2401, has now entered a clinical phase 2b trial in a collaboration between BioArctic Neuroscience and Eisai without the safety concerns seen

  7. Osthole decreases beta amyloid levels through up-regulation of miR-107 in Alzheimer's disease.

    Science.gov (United States)

    Jiao, Yanan; Kong, Liang; Yao, Yingjia; Li, Shaoheng; Tao, Zhenyu; Yan, Yuhui; Yang, Jingxian

    2016-09-01

    Accumulation of β-amyloid peptide (Aβ) in the brain plays an important role in the pathogenesis of Alzheimer's disease (AD). Although osthole has been shown to neuroprotective activity in AD, the exact molecular mechanism of its neuroprotective effects has not yet been fully elucidated. Recently, microRNAs (miRNAs) have been reported to regulate multiple aspects of AD development and progression, indicating that targeting miRNAs could be a novel strategy to treat AD. In the current study, we investigated whether a natural coumarin derivative osthole could up-regulate miR-107, resulting in facilitating the cells survival, reducing LDH leakage, inhibiting apoptosis and reducing beta amyloid (Aβ) production in AD. We found that osthole treatment significantly up-regulate miR-107 expression and inhibited BACE1, one of the targets of miR-107. Administration of osthole to APP/PS1 transgenic mice resulted in a significant improvement in learning and memory function, which was associated with a significant a decrease in Aβ in the hippocampal and cortex region of the brain. Our findings demonstrated that osthole plays a neuroprotective activity role in part through up-regulate miR-107 in AD. PMID:27143098

  8. Sorting of the Alzheimer's Disease Amyloid Precursor Protein Mediated by the AP-4 Complex

    Energy Technology Data Exchange (ETDEWEB)

    Burgos, Patricia V.; Mardones, Gonzalo A.; Rojas, Adriana L.; daSilva, Luis L.P.; Prabhu, Yogikala; Hurley, James H.; Bonifacino, Juan S. (NIH)

    2010-08-12

    Adaptor protein 4 (AP-4) is the most recently discovered and least well-characterized member of the family of heterotetrameric adaptor protein (AP) complexes that mediate sorting of transmembrane cargo in post-Golgi compartments. Herein, we report the interaction of an YKFFE sequence from the cytosolic tail of the Alzheimer's disease amyloid precursor protein (APP) with the {micro}4 subunit of AP-4. Biochemical and X-ray crystallographic analyses reveal that the properties of the APP sequence and the location of the binding site on 4 are distinct from those of other signal-adaptor interactions. Disruption of the APP-AP-4 interaction decreases localization of APP to endosomes and enhances {gamma}-secretase-catalyzed cleavage of APP to the pathogenic amyloid-{beta} peptide. These findings demonstrate that APP and AP-4 engage in a distinct type of signal-adaptor interaction that mediates transport of APP from the trans-Golgi network (TGN) to endosomes, thereby reducing amyloidogenic processing of the protein.

  9. Inhibition of aggregation of amyloid peptides by beta-sheet breaker peptides and their binding affinity.

    Science.gov (United States)

    Viet, Man Hoang; Ngo, Son Tung; Lam, Nguyen Sy; Li, Mai Suan

    2011-06-01

    The effects of beta-sheet breaker peptides KLVFF and LPFFD on the oligomerization of amyloid peptides were studied by all-atom simulations. It was found that LPFFD interferes the aggregation of Aβ(16-22) peptides to a greater extent than does KLVFF. Using the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method, we found that the former binds more strongly to Aβ(16-22). Therefore, by simulations, we have clarified the relationship between aggregation rates and binding affinity: the stronger the ligand binding, the slower the oligomerization process. The binding affinity of pentapeptides to full-length peptide Aβ(1-40) and its mature fibrils has been considered using the Autodock and MM-PBSA methods. The hydrophobic interaction between ligands and receptors plays a more important role for association than does hydrogen bonding. The influence of beta-sheet breaker peptides on the secondary structures of monomer Aβ(1-40) was studied in detail, and it turns out that, in their presence, the total beta-sheet content can be enhanced. However, the aggregation can be slowed because the beta-content is reduced in fibril-prone regions. Both pentapeptides strongly bind to monomer Aβ(1-40), as well as to mature fibrils, but KLVFF displays a lower binding affinity than LPFFD. Our findings are in accord with earlier experiments that both of these peptides can serve as prominent inhibitors. In addition, we predict that LPFFD inhibits/degrades the fibrillogenesis of full-length amyloid peptides better than KLVFF. This is probably related to a difference in their total hydrophobicities in that the higher the hydrophobicity, the lower the inhibitory capacity. The GROMOS96 43a1 force field with explicit water and the force field proposed by Morris et al. (Morris et al. J. Comput. Chem. 1998, 19, 1639 ) were employed for all-atom molecular dynamics simulations and Autodock experiments, respectively. PMID:21563780

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  11. Control of Alzheimer's amyloid beta toxicity by the high molecular weight immunophilin FKBP52 and copper homeostasis in Drosophila.

    Directory of Open Access Journals (Sweden)

    Reiko Sanokawa-Akakura

    Full Text Available FK506 binding proteins (FKBPs, also called immunophilins, are prolyl-isomerases (PPIases that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP. Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Abeta toxicity. Towards this goal, we generated Abeta transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Abeta and increased lifespan in Abeta flies, whereas loss of function of FKBP52 exacerbated these Abeta phenotypes. Interestingly, the Abeta pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (-/- cells have increased intracellular copper and higher levels of Abeta. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Abeta peptides.

  12. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.

    Science.gov (United States)

    Zhao, Lingzhi; Gottesdiener, Andrew J; Parmar, Mayur; Li, Mingjie; Kaminsky, Stephen M; Chiuchiolo, Maria J; Sondhi, Dolan; Sullivan, Patrick M; Holtzman, David M; Crystal, Ronald G; Paul, Steven M

    2016-08-01

    The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-β (Aβ) peptide deposition and amyloid burden (ε4 >ε3 >ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)-mediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Aβ levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Aβ burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Aβ and amyloid deposition. We further demonstrate that a widespread reduction of brain Aβ burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease. PMID:27318144

  13. Amyloid-β-Secondary Structure Distribution in Cerebrospinal Fluid and Blood Measured by an Immuno-Infrared-Sensor: A Biomarker Candidate for Alzheimer's Disease.

    Science.gov (United States)

    Nabers, Andreas; Ollesch, Julian; Schartner, Jonas; Kötting, Carsten; Genius, Just; Hafermann, Henning; Klafki, Hans; Gerwert, Klaus; Wiltfang, Jens

    2016-03-01

    The misfolding of the Amyloid-beta (Aβ) peptide into β-sheet enriched conformations was proposed as an early event in Alzheimer's Disease (AD). Here, the Aβ peptide secondary structure distribution in cerebrospinal fluid (CSF) and blood plasma of 141 patients was measured with an immuno-infrared-sensor. The sensor detected the amide I band, which reflects the overall secondary structure distribution of all Aβ peptides extracted from the body fluid. We observed a significant downshift of the amide I band frequency of Aβ peptides in Dementia Alzheimer type (DAT) patients, which indicated an overall shift to β-sheet. The secondary structure distribution of all Aβ peptides provides a better marker for DAT detection than a single Aβ misfold or the concentration of a specific oligomer. The discrimination between DAT and disease control patients according to the amide I frequency was in excellent agreement with the clinical diagnosis (accuracy 90% for CSF and 84% for blood). The amide I band maximum above or below the decisive marker frequency appears as a novel spectral biomarker candidate of AD. Additionally, a preliminary proof-of-concept study indicated an amide I band shift below the marker band already in patients with mild cognitive impairment due to AD. The presented immuno-IR-sensor method represents a promising, simple, robust, and label-free diagnostic tool for CSF and blood analysis. PMID:26828829

  14. Mutation-based structural modification and dynamics study of amyloid beta peptide (1–42: An in-silico-based analysis to cognize the mechanism of aggregation

    Directory of Open Access Journals (Sweden)

    Pritam Kumar Panda

    2016-03-01

    Full Text Available Alzheimer's disease is the prevalent cause of premature senility, a progressive mental disorder due to degeneration in brain and deposition of amyloid β peptide (1–42, a misfolded protein in the form of aggregation that prevails for a prolonged time and obstructs every aspect of life. One of the primary hallmarks of the neuropathological disease is the accretion of amyloid β peptide in the brain that leads to Alzheimer's disease, but the mechanism is still a mystery. Several investigations have shown that mutations at specific positions have a significant impact in stability of the peptide as predicted from aggregation profiles. Here in our study, we have analyzed the mutations by substituting residues at position A22G, E22G, E22K, E22Q, D23N, L34V and molecular dynamics have been performed to check the deviation in stability and conformation of the peptide. The results validated that the mutations at specific positions lead to instability and the proline substitution at E22P and L34P stalled the aggregation of the peptide.

  15. In Silico and in Vitro Study of Binding Affinity of Tripeptides to Amyloid β Fibrils: Implications for Alzheimer's Disease.

    Science.gov (United States)

    Viet, Man Hoang; Siposova, Katarina; Bednarikova, Zuzana; Antosova, Andrea; Nguyen, Truc Trang; Gazova, Zuzana; Li, Mai Suan

    2015-04-23

    Self-assembly of Aβ peptides into amyloid aggregates has been suggested as the major cause of Alzheimer's disease (AD). Nowadays, there is no medication for AD, but experimental data indicate that reversion of the process of amyloid aggregation reduces the symptoms of disease. In this paper, all 8000 tripeptides were studied for their ability to destroy Aβ fibrils. The docking method and the more sophisticated MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) method were employed to calculate the binding affinity and mode of tripeptides to Aβ fibrils. The ability of these peptides to depolymerize Aβ fibrils was also investigated experimentally using atomic force microscopy and fluorescence spectroscopy (Thioflavin T assay). It was shown that tripeptides prefer to bind to hydrophobic regions of 6Aβ9-40 fibrils. Tripeptides WWW, WWP, WPW and PWW were found to be the most potent binders. In vitro experiments showed that tight-binding tripeptides have significant depolymerizing activities and their DC50 values determined from dose-response curves were in micromolar range. The ability of nonbinding (GAM, AAM) and weak-binding (IVL and VLA) tripeptides to destroy Aβ fibrils was negligible. In vitro data of tripeptide depolymerizing activities support the predictions obtained by molecular docking and all-atom simulation methods. Our results suggest that presence of multiple complexes of heterocycles forming by tryptophan and proline residues in tripeptides is crucial for their tight binding to Aβ fibrils as well as for extensive fibril depolymerization. We recommend PWW for further studies as it has the lowest experimental binding constant. PMID:25815792

  16. Copper in Alzheimer's disease: Implications in amyloid aggregation and neurotoxicity

    Science.gov (United States)

    Gamez, Patrick; Caballero, Ana B.

    2015-09-01

    The relationship of copper dyshomeostasis with neurodegenerative diseases has become evident in the last years. Because of the major role that this metal ion plays in biological processes, most of which being located in the brain, it is not surprising that changes in its distribution are closely related with the advent of neurodegenerative disorders such as Alzheimer's disease (AD). An increasing number of works have dealt with this subject in the last years, and opened an intense debate in some points while raising new questions that still remain unanswered. This revision work puts together and discusses the latest findings and insights on how copper ions are involved in AD progression, including its interaction with Aβ and its consequently induced aggregation.

  17. Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease.

    Science.gov (United States)

    Ryan, Natalie S; Biessels, Geert-Jan; Kim, Lois; Nicholas, Jennifer M; Barber, Philip A; Walsh, Phoebe; Gami, Priya; Morris, Huw R; Bastos-Leite, António J; Schott, Jonathan M; Beck, Jon; Mead, Simon; Chavez-Gutierrez, Lucia; de Strooper, Bart; Rossor, Martin N; Revesz, Tamas; Lashley, Tammaryn; Fox, Nick C

    2015-12-01

    Familial Alzheimer's disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid beta coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on magnetic resonance imaging, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 precodon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (5 precodon 200) had postmortem examination. Increased WMH were observed in the PSEN1 postcodon 200 group and in the single APP patient with an amyloid beta coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The precodon 200 group had younger ages at onset, decreased axonal density and/or integrity, and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD. PMID:26410308

  18. Biophysical insights into the membrane interaction of the core amyloid-forming Aβ40 fragment K16-K28 and its role in the pathogenesis of Alzheimer's disease.

    Science.gov (United States)

    Bera, Swapna; Korshavn, Kyle J; Kar, Rajiv K; Lim, Mi Hee; Ramamoorthy, Ayyalusamy; Bhunia, Anirban

    2016-06-22

    The aggregation of amyloid-β (Aβ) on neuronal membranes is implicated in both neuronal toxicity and the progression of Alzheimer's disease. Unfortunately, the heterogeneous environment that results from peptide aggregation in the presence of lipids makes the details of these pathways difficult to interrogate. In this study, we report an investigation of the membrane interaction of an Aβ fragment (K16LVFFAEDVGSNK28, KK13), which maintains the amyloidogenic nature of the full-length peptide and is implicated in membrane-mediated folding, through a combination of NMR spectroscopy and molecular dynamics simulations. Despite KK13's ability to form amyloids in solution, the monomer remains unstructured in the presence of lipid bilayers, unlike its full-length parent peptide. Additionally, NMR and molecular dynamics simulation results support that the presence of GM1 ganglioside, a lipid which strongly promotes binding between Aβ and lipid bilayers, promotes KK13 binding to but not folding on the membrane. Finally, we show that the peptide partitions between the membrane and aqueous solution based on the hydrophobicity of the N-terminal residues, regardless of lipid composition. These results support previous discoveries suggesting the importance of GM1 ganglioside in exacerbating membrane-driven aggregation while identifying the potential importance of C-terminal residues in membrane binding and folding, which has previously been unclear. PMID:27282693

  19. Using bacterial inclusion bodies to screen for amyloid aggregation inhibitors

    OpenAIRE

    Villar-Piqué Anna; Espargaró Alba; Sabaté Raimon; de Groot Natalia S; Ventura Salvador

    2012-01-01

    Abstract Background The amyloidpeptide (Aβ42) is the main component of the inter-neuronal amyloid plaques characteristic of Alzheimer's disease (AD). The mechanism by which Aβ42 and other amyloid peptides assemble into insoluble neurotoxic deposits is still not completely understood and multiple factors have been reported to trigger their formation. In particular, the presence of endogenous metal ions has been linked to the pathogenesis of AD and other neurodegenerative disorders. Results ...

  20. The nootropic and neuroprotective proline-containing dipeptide noopept restores spatial memory and increases immunoreactivity to amyloid in an Alzheimer's disease model.

    Science.gov (United States)

    Ostrovskaya, Rita U; Gruden, Marina A; Bobkova, Natalya A; Sewell, Robert D E; Gudasheva, Tatyana A; Samokhin, Alexander N; Seredinin, Sergey B; Noppe, Wim; Sherstnev, Vladimir V; Morozova-Roche, Ludmilla A

    2007-08-01

    The effects of the novel proline-containing nootropic and neuroprotective dipeptide, noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were investigated in NMRI mice following olfactory bulbectomy. We have shown previously that these animals developed Alzheimer's disease (AD)-like behaviour, morphology and biochemistry including impairment of spatial memory, regional neuronal degeneration and elevated Abeta peptide brain levels. In the current investigation, spatial memory was assessed using the Morris water maze and serum antibodies to in vitro morphologically characterized amyloid structures of both Abeta((25-35)) peptide and equine lysozyme, as well as to neurotrophic glial factor S100b, were analyzed by enzyme-linked immunosorbent assay (ELISA). Noopept (administered at a dose of 0.01 mg/kg for a period of 21 days and during a further 5 days training) restored spatial memory and increased serum antibody levels to oligomers of Abeta((25-35)) peptide but not to equine lysozyme amyloid or S100b protein in bulbectomized animals. The positive immunotropic effect of noopept to Abeta((25-35)) peptide prefibrillar aggregates was more marked in sham-operated compared to the bulbectomized subjects which were characterized by an overall suppression of immunoreactivity. Enhancement of the immune response to Abeta((25-35)) peptide prefibrils caused by noopept may attenuate the neurotoxic consequences of amyloid fibrillization and also be associated with an improvement in spatial memory in bulbectomized mice. These actions of noopept, combined with its previously reported neuroprotective and cholinomimetic properties, suggests that this dipeptide may well be useful for improving cognitive deficits induced by neurodegenerative diseases. PMID:17092975

  1. Viscoelastic response of neural cells governed by the deposition of amyloidpeptides (Aβ)

    Science.gov (United States)

    Gong, Ze; You, Ran; Chang, Raymond Chuen-Chung; Lin, Yuan

    2016-06-01

    Because of its intimate relation with Alzheimer's disease (AD), the question of how amyloidpeptide (Aβ) deposition alters the membrane and cytoskeltal structure of neural cells and eventually their mechanical response has received great attention. In this study, the viscoelastic properties of primary neurons subjected to various Aβ treatments were systematically characterized using atomic force microrheology. It was found that both the storage ( G ') and loss ( G ″) moduli of neural cells are rate-dependent and grow by orders of magnitude as the driving frequency ω varies from 1 to 100 Hz. However, a much stronger frequency dependence was observed in the loss moduli (with a scaling exponent of ˜0.96) than that in G ' ( ˜ ω 0.2 ). Furthermore, both cell moduli increase gradually within the first 6 h of Aβ treatment before steady-state values are reached, with a higher dosage of Aβ leading to larger changes in cell properties. Interestingly, we showed that the measured neuron response can be well-explained by a power law structural damping model. Findings here establish a quantitative link between Aβ accumulation and the physical characteristics of neural cells and hence could provide new insights into how disorders like AD affect the progression of different neurological processes from a mechanics point of view.

  2. Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease.

    Science.gov (United States)

    Sadleir, Katherine R; Kandalepas, Patty C; Buggia-Prévot, Virginie; Nicholson, Daniel A; Thinakaran, Gopal; Vassar, Robert

    2016-08-01

    Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of

  3. In silico study of amyloid beta-protein folding relevant to Alzheimer's disease

    Science.gov (United States)

    Lam Ng, Alfonso Ramon

    Amyloid beta-protein (Abeta) folding is the initial step in the formation of the early toxic Abeta assemblies that are critically linked to Alzheimer's disease (AD). Abeta exists in two main alloforms, Abeta40 and Abeta42, composed of 40 and 42 residues, respectively. Abeta42 aggregates faster, forms more toxic assemblies, and is linked more strongly to AD. Two amino acids of Abeta42, I41 and A42, profoundly affect the behavior of Abeta40 and Abeta42. To examine why this happens, I study Abeta40 and Abeta42 folding using discrete molecular dynamics and a four-bead protein model with backbone hydrogen bonding and residue-specific effective hydropathic and electrostatic interactions. In particular, I explore a range of values of the hydropathic (EHP) and electrostatic (ECH) potential energies. For each peptide, I create a hundred different initial conformations for each set of parameters (EHP,E CH). I investigate the Abeta40 and Abeta42 monomer folding in a wide temperature range and quantify the folded structures by calculating the secondary structure propensities and the intramolecular contact maps. For each set of parameters (EHP,ECH), I calculate an average beta-strand secondary structure propensity in the Abeta40 and Abeta42 monomers as a function of temperature. I compare these simulated results with experimental circular dichroism measurements and estimate the model physiological temperature and the model parameters (E HP,ECH) that best fit the experimental conditions. The results show that in the temperature range [278K,350K], the average beta-strand in Abeta42 is larger than that of Abeta40, which is in agreement with experiments. The model predicts that the average beta-strand propensity should decrease for T>350K. At low temperatures, both Abeta40 and Abeta42 adopt a predominantly collapsed-coil conformation with small amounts of an beta-helical secondary structure (<1%). At high temperatures, beta-strand rich structures are more prominent (19%). Also, the

  4. Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment.

    Science.gov (United States)

    Mattsson, Niklas; Tosun, Duygu; Insel, Philip S; Simonson, Alix; Jack, Clifford R; Beckett, Laurel A; Donohue, Michael; Jagust, William; Schuff, Norbert; Weiner, Michael W

    2014-05-01

    Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to

  5. Amyloid PET imaging in Alzheimer's disease: a comparison of three radiotracers

    International Nuclear Information System (INIS)

    The increasing use of amyloid PET in Alzheimer's disease research and clinical trials has motivated efforts to standardize methodology. We compared retention of the 11C radiotracer Pittsburgh Compound B (PiB) and that of two 18F amyloid radiotracers (florbetapir and flutemetamol) using two study populations. We also examined the feasibility of converting between tracer-specific measures, using PiB as the common link between the two 18F tracers. One group of 40 subjects underwent PiB and flutemetamol imaging sessions and a separate group of 32 subjects underwent PiB and florbetapir imaging sessions. We compared cortical and white matter retention for each 18F tracer relative to that of PiB, as well as retention in several reference regions and image analysis methods. Correlations between tracer pairs were used to convert tracer-specific threshold values for amyloid positivity between tracers. Cortical retention for each pair of tracers was strongly correlated regardless of reference region (PiB-flutemetamol, ρ = 0.84-0.99; PiB-florbetapir, ρ = 0.83-0.97) and analysis method (ρ = 0.90-0.99). Compared to PiB, flutemetamol had higher white matter retention, while florbetapir had lower cortical retention. Two previously established independent thresholds for amyloid positivity were highly consistent when values were converted between tracer pairs. Despite differing white and grey matter retention characteristics, cortical retention for each 18F tracer was highly correlated with that of PiB, enabling conversion of thresholds across tracer measurement scales with a high level of internal consistency. Standardization of analysis methods and measurement scales may facilitate the comparison of amyloid PET data obtained using different tracers. (orig.)

  6. Amyloid PET imaging in Alzheimer's disease: a comparison of three radiotracers

    Energy Technology Data Exchange (ETDEWEB)

    Landau, S.M.; Jagust, W.J. [University of California, Berkeley, Helen Wills Neuroscience Institute, Berkeley, CA (United States); Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA (United States); Thomas, B.A. [University College London, Institute of Nuclear Medicine, London (United Kingdom); Thurfjell, L. [GE Healthcare, Uppsala (Sweden); Schmidt, M. [Janssen Pharmaceutica, NV, Beerse (Belgium); Margolin, R. [Janssen Alzheimer Immunotherapy, South San Francisco, CA (United States); Mintun, M.; Pontecorvo, M. [Avid Radiopharmaceuticals, Inc., Philadelphia, PA (United States); Baker, S.L. [Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA (United States); Collaboration: The Alzheimer' s Disease Neuroimaging Initiative

    2014-07-15

    The increasing use of amyloid PET in Alzheimer's disease research and clinical trials has motivated efforts to standardize methodology. We compared retention of the {sup 11}C radiotracer Pittsburgh Compound B (PiB) and that of two {sup 18}F amyloid radiotracers (florbetapir and flutemetamol) using two study populations. We also examined the feasibility of converting between tracer-specific measures, using PiB as the common link between the two {sup 18}F tracers. One group of 40 subjects underwent PiB and flutemetamol imaging sessions and a separate group of 32 subjects underwent PiB and florbetapir imaging sessions. We compared cortical and white matter retention for each {sup 18}F tracer relative to that of PiB, as well as retention in several reference regions and image analysis methods. Correlations between tracer pairs were used to convert tracer-specific threshold values for amyloid positivity between tracers. Cortical retention for each pair of tracers was strongly correlated regardless of reference region (PiB-flutemetamol, ρ = 0.84-0.99; PiB-florbetapir, ρ = 0.83-0.97) and analysis method (ρ = 0.90-0.99). Compared to PiB, flutemetamol had higher white matter retention, while florbetapir had lower cortical retention. Two previously established independent thresholds for amyloid positivity were highly consistent when values were converted between tracer pairs. Despite differing white and grey matter retention characteristics, cortical retention for each {sup 18}F tracer was highly correlated with that of PiB, enabling conversion of thresholds across tracer measurement scales with a high level of internal consistency. Standardization of analysis methods and measurement scales may facilitate the comparison of amyloid PET data obtained using different tracers. (orig.)

  7. Peptide p5 binds both heparinase-sensitive glycosaminoglycans and fibrils in patient-derived AL amyloid extracts

    International Nuclear Information System (INIS)

    Highlights: •Polybasic peptide p5 binds human light chain amyloid extracts. •The binding of p5 with amyloid involves both glycosaminoglycans and fibrils. •Heparinase treatment led to a correlation between p5 binding and fibril content. •p5 binding to AL amyloid requires electrostatic interactions. -- Abstract: In previously published work, we have described heparin-binding synthetic peptides that preferentially recognize amyloid deposits in a mouse model of reactive systemic (AA) amyloidosis and can be imaged by using positron and single photon emission tomographic imaging. We wanted to extend these findings to the most common form of visceral amyloidosis, namely light chain (AL); however, there are no robust experimental animal models of AL amyloidosis. To further define the binding of the lead peptide, p5, to AL amyloid, we characterized the reactivity in vitro of p5 with in situ and patient-derived AL amyloid extracts which contain both hypersulfated heparan sulfate proteoglycans as well as amyloid fibrils. Histochemical staining demonstrated that the peptide specifically localized with tissue-associated AL amyloid deposits. Although we anticipated that p5 would undergo electrostatic interactions with the amyloid-associated glycosaminoglycans expressing heparin-like side chains, no significant correlation between peptide binding and glycosaminoglycan content within amyloid extracts was observed. In contrast, following heparinase I treatment, although overall binding was reduced, a positive correlation between peptide binding and amyloid fibril content became evident. This interaction was further confirmed using synthetic light chain fibrils that contain no carbohydrates. These data suggest that p5 can bind to both the sulfated glycosaminoglycans and protein fibril components of AL amyloid. Understanding these complex electrostatic interactions will aid in the optimization of synthetic peptides for use as amyloid imaging agents and potentially as

  8. Amyloid β-peptide directly induces spontaneous calcium transients, delayed intercellular calcium waves and gliosis in rat cortical astrocytes

    Directory of Open Access Journals (Sweden)

    Marius Buibas

    2010-01-01

    Full Text Available The contribution of astrocytes to the pathophysiology of AD (Alzheimer's disease and the molecular and signalling mechanisms that potentially underlie them are still very poorly understood. However, there is mounting evidence that calcium dysregulation in astrocytes may be playing a key role. Intercellular calcium waves in astrocyte networks in vitro can be mechanically induced after Aβ (amyloid β-peptide treatment, and spontaneously forming intercellular calcium waves have recently been shown in vivo in an APP (amyloid precursor protein/PS1 (presenilin 1 Alzheimer's transgenic mouse model. However, spontaneous intercellular calcium transients and waves have not been observed in vitro in isolated astrocyte cultures in response to direct Aβ stimulation in the absence of potentially confounding signalling from other cell types. Here, we show that Aβ alone at relatively low concentrations is directly able to induce intracellular calcium transients and spontaneous intercellular calcium waves in isolated astrocytes in purified cultures, raising the possibility of a potential direct effect of Aβ exposure on astrocytes in vivo in the Alzheimer's brain. Waves did not occur immediately after Aβ treatment, but were delayed by many minutes before spontaneously forming, suggesting that intracellular signalling mechanisms required sufficient time to activate before intercellular effects at the network level become evident. Furthermore, the dynamics of intercellular calcium waves were heterogeneous, with distinct radial or longitudinal propagation orientations. Lastly, we also show that changes in the expression levels of the intermediate filament proteins GFAP (glial fibrillary acidic protein and S100B are affected by Aβ-induced calcium changes differently, with GFAP being more dependent on calcium levels than S100B.

  9. Detection of amyloid in Alzheimer's disease with positron emission tomography using [11C]AZD2184

    International Nuclear Information System (INIS)

    Current positron emission tomography (PET) radioligands for detection of Aβ amyloid in Alzheimer's disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [11C]AZD2184 and report here the first clinical evaluation. Eight AD patients and four younger control subjects underwent 93-min PET measurements with [11C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters. Brain uptake of [11C]AZD2184 peaked within 1 min at 3-4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57. [11C]AZD2184 is a promising radioligand for detailed mapping of Aβ amyloid depositions in Alzheimer's disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium. (orig.)

  10. Is pathological aging a successful resistance against amyloid-beta or preclinical Alzheimer's disease?

    Science.gov (United States)

    Murray, Melissa E; Dickson, Dennis W

    2014-01-01

    Individuals with pathological aging, a form of cerebral amyloidosis in older people, have widespread extracellular amyloid-beta (Aβ) senile plaque deposits in the setting of limited neurofibrillary tau pathology. Unlike the characteristic finding of antemortem cognitive impairment in Alzheimer's disease patients, individuals with pathological aging usually lack cognitive impairment despite similar Aβ senile plaque burdens. It has been hypothesized that protective or resistance factors may underlie pathological aging, thus minimizing or preventing deleterious effects on cognition. Despite increasing interest and recognition, a review of the literature remains challenging given the range of terms used to describe pathological aging. This debate briefly reviews neuropathologic and biochemical evidence that pathological aging individuals have resistance factors to Aβ plaque pathology. Additionally, we will discuss evidence of pathological aging as an intermediate between normal individuals and Alzheimer's disease patients, and discuss protective or resistance factors against vascular disease and neurofibrillary pathology. Lastly, we will emphasize the need for longitudinal biomarker evidence using amyloid positron emission tomography, which will provide a better understanding of the kinetics of Aβ deposition in pathological aging. PMID:25031637

  11. Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease

    Science.gov (United States)

    Sundgren, Pia C.; Strandberg, Olof; Zetterberg, Henrik; Minthon, Lennart; Blennow, Kaj; Wahlund, Lars-Olof; Westman, Eric

    2016-01-01

    Objective: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity. Methods: In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [18F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE. Results: Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [18F] flutemetamol tracer ( = 0.44, p = 0.02 and = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = −0.16, p = 0.02), independently of amyloid pathology. Conclusions: mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology. PMID:27164711

  12. Identification of Human Serum Proteins Which Interact With Alzheimer`s Amyloid �A4 Protein

    Directory of Open Access Journals (Sweden)

    Golam Sadik

    2000-01-01

    Full Text Available Alzheimer`s amyloid βA4 protein fused with glutathione S-transferase (GST was highly expressed using a strong prokaryotic expression system in Escherichia coli. The expressed protein had expected molecular mass on SDS-PAGE and appeared exclusively immunoreactive with antibody specific for βA4 epitope. This recombinant protein was purified with a combination of urea solubilization and ion exchange chromatography. To identify the human serum proteins which interact with βA4, affinity columns were prepared by immobilizing GST- βA4 and GST respectively. Using the affinity columns and human serum, we have observed an interaction of βA4 with serum proteins. Two proteins of Mr 45 and 15 kDa were identified on SDS-PAGE to be involved in the interaction. Our demonstration of the ability of βA4 to interact with serum protein strongly support the notion that such an interaction may underlie with the biological function of βA4 in vivo.

  13. Amyloidpeptide aggregation and the influence of carbon nanoparticles

    Science.gov (United States)

    Wen-Hui, Xi; Guang-Hong, Wei

    2016-01-01

    Soluble peptides or proteins can self-aggregate into insoluble, ordered amyloid fibrils under appropriate conditions. These amyloid aggregates are the hallmarks of several human diseases ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we first introduce the common structural features of amyloid fibrils and the amyloid fibrillation kinetics determined from experimental studies. Then, we discuss the structural models of Alzheimer’s amyloid-β (Aβ) fibrils derived from solid-state nuclear magnetic resonance spectroscopy. On the computational side, molecular dynamics simulations can provide atomic details of structures and the underlying oligomerization mechanisms. We finally summarize recent progress in atomistic simulation studies on the oligomerization of Aβ (including full-length Aβ and its fragments) and the influence of carbon nanoparticles. Project supported by the National Natural Science Foundation of China (Grant Nos. 11274075 and 91227102).

  14. The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy.

    Science.gov (United States)

    Smilansky, Angela; Dangoor, Liron; Nakdimon, Itay; Ben-Hail, Danya; Mizrachi, Dario; Shoshan-Barmatz, Varda

    2015-12-25

    The voltage-dependent anion channel 1 (VDAC1), found in the mitochondrial outer membrane, forms the main interface between mitochondrial and cellular metabolisms, mediates the passage of a variety of molecules across the mitochondrial outer membrane, and is central to mitochondria-mediated apoptosis. VDAC1 is overexpressed in post-mortem brains of Alzheimer disease (AD) patients. The development and progress of AD are associated with mitochondrial dysfunction resulting from the cytotoxic effects of accumulated amyloid β (Aβ). In this study we demonstrate the involvement of VDAC1 and a VDAC1 N-terminal peptide (VDAC1-N-Ter) in Aβ cell penetration and cell death induction. Aβ directly interacted with VDAC1 and VDAC1-N-Ter, as monitored by VDAC1 channel conductance, surface plasmon resonance, and microscale thermophoresis. Preincubated Aβ interacted with bilayer-reconstituted VDAC1 and increased its conductance ∼ 2-fold. Incubation of cells with Aβ resulted in mitochondria-mediated apoptotic cell death. However, the presence of non-cell-penetrating VDAC1-N-Ter peptide prevented Aβ cellular entry and Aβ-induced mitochondria-mediated apoptosis. Likewise, silencing VDAC1 expression by specific siRNA prevented Aβ entry into the cytosol as well as Aβ-induced toxicity. Finally, the mode of Aβ-mediated action involves detachment of mitochondria-bound hexokinase, induction of VDAC1 oligomerization, and cytochrome c release, a sequence of events leading to apoptosis. As such, we suggest that Aβ-mediated toxicity involves mitochondrial and plasma membrane VDAC1, leading to mitochondrial dysfunction and apoptosis induction. The VDAC1-N-Ter peptide targeting Aβ cytotoxicity is thus a potential new therapeutic strategy for AD treatment. PMID:26542804

  15. Surface-bound basement membrane components accelerate amyloidpeptide nucleation in air-free wells: an in vitro model of cerebral amyloid angiopathy.

    Science.gov (United States)

    Hasegawa, Kazuhiro; Ozawa, Daisaku; Ookoshi, Tadakazu; Naiki, Hironobu

    2013-08-01

    Cerebral amyloid angiopathy is caused by deposition of the amyloid β-peptide which consists of mainly 39-40 residues to the cortical and leptomeningeal vessel walls. There are no definite in vitro systems to support the hypothesis that the vascular basement membrane may act as a scaffold of amyloid β-peptide carried by perivascular drainage flow and accelerate its amyloid fibril formation in vivo. We previously reported the critical roles of interfaces and agitation on the nucleation of amyloid fibrils at low concentrations of amyloid β-peptide monomers. Here, we reproduced the perivascular drainage flow in vitro by using N-hydroxysuccinimide-Sepharose 4 Fast flow beads as an inert stirrer in air-free wells rotated at 1rpm. We then reproduced the basement membranes in the media of cerebral arteries in vitro by conjugating Matrigel and other proteins on the surface of Sepharose beads. These beads were incubated with 5μM amyloid β(1-40) at 37°C without air, where amyloid β(1-40) alone does not form amyloid fibrils. Using the initiation time of fibril growth kinetics (i.e., the lag time of fibril growth during which nuclei, on-pathway oligomers and protofibrils are successively formed) as a parameter of the efficiency of biological molecules to induce amyloid fibril formation, we found that basement membrane components including Matrigel, laminin, fibronectin, collagen type IV and fibrinogen accelerate the initiation of amyloid β-peptide fibril growth in vitro. These data support the essential role of vascular basement membranes in the development of cerebral amyloid angiopathy. PMID:23608949

  16. 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...... addition, such biological amyloid fibril structures with highly stable mechanical properties can potentially be used to produce nanofibres (nanowires) that may be suitable for nanotechnological applications....

  17. Ketones block amyloid entry and improve cognition in an Alzheimer's model.

    Science.gov (United States)

    Yin, Jun Xiang; Maalouf, Marwan; Han, Pengcheng; Zhao, Minglei; Gao, Ming; Dharshaun, Turner; Ryan, Christopher; Whitelegge, Julian; Wu, Jie; Eisenberg, David; Reiman, Eric M; Schweizer, Felix E; Shi, Jiong

    2016-03-01

    Sporadic Alzheimer's disease (AD) is responsible for 60%-80% of dementia cases, and the most opportune time for preventive intervention is in the earliest stage of its preclinical phase. As traditional mitochondrial energy substrates, ketone bodies (ketones, for short), beta-hydroxybutyrate, and acetoacetate, have been reported to provide symptomatic improvement and disease-modifying activity in epilepsy and neurodegenerative disorders. Recently, ketones are thought as more than just metabolites and also as endogenous factors protecting against AD. In this study, we discovered a novel neuroprotective mechanism of ketones in which they blocked amyloid-β 42, a pathologic hallmark protein of AD, entry into neurons. The suppression of intracellular amyloid-β 42 accumulation rescued mitochondrial complex I activity, reduced oxidative stress, and improved synaptic plasticity. Most importantly, we show that peripheral administration of ketones significantly reduced amyloid burden and greatly improved learning and memory ability in a symptomatic mouse model of AD. These observations provide us insights to understand and to establish a novel therapeutic use of ketones in AD prevention. PMID:26923399

  18. Amyloid Plaques in PSAPP Mice Bind Less Metal than Plaques in Human Alzheimer's Disease

    International Nuclear Information System (INIS)

    Amyloid beta (AΒ) is the primary component of Alzheimer's disease (AD) plaques, a key pathological feature of the disease. Metal ions of zinc (Zn), copper (Cu), iron (Fe), and calcium (Ca) are elevated in human amyloid plaques and are thought to be involved in neurodegeneration. Transgenic mouse models of AD also exhibit amyloid plaques, but fail to exhibit the high degree of neurodegeneration observed in humans. In this study, we imaged the Zn, Cu, Fe, and Ca ion distribution in the PSAPP transgenic mouse model representing end-stage AD (N = 6) using synchrotron X-ray fluorescence (XRF) microprobe. In order to account for differences in density in the plaques, the relative protein content was imaged with synchrotron Fourier transform infrared microspectroscopy (FTIRM) on the same samples. FTIRM results revealed a 61% increase in protein content in the plaques compared to the surrounding tissue. After normalizing to protein density, we found that the PSAPP plaques contained only a 29% increase in Zn and there was actually less Cu, Fe, and Ca in the plaque compared to the surrounding tissue. Since metal binding to Aβ is thought to induce redox chemistry that is toxic to neurons, the reduced metal binding in PSAPP mice is consistent with the lack of neurodegeneration in these animals. These findings were in stark contrast to the high metal ion content observed in human AD plaques, further implicating the role of metal ions in human AD pathology.

  19. Clearance of amyloid-beta in Alzheimer's disease: shifting the action site from center to periphery.

    Science.gov (United States)

    Liu, Yu-Hui; Wang, Ye-Ran; Xiang, Yang; Zhou, Hua-Dong; Giunta, Brian; Mañucat-Tan, Noralyn B; Tan, Jun; Zhou, Xin-Fu; Wang, Yan-Jiang

    2015-02-01

    Amyloid-beta (Aβ) is suggested to play a causal role in the pathogenesis of Alzheimer's disease (AD). Immunotherapies are among the most promising Aβ-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aβ vaccination (AN1792), anti-Aβ antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aβ oligomerization from plaques, neuroinflammation related to opsonized Aβ phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aβ clearance would be effective and safe for future Aβ-targeting therapies. PMID:24733588

  20. The immunotherapy of Alzheimer's disease

    OpenAIRE

    Weksler Marc E

    2004-01-01

    Abstract Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's d...

  1. The Vitamin A Derivative All-Trans Retinoic Acid Repairs Amyloid-β-Induced Double-Strand Breaks in Neural Cells and in the Murine Neocortex

    OpenAIRE

    Emmanuelle Gruz-Gibelli; Natacha Chessel; Clélia Allioux; Pascale Marin; Françoise Piotton; Geneviève Leuba; Herrmann, François R.; Armand Savioz

    2016-01-01

    The amyloidpeptide or Aβ is the key player in the amyloid-cascade hypothesis of Alzheimer's disease. Aβ appears to trigger cell death but also production of double-strand breaks (DSBs) in aging and Alzheimer's disease. All-trans retinoic acid (RA), a derivative of vitamin A, was already known for its neuroprotective effects against the amyloid cascade. It diminishes, for instance, the production of Aβ peptides and their oligomerisation. In the present work we investigat...

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

    OpenAIRE

    Rasha Mohamed Hussein; Rashed, Laila A

    2015-01-01

    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 dis...

  3. Rational design and identification of a non-peptidic aggregation inhibitor of amyloid-β based on a pharmacophore motif obtained from cyclo[-Lys-Leu-Val-Phe-Phe-].

    Science.gov (United States)

    Arai, Tadamasa; Araya, Takushi; Sasaki, Daisuke; Taniguchi, Atsuhiko; Sato, Takeshi; Sohma, Youhei; Kanai, Motomu

    2014-07-28

    Inhibition of pathogenic protein aggregation may be an important and straightforward therapeutic strategy for curing amyloid diseases. Small-molecule aggregation inhibitors of Alzheimer's amyloid-β (Aβ) are extremely scarce, however, and are mainly restricted to dye- and polyphenol-type compounds that lack drug-likeness. Based on the structure-activity relationship of cyclic Aβ16-20 (cyclo-[KLVFF]), we identified unique pharmacophore motifs comprising side-chains of Leu(2), Val(3), Phe(4), and Phe(5) residues without involvement of the backbone amide bonds to inhibit Aβ aggregation. This finding allowed us to design non-peptidic, small-molecule aggregation inhibitors that possess potent activity. These molecules are the first successful non-peptidic, small-molecule aggregation inhibitors of amyloids based on rational molecular design. PMID:24931598

  4. Probing structural features of Alzheimer's amyloid-β pores in bilayers using site-specific amino acid substitutions.

    Science.gov (United States)

    Capone, Ricardo; Jang, Hyunbum; Kotler, Samuel A; Kagan, Bruce L; Nussinov, Ruth; Lal, Ratnesh

    2012-01-24

    A current hypothesis for the pathology of Alzheimer's disease (AD) proposes that amyloid-β (Aβ) peptides induce uncontrolled, neurotoxic ion flux across cellular membranes. The mechanism of ion flux is not fully understood because no experiment-based Aβ channel structures at atomic resolution are currently available (only a few polymorphic states have been predicted by computational models). Structural models and experimental evidence lend support to the view that the Aβ channel is an assembly of loosely associated mobile β-sheet subunits. Here, using planar lipid bilayers and molecular dynamics (MD) simulations, we show that amino acid substitutions can be used to infer which residues are essential for channel structure. We created two Aβ(1-42) peptides with point mutations: F19P and F20C. The substitution of Phe19 with Pro inhibited channel conductance. MD simulation suggests a collapsed pore of F19P channels at the lower bilayer leaflet. The kinks at the Pro residues in the pore-lining β-strands induce blockage of the solvated pore by the N-termini of the chains. The cysteine mutant is capable of forming channels, and the conductance behavior of F20C channels is similar to that of the wild type. Overall, the mutational analysis of the channel activity performed in this work tests the proposition that the channels consist of a β-sheet rich organization, with the charged/polar central strand containing the mutation sites lining the pore, and the C-terminal strands facing the hydrophobic lipid tails. A detailed understanding of channel formation and its structure should aid studies of drug design aiming to control unregulated Aβ-dependent ion fluxes. PMID:22242635

  5. AmyloidPeptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons.

    Science.gov (United States)

    Gunn, Adam P; Wong, Bruce X; Johanssen, Timothy; Griffith, James C; Masters, Colin L; Bush, Ashley I; Barnham, Kevin J; Duce, James A; Cherny, Robert A

    2016-03-18

    Pyroglutamate-modified amyloid-β (pE-Aβ) is a highly neurotoxic amyloid-β (Aβ) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of Aβ oligomerization and alters the interactions of Aβ with Cu(2+) and lipids; however, a link between these properties and the toxicity of pE-Aβ peptides has not been established. We report here that Aβ3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the full-length isoform (Aβ(1-42)). In contrast, Aβ(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas Aβ3pE-42 did not. We also report that Aβ3pE-42 preferentially associates with neuronal membranes and triggers Ca(2+) influx that can be partially blocked by the N-methyl-d-aspartate receptor antagonist MK-801. Aβ3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than Aβ(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of Aβ-dityrosine oligomer formation mediated by copper-redox cycling. PMID:26697885

  6. Molecular modeling of the inhibitory mechanism of copper(II) on aggregation of amyloid β-peptide

    Institute of Scientific and Technical Information of China (English)

    JIAO Yong; HAN Daxiong; YANG Pin

    2005-01-01

    Aggregation of amyloid β-peptide (Aβ) into insoluble fibrils is a key pathological event in Alzheimer's disease (AD). Under certain conditions, Cu(Ⅱ) exhibits strong inhibitory effect on the Zn(Ⅱ)-induced aggregation, which occurs significantly even at nearly physiological concentrations of zinc ion in vitro. Cu(Ⅱ) is considered as a potential factor in the normal brain preventing Aβ from aggregating. The possible mechanism of the inhibitory effect of Cu(Ⅱ) is investigated for the first time by molecular modeling method. In the mono-ring mode, the Y10 residue promotes typical quasi-helix conformations of Aβ. Specially, [Cu-H13(Nπ)-Y10(OH)] complex forms a local 3.010 helix conformation. In the multi-ring mode, the side chains of Q15 and E11 residues collaborate harmoniously with other chelating ligands producing markedly low energies and quasi-helix conformations. [Cu-3N-Q15(O)-E11(O1)] and [Cu-H13(Nπ)-Y10(OH)] complex with quasi-helix conformations may prefer soluble forms in solution. In addition, hydrogen-bond interactions may be the main driving force for Aβaggregation. All the results will provide helpful clues for an improved understanding of the role of Cu(Ⅱ) in the pathogenesis of AD and contribute to the development of an "anti-amyloid" therapeutic strategy.

  7. Difference in aggregation between functional and toxic amyloids studied by atomistic simulations

    Science.gov (United States)

    Carballo Pacheco, Martin; Ismail, Ahmed E.; Strodel, Birgit

    Amyloids are highly structured protein aggregates, normally associated with neurodegenerative diseases such as Alzheimer's disease. In recent years, a number of nontoxic amyloids with physiologically normal functions, called functional amyloids, have been found. It is known that soluble small oligomers are more toxic than large fibrils. Thus, we study with atomistic explicit-solvent molecular dynamics simulations the oligomer formation of the amyloid- β peptide Aβ25 - 35, associated with Alzheimer's disease, and two functional amyloid-forming tachykinin peptides: kassinin and neuromedin K. Our simulations show that monomeric peptides in extended conformations aggregate faster than those in collapsed hairpin-like conformations. In addition, we observe faster aggregation by functional amyloids than toxic amyloids, which could explain their lack of toxicity.

  8. Appropriate Use Criteria for Amyloid PET: A Report of the Amyloid Imaging Task Force (AIT), the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the Alzheimer Association (AA)

    OpenAIRE

    Johnson, Keith A; Minoshima, Satoshi; Bohnen, Nicolaas I.; Donohoe, Kevin J.; Foster, Norman L.; Herscovitch, Peter; Karlawish, Jason H.; Rowe, Christopher C; Carrillo, Maria C.; Hartley, Dean M.; Hedrick, Saima; Mitchell, Kristi; Pappas, Virginia; Thies, William H.

    2013-01-01

    Positron Emission Tomography (PET) of brain amyloid-beta is a technology that is becoming more available, but its clinical utility in medical practice requires careful definition. In order to provide guidance to dementia care practitioners, patients and caregivers, the Alzheimer Association and the Society of Nuclear Medicine and Molecular Imaging convened the Amyloid Imaging Taskforce (AIT). The AIT considered a broad range of specific clinical scenarios in which amyloid PET could potentiall...

  9. Synthesis and evaluation of 18F-fluoroethylated benzothiazole derivatives for in vivo imaging of amyloid plaques in Alzheimer's disease

    International Nuclear Information System (INIS)

    Amyloid aggregates play a major role in the development of Alzheimer's disease. Targeting these aggregates by PET probes enables non-invasively the detection and quantification of amyloid deposit distribution in human brains. Based on benzothiazole core structure a series of amyloid imaging agents were developed. Currently [11C]2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B (PIB) is the most specific and widely used amyloid imaging ligand. But due to the short half life of 11C, longer lived 18F-labeled derivatives offer logistic advantages and higher contrast images. In this work, three different [18F]fluoroethoxy-substituted benzothiazole derivatives ([18F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole, [18F]2-((2'-(2-fluoroethoxy)-4'-amino)phenyl)benzothiazole and [18F]2-(3'-((2-fluoroethoxy)-4'-amino)phenyl)benzothiazole) were synthesized via [18F]fluoroethylation. The latter two derivatives with fluoroethoxy-substitution on the aromatic amino group showed very low binding affinity for amyloid aggregates. In contrast [18F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole with [18F]fluoroethoxy-substitution in 6-position showed excellent amyloid imaging properties with respect to lipophilicity, brain entry and brain clearance in normal SCID mice, amyloid plaque binding affinity and specificity.

  10. 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 BACKGROUND: 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. METHODOLOGY: 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. CONCLUSIONS: 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

  11. The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's Disease.

    Science.gov (United States)

    Walker, Lary C; Schelle, Juliane; Jucker, Mathias

    2016-01-01

    Since the discovery that prion diseases can be transmitted to experimental animals by inoculation with afflicted brain matter, researchers have speculated that the brains of patients suffering from other neurodegenerative diseases might also harbor causative agents with transmissible properties. Foremost among these disorders is Alzheimer's disease (AD), the most common cause of dementia in the elderly. A growing body of research supports the concept that the pathogenesis of AD is initiated and sustained by the endogenous, seeded misfolding and aggregation of the protein fragment amyloid-β (Aβ). At the molecular level, this mechanism of nucleated protein self-assembly is virtually identical to that of prions consisting of the prion protein (PrP). The formation, propagation, and spread of Aβ seeds within the brain can thus be considered a fundamental feature of AD pathogenesis. PMID:27270558

  12. Cerebral serotonin 4 receptors and amyloid-β in early Alzheimer's disease

    DEFF Research Database (Denmark)

    Madsen, Karine; Neumann, Wolf-Julian; Holst, Klaus Kähler;

    2011-01-01

    The 5-HT4 receptor may play a role in memory and learning and 5-HT4 receptor activation has been suggested to modulate acetylcholine release and to reduce amyloid-ß (Aß) accumulation. The aim of this study was for the first time to investigate the in vivo cerebral 5-HT4 receptor binding in early...... Alzheimer disease (AD) patients in relation to cortical Aß burden. Eleven newly diagnosed untreated AD patients (mean MMSE 24, range 19–27) and twelve age- and gender-matched healthy controls underwent a two-hour dynamic [11C]SB207145 PET scan to measure the binding potential of the 5-HT4 receptor. All AD...

  13. Astrocytic gap junctional communication is reduced in amyloid-β-treated cultured astrocytes, but not in Alzheimer's disease transgenic mice

    Directory of Open Access Journals (Sweden)

    Gerald A Dienel

    2010-08-01

    Full Text Available 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-β on astrocyte gap junctional communication, cultured astrocytes were treated with monomerized amyloid-β1–40 (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.

  14. Cratoxylum formosum Extract Protects against Amyloid-Beta Toxicity in a Caenorhabditis elegans Model of Alzheimer's Disease.

    Science.gov (United States)

    Keowkase, Roongpetch; Weerapreeyakul, Natthida

    2016-04-01

    Amyloid-β, one of the hallmarks of Alzheimer's disease, is toxic to neurons and causes cell death in the brain. Oxidative stress is known to play an important role in Alzheimer's disease, and there is strong evidence linking oxidative stress to amyloid-β. The herbal plant "Tiew kon" (Cratoxylum formosum ssp. pruniflorum) is an indigenous vegetable that is grown in Southeast Asia. Many reports suggested that the twig extract from C. formosum possesses an antioxidant property. The purpose of this study was to investigate the protective effect of the twig extract from C. formosum against amyloid-β toxicity using the transgenic Caenorhabditis elegans model. This study demonstrated that the extract significantly delayed amyloid-β-induced paralysis in the C. elegans model of Alzheimer's disease. Using a genetic approach, we found that DAF-16/FOXO transcription factor, heat shock factor 1, and SKN-1 (Nrf2 in mammals) were required for the extract-mediated delayed paralysis. The extract ameliorated oxidative stress by reducing the level of H2O2, which appeared to account for the protective action of the extract. The extract possesses antioxidant activity against juglone-induced oxidative stress as it was shown to increase survival of the stressed worms. In addition, C. formosum decreased the expression of the heat shock protein-16.2 gene which was induced by thermal stress, indicating its ability to reduce cellular stress. The results from this study support the C. elegans model in the search for disease-modifying agents to treat Alzheimer's disease and indicate the potential of the extract from C. formosum ssp. pruniflorum as a source for the development of anti-Alzheimer's drugs. PMID:26845710

  15. Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease.

    Science.gov (United States)

    Rosen, Rebecca F; Tomidokoro, Yasushi; Farberg, Aaron S; Dooyema, Jeromy; Ciliax, Brian; Preuss, Todd M; Neubert, Thomas A; Ghiso, Jorge A; LeVine, Harry; Walker, Lary C

    2016-08-01

    The misfolding and accumulation of the protein fragment β-amyloid (Aβ) is an early and essential event in the pathogenesis of Alzheimer's disease (AD). Despite close biological similarities among primates, humans appear to be uniquely susceptible to the profound neurodegeneration and dementia that characterize AD, even though nonhuman primates deposit copious Aβ in senile plaques and cerebral amyloid-β angiopathy as they grow old. Because the amino acid sequence of Aβ is identical in all primates studied to date, we asked whether differences in the properties of aggregated Aβ might underlie the vulnerability of humans and the resistance of other primates to AD. In a comparison of aged squirrel monkeys (Saimiri sciureus) and humans with AD, immunochemical and mass spectrometric analyses indicate that the populations of Aβ fragments are largely similar in the 2 species. In addition, Aβ-rich brain extracts from the brains of aged squirrel monkeys and AD patients similarly seed the deposition of Aβ in a transgenic mouse model. However, the epitope exposure of aggregated Aβ differs in sodium dodecyl sulfate-stable oligomeric Aβ from the 2 species. In addition, the high-affinity binding of (3)H Pittsburgh Compound B to Aβ is significantly diminished in tissue extracts from squirrel monkeys compared with AD patients. These findings support the hypothesis that differences in the pathobiology of aggregated Aβ among primates are linked to post-translational attributes of the misfolded protein, such as molecular conformation and/or the involvement of species-specific cofactors. PMID:27318146

  16. Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets?

    Science.gov (United States)

    Moreth, Jens; Mavoungou, Chrystelle; Schindowski, Katharina

    2013-01-01

    Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. The dementia causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. AD is strongly associated with Amyloid-beta (Aβ) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics. Within the past decade convincing data has arisen positioning the soluble prefibrillar Aβ-aggregates as the prime toxic agents in AD. However, different Aβ aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Aβ is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function. Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Aβ-aggregates than to focus on a single aggregate species for immunization. PMID:23663286

  17. Polarization properties of amyloid-beta plaques in Alzheimer's disease (Conference Presentation)

    Science.gov (United States)

    Baumann, Bernhard; Wöhrer, Adelheid; Ricken, Gerda; Pircher, Michael; Kovacs, Gabor G.; Hitzenberger, Christoph K.

    2016-03-01

    In histopathological practice, birefringence is used for the identification of amyloidosis in numerous tissues. Amyloid birefringence is caused by the parallel arrangement of fibrous protein aggregates. Since neurodegenerative processes in Alzheimer's disease (AD) are also linked to the formation of amyloid-beta (Aβ) plaques, optical methods sensitive to birefringence may act as non-invasive tools for Aβ identification. At last year's Photonics West, we demonstrated polarization-sensitive optical coherence tomography (PS-OCT) imaging of ex vivo cerebral tissue of advanced stage AD patients. PS-OCT provides volumetric, structural imaging based on both backscatter contrast and tissue polarization properties. In this presentation, we report on polarization-sensitive neuroimaging along with numerical simulations of three-dimensional Aβ plaques. High speed PS-OCT imaging was performed using a spectral domain approach based on polarization maintaining fiber optics. The sample beam was interfaced to a confocal scanning microscope arrangement. Formalin-fixed tissue samples as well as thin histological sections were imaged. For comparison to the PS-OCT results, ray propagation through plaques was modeled using Jones analysis and various illumination geometries and plaque sizes. Characteristic polarization patterns were found. The results of this study may not only help to understand PS-OCT imaging of neuritic Aβ plaques but may also have implications for polarization-sensitive imaging of other fibrillary structures.

  18. Vitamin B6s inhibit oxidative stress caused by Alzheimer's disease-related Cu(II)-β-amyloid complexes-cooperative action of phospho-moiety.

    Science.gov (United States)

    Hashim, Alaa; Wang, Le; Juneja, Kashmir; Ye, Yong; Zhao, Yufen; Ming, Li-June

    2011-11-01

    Cu(II) complexes of Alzheimer's disease-related β-amyloid (Aβ) peptides exhibit metal-centered oxidation chemistry. The metallo-Aβ complexes are the hallmark of the disease and have been attributed to the generation of reactive oxygen species (ROS), causing oxidative stress. In this communication, the inhibitions of the oxidative activity of Cu(II)-Aβ by vitamin B6 compounds pyridoxamine (PM), pyridoxine (PN), pyridoxal (PL), and pyridoxal-5'-phosphate (PLP) are presented. These B6's are competitive inhibitors toward dopamine oxidation by Cu(II)-Aβ(1-20), with K(i) values of 1.4, 8.3, 1.2, and 0.2mM, respectively. The phospho-moiety in PLP seems to exhibit cooperative inhibition, affording a clue for future design of inhibitors. PMID:21944860

  19. Manipulation of self-assembly amyloid peptide nanotubes by dielectrophoresis (DEP)

    DEFF Research Database (Denmark)

    Castillo, Jaime; Tanzi, Simone; Dimaki, Maria; Svendsen, Winnie Edith

    2008-01-01

    Self-assembled amyloid peptide nanotubes (SAPNT) were manipulated and immobilized using dielectrophoresis. Micro-patterned electrodes of Au were fabricated by photolithography and lifted off on a silicon dioxide layer. SAPNT were manipulated by adjusting the amplitude and frequency of the applied...

  20. 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...

  1. Subcellular trafficking of the amyloid precursor protein gene family and its pathogenic role in Alzheimer's disease.

    Science.gov (United States)

    Kins, Stefan; Lauther, Nadine; Szodorai, Anita; Beyreuther, Konrad

    2006-01-01

    Changes in the intracellular transport of amyloid precursor protein (APP) affect the extent to which APP is exposed to alpha- or beta-secretase in a common subcellular compartment and therefore directly influence the degree to which APP undergoes the amyloidogenic pathway leading to generation of beta-amyloid. As the presynaptic regions of neurons are thought to be the main source of beta-amyloid in the brain, attention has been focused on axonal APP trafficking. APP is transported along axons by a fast, kinesin-dependent anterograde transport mechanism. Despite the wealth of in vivo and in vitro data that have accumulated regarding the connection of APP to kinesin transport, it is not yet clear if APP is coupled to its specific motor protein via an intracellular interaction partner, such as the c-Jun N-terminal kinase-interacting protein, or by yet another unknown molecular mechanism. The cargo proteins that form a functional complex with APP are also unknown. Due to the long lifespan, and vast extent, of neurons, in particular axons, neurons are highly sensitive to changes in subcellular transport. Recent in vitro and in vivo studies have shown that variations in APP or tau affect mitochondrial and synaptic vesicle transport. Further, it was shown that this axonal dysfunction might lead to impaired synaptic plasticity, which is crucial for neuronal viability and function. Thus, changes in APP and tau expression may cause perturbed axonal transport and changes in APP processing, contributing to cognitive decline and neurodegeneration in Alzheimer's disease. PMID:17047360

  2. Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease.

    Science.gov (United States)

    Shinohara, Mitsuru; Murray, Melissa E; Frank, Ryan D; Shinohara, Motoko; DeTure, Michael; Yamazaki, Yu; Tachibana, Masaya; Atagi, Yuka; Davis, Mary D; Liu, Chia-Chen; Zhao, Na; Painter, Meghan M; Petersen, Ronald C; Fryer, John D; Crook, Julia E; Dickson, Dennis W; Bu, Guojun; Kanekiyo, Takahisa

    2016-08-01

    Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of amyloid-β (Aβ) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aβ40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4. The ratio of Aβ40/Aβ42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble Aβ40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aβ42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aβ40 and apoE. PMID:27179972

  3. Cellular prion protein expression is not regulated by the Alzheimer's amyloid precursor protein intracellular domain.

    Directory of Open Access Journals (Sweden)

    Victoria Lewis

    Full Text Available There is increasing evidence of molecular and cellular links between Alzheimer's disease (AD and prion diseases. The cellular prion protein, PrP(C, modulates the post-translational processing of the AD amyloid precursor protein (APP, through its inhibition of the β-secretase BACE1, and oligomers of amyloid-β bind to PrP(C which may mediate amyloid-β neurotoxicity. In addition, the APP intracellular domain (AICD, which acts as a transcriptional regulator, has been reported to control the expression of PrP(C. Through the use of transgenic mice, cell culture models and manipulation of APP expression and processing, this study aimed to clarify the role of AICD in regulating PrP(C. Over-expression of the three major isoforms of human APP (APP(695, APP(751 and APP(770 in cultured neuronal and non-neuronal cells had no effect on the level of endogenous PrP(C. Furthermore, analysis of brain tissue from transgenic mice over-expressing either wild type or familial AD associated mutant human APP revealed unaltered PrP(C levels. Knockdown of endogenous APP expression in cells by siRNA or inhibition of γ-secretase activity also had no effect on PrP(C levels. Overall, we did not detect any significant difference in the expression of PrP(C in any of the cell or animal-based paradigms considered, indicating that the control of cellular PrP(C levels by AICD is not as straightforward as previously suggested.

  4. Basal forebrain atrophy correlates with amyloid β burden in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Georg M Kerbler

    2015-01-01

    Full Text Available The brains of patients suffering from Alzheimer's disease (AD have three classical pathological hallmarks: amyloid-beta (Aβ plaques, tau tangles, and neurodegeneration, including that of cholinergic neurons of the basal forebrain. However the relationship between Aβ burden and basal forebrain degeneration has not been extensively studied. To investigate this association, basal forebrain volumes were determined from magnetic resonance images of controls, subjects with amnestic mild cognitive impairment (aMCI and AD patients enrolled in the longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI and Australian Imaging, Biomarkers and Lifestyle (AIBL studies. In the AIBL cohort, these volumes were correlated within groups to neocortical gray matter retention of Pittsburgh compound B (PiB from positron emission tomography images as a measure of Aβ load. The basal forebrain volumes of AD and aMCI subjects were significantly reduced compared to those of control subjects. Anterior basal forebrain volume was significantly correlated to neocortical PiB retention in AD subjects and aMCI subjects with high Aβ burden, whereas posterior basal forebrain volume was significantly correlated to neocortical PiB retention in control subjects with high Aβ burden. Therefore this study provides new evidence for a correlation between neocortical Aβ accumulation and basal forebrain degeneration. In addition, cluster analysis showed that subjects with a whole basal forebrain volume below a determined cut-off value had a 7 times higher risk of having a worse diagnosis within ~18 months.

  5. 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.

  6. 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.

  7. Lipid rafts participate in aberrant degradative autophagic-lysosomal pathway of amyloid-beta peptide in Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou; Chun Yang; Yufeng Liu; Peng Li; Huiying Yang; Jingxing Dai; Rongmei Qu; Lin Yuan

    2014-01-01

    Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzhei-mer’s disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer’s disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant deg-radative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer’s disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer’s disease treatment.

  8. Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloidpeptide.

    Science.gov (United States)

    Keilani, Serene; Lun, Yi; Stevens, Anthony C; Williams, Hadis N; Sjoberg, Eric R; Khanna, Richie; Valenzano, Kenneth J; Checler, Frederic; Buxbaum, Joseph D; Yanagisawa, Katsuhiko; Lockhart, David J; Wustman, Brandon A; Gandy, Sam

    2012-04-11

    Alterations in the lipid composition of endosomal-lysosomal membranes may constitute an early event in Alzheimer's disease (AD) pathogenesis. In this study, we investigated the possibility that GM2 ganglioside accumulation in a mouse model of Sandhoff disease might be associated with the accumulation of intraneuronal and extracellular proteins commonly observed in AD. Our results show intraneuronal accumulation of amyloidpeptide (Aβ)-like, α-synuclein-like, and phospho-tau-like immunoreactivity in the brains of β-hexosaminidase knock-out (HEXB KO) mice. Biochemical and immunohistochemical analyses confirmed that at least some of the intraneuronal Aβ-like immunoreactivity (iAβ-LIR) represents amyloid precursor protein C-terminal fragments (APP-CTFs) and/or Aβ. In addition, we observed increased levels of Aβ40 and Aβ42 peptides in the lipid-associated fraction of HEXB KO mouse brains, and intraneuronal accumulation of ganglioside-bound Aβ (GAβ) immunoreactivity in a brain region-specific manner. Furthermore, α-synuclein and APP-CTFs and/or Aβ were found to accumulate in different regions of the substantia nigra, indicating different mechanisms of accumulation or turnover pathways. Based on the localization of the accumulated iAβ-LIR to endosomes, lysosomes, and autophagosomes, we conclude that a significant accumulation of iAβ-LIR may be associated with the lysosomal-autophagic turnover of Aβ and fragments of APP-containing Aβ epitopes. Importantly, intraneuronal GAβ immunoreactivity, a proposed prefibrillar aggregate found in AD, was found to accumulate throughout the frontal cortices of postmortem human GM1 gangliosidosis, Sandhoff disease, and Tay-Sachs disease brains. Together, these results establish an association between the accumulation of gangliosides, autophagic vacuoles, and the intraneuronal accumulation of proteins associated with AD. PMID:22496568

  9. Induction of serine racemase expression and D-serine release from microglia by amyloid β-peptide

    Directory of Open Access Journals (Sweden)

    Griffin W Sue T

    2004-04-01

    Full Text Available Abstract Background Roles for excitotoxicity and inflammation in Alzheimer's disease have been hypothesized. Proinflammatory stimuli, including amyloid β-peptide (Aβ, elicit a release of glutamate from microglia. We tested the possibility that a coagonist at the NMDA class of glutamate receptors, D-serine, could respond similarly. Methods Cultured microglial cells were exposed to Aβ. The culture medium was assayed for levels of D-serine by HPLC and for effects on calcium and survival on primary cultures of rat hippocampal neurons. Microglial cell lysates were examined for the levels of mRNA and protein for serine racemase, the enzyme that forms D-serine from L-serine. The racemase mRNA was also assayed in Alzheimer hippocampus and age-matched controls. A microglial cell line was transfected with a luciferase reporter construct driven by the putative regulatory region of human serine racemase. Results Conditioned medium from Aβ-treated microglia contained elevated levels of D-serine. Bioassays of hippocampal neurons with the microglia-conditioned medium indicated that Aβ elevated a NMDA receptor agonist that was sensitive to an antagonist of the D-serine/glycine site (5,7-dicholorokynurenic acid; DCKA and to enzymatic degradation of D-amino acids by D-amino acid oxidase (DAAOx. In the microglia, Aβ elevated steady-state levels of dimeric serine racemase, the apparent active form of the enzyme. Promoter-reporter and mRNA analyses suggest that serine racemase is transcriptionally induced by Aβ. Finally, the levels of serine racemase mRNA were elevated in Alzheimer's disease hippocampus, relative to age-matched controls. Conclusions These data suggest that Aβ could contribute to neurodegeneration through stimulating microglia to release cooperative excitatory amino acids, including D-serine.

  10. Aβ42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-β42 species and protects synaptic structure and function

    Science.gov (United States)

    Barucker, Christian; Bittner, Heiko J.; Chang, Philip K.-Y.; Cameron, Scott; Hancock, Mark A.; Liebsch, Filip; Hossain, Shireen; Harmeier, Anja; Shaw, Hunter; Charron, François M.; Gensler, Manuel; Dembny, Paul; Zhuang, Wei; Schmitz, Dietmar; Rabe, Jürgen P.; Rao, Yong; Lurz, Rudi; Hildebrand, Peter W.; McKinney, R. Anne; Multhaup, Gerhard

    2015-10-01

    The amyloid-β42 (Aβ42) peptide is believed to be the main culprit in the pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Aβ42 oligomers are highly toxic and contribute to progressive neuronal dysfunction, loss of synaptic spine density, and affect long-term potentiation (LTP). We have characterized a short, L-amino acid Aβ-oligomer Interacting Peptide (AIP) that targets a relatively well-defined population of low-n Aβ42 oligomers, rather than simply inhibiting the aggregation of Aβ monomers into oligomers. Our data show that AIP diminishes the loss of Aβ42-induced synaptic spine density and rescues LTP in organotypic hippocampal slice cultures. Notably, the AIP enantiomer (comprised of D-amino acids) attenuated the rough-eye phenotype in a transgenic Aβ42 fly model and significantly improved the function of photoreceptors of these flies in electroretinography tests. Overall, our results indicate that specifically “trapping” low-n oligomers provides a novel strategy for toxic Aβ42-oligomer recognition and removal.

  11. Identification of a Novel Parallel beta-Strand Conformation within Molecular Monolayer of Amyloid Peptide

    DEFF Research Database (Denmark)

    Liu, Lei; Li, Qiang; Zhang, Shuai;

    2016-01-01

    . In this work, the early A beta(33-42) aggregates forming the molecular monolayer at hydrophobic interface are investigated. The molecular monolayer of amyloid peptide A beta(33-42) consisting of novel parallel beta-strand-like structure is further revealed by means of a quantitative nanomechanical...... spectroscopy technique with force controlled in pico-Newton range, combining with molecular dynamic simulation. The identified parallel beta-strand-like structure of molecular monolayer is distinct from the antiparallel beta-strand structure of A beta(33-42) amyloid fibril. This finding enriches the molecular...

  12. Levels of alpha- and beta-secretase cleaved amyloid precursor protein in the cerebrospinal fluid of Alzheimer's disease patients

    DEFF Research Database (Denmark)

    Sennvik, K; Fastbom, J; Blomberg, M;

    2000-01-01

    Alternative cleavage of the amyloid precursor protein (APP) results in generation and secretion of both soluble APP (sAPP) and beta-amyloid (Abeta). Abeta is the main component of the amyloid depositions in the brains of Alzheimer's disease (AD) patients. Using Western blotting, we compared the...... levels of alpha-secretase cleaved sAPP, beta-secretase cleaved sAPP and total sAPP, in cerebrospinal fluid (CSF) from 13 sporadic AD patients and 13 healthy controls. Our findings show significant amounts of beta-secretase cleaved sAPP in CSF. There was no statistically significant difference in the...... levels of beta-secretase cleaved sAPP between AD patients and controls. The levels of alpha-secretase cleaved sAPP and total sAPP were, however, found to be significantly lower in the AD patients than in the controls....

  13. Glutamate carboxypeptidase II does not process amyloid-beta peptide

    Czech Academy of Sciences Publication Activity Database

    Sedlák, František; Šácha, Pavel; Blechová, Miroslava; Březinová, Anna; Šafařík, Martin; Šebestík, Jaroslav; Konvalinka, Jan

    2013-01-01

    Roč. 27, č. 7 (2013), s. 2626-2632. ISSN 0892-6638 R&D Projects: GA ČR GAP304/12/0847 Institutional support: RVO:61388963 Keywords : PSMA * Alzheimer's disease * disaggregation * exopeptidase * substrate specificity * depsipeptide Subject RIV: CE - Biochemistry Impact factor: 5.480, year: 2013

  14. Peptide fingerprinting of Alzheimer's disease in cerebrospinal fluid: identification and prospective evaluation of new synaptic biomarkers.

    Directory of Open Access Journals (Sweden)

    Holger Jahn

    Full Text Available BACKGROUND: Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer's disease (AD using capillary-electrophoresis coupled to mass-spectrometry (CE-MS and to assess the potential of early diagnosis of AD. METHODS AND FINDINGS: Cerebrospinal fluid (CSF of 159 out-patients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer's disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI. The AD-pattern was tested in a prospective sample of patients (n = 100 and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho(181-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A. CONCLUSIONS: The method may allow early differential

  15. Monodisperse carboxyl-functionalized poly(ethylene glycol)-coated magnetic poly(glycidyl methacrylate) microspheres: application to the immunocapture of β-amyloid peptides.

    Science.gov (United States)

    Horák, Daniel; Hlídková, Helena; Hiraoui, Mohamed; Taverna, Myriam; Proks, Vladimír; Mázl Chánová, Eliška; Smadja, Claire; Kučerová, Zdenka

    2014-11-01

    Identification and evaluation of small changes in β-amyloid peptide (Aβ) levels in cerebrospinal fluid is of crucial importance for early detection of Alzheimer's disease. Microfluidic detection methods enable effective preconcentration of Aβ using magnetic microparticles coated with Aβ antibodies. Poly(glycidyl methacrylate) microspheres are coated with α-amino-ω-methoxy-PEG5000 /α-amino-ω-Boc-NH-PEG5000 Boc groups deprotected and NH2 succinylated to introduce carboxyl groups. Capillary electrophoresis with laser-induced fluorescence detection confirms the efficient capture of Aβ 1-40 peptides on the microspheres with immobilized monoclonal anti-Aβ 6E10. The capture specificity is confirmed by comparing Aβ 1-40 levels on the anti-IgG-immobilized particles used as a control. PMID:25142028

  16. Neurogenesis, Neurodegeneration, Interneuron Vulnerability, and Amyloid-β in the Olfactory Bulb of APP/PS1 Mouse Model of Alzheimer's Disease

    Science.gov (United States)

    De la Rosa-Prieto, Carlos; Saiz-Sanchez, Daniel; Ubeda-Banon, Isabel; Flores-Cuadrado, Alicia; Martinez-Marcos, Alino

    2016-01-01

    Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, mostly idiopathic and with palliative treatment. Neuropathologically, it is characterized by intracellular neurofibrillary tangles of tau protein and extracellular plaques of amyloid β peptides. The relationship between AD and neurogenesis is unknown, but two facts are particularly relevant. First, early aggregation sites of both proteinopathies include the hippocampal formation and the olfactory bulb (OB), which have been correlated to memory and olfactory deficits, respectively. These areas are well-recognized integration zones of newly-born neurons in the adult brain. Second, molecules, such as amyloid precursor protein (APP) and presenilin-1 are common to both AD etiology and neurogenic development. Adult neurogenesis in AD models has been studied in the hippocampus, but only occasionally addressed in the OB and results are contradictory. To gain insight on the relationship between adult neurogenesis and AD, this work analyzes neurogenesis, neurodegeneration, interneuron vulnerability, and amyloid-β involvement in the OB of an AD model. Control and double-transgenic mice carrying the APP and the presenilin-1 genes, which give rise amyloid β plaques have been used. BrdU-treated animals have been studied at 16, 30, 43, and 56 weeks of age. New-born cell survival (BrdU), neuronal loss (using neuronal markers NeuN and PGP9.5), differential interneuron (calbindin-, parvalbumin-, calretinin- and somatostatin-expressing populations) vulnerability, and involvement by amyloid β have been analyzed. Neurogenesis increases with aging in the granule cell layer of control animals from 16 to 43 weeks. No neuronal loss has been observed after quantifying NeuN or PGP9.5. Regarding interneuron population vulnerability: calbindin-expressing neurons remains unchanged; parvalbumin-expressing neurons trend to increase with aging in transgenic animals; calretinin-expressing neurons increase with aging in

  17. Imaging of amyloid-β in Alzheimer's disease transgenic mouse brains with ToF-SIMS using immunoliposomes.

    Science.gov (United States)

    Carlred, Louise; Vukojević, Vladana; Johansson, Björn; Schalling, Martin; Höök, Fredrik; Sjövall, Peter

    2016-06-01

    Time-of-flight secondary ion mass spectrometry (ToF-SIMS) has been proven to successfully image different kinds of molecules, especially a variety of lipids, in biological samples. Proteins, however, are difficult to detect as specific entities with this method due to extensive fragmentation. To circumvent this issue, the authors present in this work a method developed for detection of proteins using antibody-conjugated liposomes, so called immunoliposomes, which are able to bind to the specific protein of interest. In combination with the capability of ToF-SIMS to detect native lipids in tissue samples, this method opens up the opportunity to analyze many different biomolecules, both lipids and proteins, at the same time, with high spatial resolution. The method has been applied to detect and image the distribution of amyloid-β (Aβ), a biologically relevant peptide in Alzheimer's disease (AD), in transgenic mouse brain tissue. To ensure specific binding, the immunoliposome binding was verified on a model surface using quartz crystal microbalance with dissipation monitoring. The immunoliposome binding was also investigated on tissue sections with fluorescence microscopy, and compared with conventional immunohistochemistry using primary and secondary antibodies, demonstrating specific binding to Aβ. Using ToF-SIMS imaging, several endogenous lipids, such as cholesterol and sulfatides, were also detected in parallel with the immunoliposome-labeled Aβ deposits, which is an advantage compared to fluorescence microscopy. This method can thus potentially provide further information about lipid-protein interactions, which is important to understand the mechanisms of neurodegeneration in AD. PMID:26801213

  18. Satureja bachtiarica ameliorate beta-amyloid induced memory impairment, oxidative stress and cholinergic deficit in animal model of Alzheimer's disease.

    Science.gov (United States)

    Soodi, Maliheh; Saeidnia, Soodabeh; Sharifzadeh, Mohammad; Hajimehdipoor, Homa; Dashti, Abolfazl; Sepand, Mohammad Reza; Moradi, Shahla

    2016-04-01

    Extracellular deposition of Beta-amyloid peptide (Aβ) is the main finding in the pathophysiology of Alzheimer's disease (AD), which damages cholinergic neurons through oxidative stress and reduces the cholinergic neurotransmission. Satureja bachtiarica is a medicinal plant from the Lamiaceae family which was widely used in Iranian traditional medicine. The aim of the present study was to investigate possible protective effects of S. bachtiarica methanolic extract on Aβ induced spatial memory impairment in Morris Water Maze (MWM), oxidative stress and cholinergic neuron degeneration. Pre- aggregated Aβ was injected into the hippocampus of each rat bilaterally (10 μg/rat) and MWM task was performed 14 days later to evaluate learning and memory function. Methanolic extract of S.bachtiarica (10, 50 and 100 mg/Kg) was injected intraperitoneally for 19 consecutive days, after Aβ injection. After the probe test the brain tissue were collected and lipid peroxidation, Acetylcholinesterase (AChE) activity and Cholin Acetyl Transferees (ChAT) immunorectivity were measured in the hippocampus. Intrahipocampal injection of Aβ impaired learning and memory in MWM in training days and probe trail. Methanolic extract of S. bachtiarica (50 and 100 mg/Kg) could attenuate Aβ-induced memory deficit. ChAT immunostaining revealed that cholinergic neurons were loss in Aβ- injected group and S. bachtiarica (100 mg/Kg) could ameliorate Aβ- induced ChAT reduction in the hippocampus. Also S. bachtiarica could ameliorate Aβ-induced lipid peroxidation and AChE activity increase in the hippocampus. In conclusion our study represent that S.bachtiarica methanolic extract can improve Aβ-induced memory impairment and cholinergic loss then we recommended this extract as a candidate for further investigation in treatment of AD. PMID:26638718

  19. The inhibitory mechanism of a fullerene derivative against amyloidpeptide aggregation: an atomistic simulation study.

    Science.gov (United States)

    Sun, Yunxiang; Qian, Zhenyu; Wei, Guanghong

    2016-05-14

    Alzheimer's disease (AD) is associated with the pathological self-assembly of amyloid-β (Aβ) peptides into β-sheet enriched fibrillar aggregates. Aβ dimers formed in the initial step of Aβ aggregation were reported to be the smallest toxic species. Inhibiting the formation of β-sheet-rich oligomers and fibrils is considered as the primary therapeutic strategy for AD. Previous studies reported that fullerene derivatives strongly inhibit Aβ fibrillation. However, the underlying inhibitory mechanism remains elusive. As a first step to understand fullerene-modulated full-length Aβ aggregation, we investigated the conformational ensemble of the Aβ1-42 dimer with and without 1,2-(dimethoxymethano)fullerene (DMF) - a more water-soluble fullerene derivative - by performing a 340 ns explicit-solvent replica exchange molecular dynamics simulation. Our simulations show that although disordered states are the most abundant conformations of the Aβ1-42 dimer, conformations containing diverse extended β-hairpins are also populated. The first most-populated β-hairpins involving residues L17-D23 and A30-V36 strongly resemble the engineered β-hairpin which is a building block of toxic Aβ oligomers. We find that the interaction of DMFs with Aβ peptides greatly impedes the formation of such β-hairpins and inter-peptide β-sheets. Binding energy analyses demonstrate that DMF preferentially binds not only to the central hydrophobic motif LVFFA of the Aβ peptide as suggested experimentally, but also to the aromatic residues including F4 and Y10 and the C-terminal hydrophobic region I31-V40. This study reveals a complete picture of the inhibitory mechanism of full-length Aβ1-42 aggregation by fullerenes, providing theoretical insights into the development of drug candidates against AD. PMID:27091578

  20. Plasma beta-amyloid as potential biomarker of Alzheimer disease: possibility of diagnostic tool for Alzheimer disease.

    Science.gov (United States)

    Takeda, Shuko; Sato, Naoyuki; Rakugi, Hiromi; Morishita, Ryuichi

    2010-10-01

    Alzheimer disease (AD), which is characterized by progressive cognitive and behavioral deficit, is the most common form of dementia. The incidence of AD is increasing at an alarming rate, and has become a major public health concern in many countries. It is well known that the onset of AD is preceded by a long preclinical period. It is thus critical to establish diagnostic biomarkers that can predict the risk of developing AD prior to clinical manifestation of dementia, for effective prevention and early intervention. With the emergence of potential promising approaches to treat AD targeting the beta-amyloid (Abeta) pathway, such as gamma-secretase inhibitors and vaccine therapy, there is an urgent need for such diagnostic markers. Although cerebrospinal fluid (CSF) Abeta and tau protein levels are candidate biomarkers for AD, the invasive sampling procedure with associated complications limits their use in routine clinical practice. Plasma Abeta has been suggested as an inexpensive and non-invasive biomarker for AD. Although most previous cross-sectional studies on plasma Abeta level in humans failed to show a significant difference between individuals with AD compared to healthy older adults, many strategies are under investigation to improve the diagnostic potential of plasma Abeta. One promising approach is to modify the plasma Abeta level using some potential modulators. It is possible that a difference in plasma Abeta level might be unmasked by evaluating the response to stimulation by a modulator. Anti-Abeta antibody and Abeta binding proteins have been reported to be such modulators of plasma Abeta. In addition, the glucometabolic or hormonal status appears to modulate the plasma Abeta level. Our recent study has shown the possibility that glucose loading could be a novel simple strategy to modulate the plasma Abeta level, making it better suited for early diagnosis. This review summarizes the utility and limitations of current biomarkers of AD and

  1. Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis

    OpenAIRE

    Ikonen, Maaria; LIU, BINGRONG; Hashimoto, Yuichi; Ma, Liqun; Lee, Kuk-Wha; Niikura, Takako; Nishimoto, Ikuo; Cohen, Pinchas

    2003-01-01

    Insulin-like growth factor-binding protein-3 (IGFBP-3) regulates IGF bioactivity and also independently modulates cell growth and survival. By using a yeast two-hybrid screen to identify IGFBP-3-interacting proteins, we cloned humanin (HN) as an IGFBP-3-binding partner. HN is a 24-aa peptide that has been shown to specifically inhibit neuronal cell death induced by familial Alzheimer's disease mutant genes and amyloid-β (Aβ). The physical interaction of HN with IGFBP-3 was determined to be of...

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

    Directory of Open Access Journals (Sweden)

    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

  3. Effect of Curcumin on the metal ion induced fibrillization of Amyloidpeptide

    Science.gov (United States)

    Banerjee, Rona

    2014-01-01

    The effect of Curcumin on Cu(II) and Zn(II) induced oligomerization and protofibrillization of the amyloid-beta (Aβ) peptide has been studied by spectroscopic and microscopic methods. Curcumin could significantly reduce the β-sheet content of the peptide in a time dependent manner. It also plays an antagonistic role in β-sheet formation that is promoted by metal ions like Cu(II) and Zn(II) as observed by Circular Dichroism (CD) spectroscopy. Atomic force microscopic (AFM) images show that spontaneous fibrillization of the peptide occurs in presence of Cu(II) and Zn(II) but is inhibited on incubation of the peptide with Curcumin indicating the beneficial role of Curcumin in preventing the aggregation of Aβ peptide.

  4. Antroquinonol Lowers Brain Amyloid-β Levels and Improves Spatial Learning and Memory in a Transgenic Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Chang, Wen-Han; Chen, Miles C; Cheng, Irene H

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia. The deposition of brain amyloidpeptides (Aβ), which are cleaved from amyloid precursor protein (APP), is one of the pathological hallmarks of AD. Aβ-induced oxidative stress and neuroinflammation play important roles in the pathogenesis of AD. Antroquinonol, a ubiquinone derivative isolated from Antrodia camphorata, has been shown to reduce oxidative stress and inflammatory cytokines via activating the nuclear transcription factor erythroid-2-related factor 2 (Nrf2) pathway, which is downregulated in AD. Therefore, we examined whether antroquinonol could improve AD-like pathological and behavioral deficits in the APP transgenic mouse model. We found that antroquinonol was able to cross the blood-brain barrier and had no adverse effects via oral intake. Two months of antroquinonol consumption improved learning and memory in the Morris water maze test, reduced hippocampal Aβ levels, and reduced the degree of astrogliosis. These effects may be mediated through the increase of Nrf2 and the decrease of histone deacetylase 2 (HDAC2) levels. These findings suggest that antroquinonol could have beneficial effects on AD-like deficits in APP transgenic mouse. PMID:26469245

  5. Ligand-binding sites in human serum amyloid P component

    DEFF Research Database (Denmark)

    Heegaard, N.H.H.; Heegaard, Peter M. H.; Roepstorff, P.; Robey, F.A.

    1996-01-01

    Amyloid P component (AP) is a naturally occurring glycoprotein that is found in serum and basement membranes, AP is also a component of all types of amyloid, including that found in individuals who suffer from Alzheimer's disease and Down's syndrome. Because AP has been found to bind strongly and...... of 25 mu M, while the IC50 of AP-(27-38)-peptide and AP-(33-38)-peptide are 10 mu M and 2 mu M, respectively, The understanding of the structure and function of active AP peptides will be useful for development of amyloid-targeted diagnostics and therapeutics....

  6. The effect of amyloid pathology and glucose metabolism on cortical volume loss over time in Alzheimer's disease

    International Nuclear Information System (INIS)

    The present multimodal neuroimaging study examined whether amyloid pathology and glucose metabolism are related to cortical volume loss over time in Alzheimer's disease (AD) patients and healthy elderly controls. Structural MRI scans of eleven AD patients and ten controls were available at baseline and follow-up (mean interval 2.5 years). Change in brain structure over time was defined as percent change of cortical volume within seven a-priori defined regions that typically show the strongest structural loss in AD. In addition, two PET scans were performed at baseline: [11C]PIB to assess amyloid-β plaque load and [18F]FDG to assess glucose metabolism. [11C]PIB binding and [18F]FDG uptake were measured in the precuneus, a region in which both amyloid deposition and glucose hypometabolism occur early in the course of AD. While amyloid-β plaque load at baseline was not related to cortical volume loss over time in either group, glucose metabolism within the group of AD patients was significantly related to volume loss over time (rho = 0.56, p 11C]PIB behaves as a trait marker (i.e., all AD patients showed elevated levels of amyloid, not related to subsequent disease course), whilst hypometabolism as measured by [18F]FDG changed over time indicating that it could serve as a state marker that is predictive of neurodegeneration. (orig.)

  7. Binding, conformational transition and dimerization of amyloidpeptide on GM1-containing ternary membrane: insights from molecular dynamics simulation.

    Directory of Open Access Journals (Sweden)

    Moutusi Manna

    Full Text Available Interactions of amyloid-β (Aβ with neuronal membrane are associated with the progression of Alzheimer's disease (AD. Ganglioside GM1 has been shown to promote the structural conversion of Aβ and increase the rate of peptide aggregation; but the exact nature of interaction driving theses processes remains to be explored. In this work, we have carried out atomistic-scale computer simulations (totaling 2.65 µs to investigate the behavior of Aβ monomer and dimers in GM1-containing raft-like membrane. The oligosaccharide head-group of GM1 was observed to act as scaffold for Aβ-binding through sugar-specific interactions. Starting from the initial helical peptide conformation, a β-hairpin motif was formed at the C-terminus of the GM1-bound Aβ-monomer; that didn't appear in absence of GM1 (both in fluid POPC and liquid-ordered cholesterol/POPC bilayers and also in aqueous medium within the simulation time span. For Aβ-dimers, the β-structure was further enhanced by peptide-peptide interactions, which might influence the propensity of Aβ to aggregate into higher-ordered structures. The salt-bridges and inter-peptide hydrogen bonds were found to account for dimer stability. We observed spontaneous formation of intra-peptide D(23-K(28 salt-bridge and a turn at V(24GSN(27 region - long been accepted as characteristic structural-motifs for amyloid self-assembly. Altogether, our results provide atomistic details of Aβ-GM1 and Aβ-Aβ interactions and demonstrate their importance in the early-stages of GM1-mediated Aβ-oligomerisation on membrane surface.

  8. Sex-dependent actions of amyloid beta peptides on hippocampal choline carriers of postnatal rats

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Říčný, Jan; Kozmiková, I.; Řípová, D.; Zach, P.; Klaschka, Jan

    2006-01-01

    Roč. 31, č. 3 (2006), s. 351-360. ISSN 0364-3190 R&D Projects: GA ČR(CZ) GA305/03/1547 Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z10300504 Keywords : amyloid beta peptide * high affinity choline transport * rat hippocampus Subject RIV: ED - Physiology Impact factor: 2.139, year: 2006

  9. Amyloid β accumulation and inner retinal degenerative changes in Alzheimer's disease transgenic mouse.

    Science.gov (United States)

    Gupta, Vivek K; Chitranshi, Nitin; Gupta, Veer B; Golzan, Mojtaba; Dheer, Yogita; Wall, Roshana Vander; Georgevsky, Dana; King, Anna E; Vickers, James C; Chung, Roger; Graham, Stuart

    2016-06-01

    The APP-PS1ΔE9 mouse model of Alzheimer's disease (AD) exhibits age dependent amyloid β (Aβ) plaque formation in their central nervous system due to high expression of mutated human APP and PSEN1 transgenes. Here we evaluated Aβ deposition and changes in soluble Aβ accumulation in the retinas of aged APP-PS1 mice using a combination of immunofluorescence, retinal flat mounts and western blotting techniques. Aβ accumulation in the retina has previously been shown to be associated with retinal ganglion cell apoptosis in animal models of glaucoma. This study investigated changes in the inner retinal function and structure in APP-PS1 mice using electrophysiology and histological approaches respectively. We report for the first time a significant decline in scotopic threshold response (STR) amplitudes which represents inner retinal function in transgenic animals compared to the wild type counterparts (p<0.0001). Thinning of the retina particularly involving inner retinal layers and reduction in axonal density in the optic nerve was also observed. TUNEL staining was performed to examine neuronal apoptosis in the inner retina. Intraocular pressure (IOP) measurements showed that APP-PS1ΔE9 mice had a slightly elevated IOP, but the significance of this finding is not yet known. Together, these results substantiate previous observations and highlight that APP-PS1ΔE9 mice show evidence of molecular, functional and morphological degenerative changes in the inner retina. PMID:27133194

  10. Does Caffeine Consumption Modify Cerebrospinal Fluid Amyloid-β Levels in Patients with Alzheimer's Disease?

    DEFF Research Database (Denmark)

    Travassos, Maria; Santana, Isabel; Baldeiras, Inês;

    2015-01-01

    Caffeine may be protective against Alzheimer's disease (AD) by modulating amyloid-β (Aβ) metabolic pathways. The present work aimed to study a possible association of caffeine consumption with the cerebrospinal fluid (CSF) biomarkers, particularly Aβ. The study included 88 patients with AD or mild...... cognitive impairment. The consumption of caffeine and theobromine was evaluated using a validated food questionnaire. Quantification of caffeine and main active metabolites was performed with liquid chromatography coupled to tandem mass spectrometry. The levels of A(1-42), total tau, and phosphorylated tau...... in the CSF were determined using sandwich ELISA methods and other Aβ species, Aβ(X-38), Aβ(X-40), and Aβ(X-42), with the MSD Aβ Triplex assay. The concentration of caffeine was 0.79±1.15 μg/mL in the CSF and 1.20±1.88 μg/mL in the plasma. No correlation was found between caffeine consumption and Aβ42...

  11. Molecular basis for mid-region amyloid-β capture by leading Alzheimer's disease immunotherapies.

    Science.gov (United States)

    Crespi, Gabriela A N; Hermans, Stefan J; Parker, Michael W; Miles, Luke A

    2015-01-01

    Solanezumab (Eli Lilly) and crenezumab (Genentech) are the leading clinical antibodies targeting Amyloid-β (Aβ) to be tested in multiple Phase III clinical trials for the prevention of Alzheimer's disease in at-risk individuals. Aβ capture by these clinical antibodies is explained here with the first reported mid-region Aβ-anti-Aβ complex crystal structure. Solanezumab accommodates a large Aβ epitope (960 Å(2) buried interface over residues 16 to 26) that forms extensive contacts and hydrogen bonds to the antibody, largely via main-chain Aβ atoms and a deeply buried Phe19-Phe20 dipeptide core. The conformation of Aβ captured is an intermediate between observed sheet and helical forms with intramolecular hydrogen bonds stabilising residues 20-26 in a helical conformation. Remarkably, Aβ-binding residues are almost perfectly conserved in crenezumab. The structure explains the observed shared cross reactivity of solanezumab and crenezumab with proteins abundant in plasma that exhibit this Phe-Phe dipeptide. PMID:25880481

  12. Amyloid-based immunotherapy for Alzheimer's disease in the time of prevention trials: the way forward.

    Science.gov (United States)

    Panza, Francesco; Solfrizzi, Vincenzo; Imbimbo, Bruno P; Tortelli, Rosanna; Santamato, Andrea; Logroscino, Giancarlo

    2014-03-01

    Both active and passive anti-β-amyloid (Aβ) immunotherapies for the treatment of Alzheimer's disease (AD) have demonstrated clearance of brain Aβ deposits. Among passive immunotherapeutics, two Phase III clinical trials in mild-to-moderate AD patients with bapineuzumab, a humanized monoclonal antibody directed at the N-terminal sequence of Aβ, were disappointing. Also solanezumab, directed at the mid-region of Aβ, failed in two Phase III trials in mild-to-moderate AD. Another Phase III trial with solanezumab is ongoing in mildly affected AD patients based on encouraging results in this subgroup. Second-generation active Aβ vaccines (CAD106, ACC-001, and Affitope AD02) and new passive anti-Aβ immunotherapies (gantenerumab and crenezumab) have been developed and are under clinical testing. These new anti-Aβ immunotherapies are being tested in prodromal AD, in presymptomatic subjects with AD-related mutations, or in asymptomatic subjects at risk of developing AD. These primary and secondary prevention trials will definitely test the Aβ cascade hypothesis of AD. PMID:24490853

  13. Type II fuzzy systems for amyloid plaque segmentation in transgenic mouse brains for Alzheimer's disease quantification

    Science.gov (United States)

    Khademi, April; Hosseinzadeh, Danoush

    2014-03-01

    Alzheimer's disease (AD) is the most common form of dementia in the elderly characterized by extracellular deposition of amyloid plaques (AP). Using animal models, AP loads have been manually measured from histological specimens to understand disease etiology, as well as response to treatment. Due to the manual nature of these approaches, obtaining the AP load is labourious, subjective and error prone. Automated algorithms can be designed to alleviate these challenges by objectively segmenting AP. In this paper, we focus on the development of a novel algorithm for AP segmentation based on robust preprocessing and a Type II fuzzy system. Type II fuzzy systems are much more advantageous over the traditional Type I fuzzy systems, since ambiguity in the membership function may be modeled and exploited to generate excellent segmentation results. The ambiguity in the membership function is defined as an adaptively changing parameter that is tuned based on the local contrast characteristics of the image. Using transgenic mouse brains with AP ground truth, validation studies were carried out showing a high degree of overlap and low degree of oversegmentation (0.8233 and 0.0917, respectively). The results highlight that such a framework is able to handle plaques of various types (diffuse, punctate), plaques with varying Aβ concentrations as well as intensity variation caused by treatment effects or staining variability.

  14. Gene expression profile of amyloid beta protein-injected mouse model for Alzheimer disease

    Institute of Scientific and Technical Information of China (English)

    Ling-na KONG; Ping-ping ZUO; Liang MU; Yan-yong LIU; Nan YANG

    2005-01-01

    Aim: To investigate the gene expression profile changes in the cerebral cortex of mice injected icv with amyloid beta-protein (Aβ) fragment 25-35 using cDNA microarray. Methods: Balb/c mice were randomly divided into a control group and Aβ-treated group. The Morris water maze test was performed to detect the effect of Aβ-injection on the learning and memory of mice. Atlas Mouse 1.2 Expression Arrays containing 1176 genes were used to investigate the gene expression pattern of each group. Results: The gene expression profiles showed that 19 genes including TBX1, NF-κB, AP-1/c-Jun, cadherin, integrin, erb-B2, and FGFR1 were up-regulated after 2 weeks oficv administration of Aβ; while 12 genes were downregulated, including NGF, glucose phosphate isomerase 1, AT motif binding factor 1, Na+/K+-ATPase, and Akt. Conclusions: The results provide important leads for pursuing a more complete understanding of the molecular events of Aβ-injection into mice with Alzheimer disease.

  15. Computed tomography of amyloid plaques in a mouse model of Alzheimers disease using diffraction enhanced imaging

    Energy Technology Data Exchange (ETDEWEB)

    Connor, D.M.; Miller, L.; Benveniste, H.; Dilmanian, A.; Kritzer, M.; Zhong, Z.

    2009-03-19

    Our understanding of early development in Alzheimer's disease (AD) is clouded by the scale at which the disease progresses; amyloid beta (A{beta}) plaques, a hallmark feature of AD, are small ({approx} 50 {micro}m) and low contrast in diagnostic clinical imaging techniques. Diffraction enhanced imaging (DEI), a phase contrast x-ray imaging technique, has greater soft tissue contrast than conventional radiography and generates higher resolution images than magnetic resonance microimaging. Thus, in this proof of principle study, DEI in micro-CT mode was performed on the brains of AD-model mice to determine if DEI can visualize A{beta} plaques. Results revealed small nodules in the cortex and hippocampus of the brain. Histology confirmed that the features seen in the DEI images of the brain were A{beta} plaques. Several anatomical structures, including hippocampal subregions and white matter tracks, were also observed. Thus, DEI has strong promise in early diagnosis of AD, as well as general studies of the mouse brain.

  16. Alzheimer's associated β-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes.

    Directory of Open Access Journals (Sweden)

    Mitchell R White

    Full Text Available Accumulation of β-Amyloid (βA is a key pathogenetic factor in Alzheimer's disease; however, the normal function of βA is unknown. Recent studies have shown that βA can inhibit growth of bacteria and fungi. In this paper we show that βA also inhibits replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV in vitro. The 42 amino acid fragment of βA (βA42 had greater activity than the 40 amino acid fragment. Direct incubation of the virus with βA42 was needed to achieve optimal inhibition. Using quantitative PCR assays βA42 was shown to reduce viral uptake by epithelial cells after 45 minutes and to reduce supernatant virus at 24 hours post infection. βA42 caused aggregation of IAV particles as detected by light transmission assays and electron and confocal microscopy. βA42 did not stimulate neutrophil H2O2 production or extracellular trap formation on its own, but it increased both responses stimulated by IAV. In addition, βA42 increased uptake of IAV by neutrophils. βA42 reduced viral protein synthesis in monocytes and reduced IAV-induced interleukin-6 production by these cells. Hence, we demonstrate for the first time that βA has antiviral activity and modulates viral interactions with phagocytes.

  17. Local atomic structure and oxidation processes of Cu(I) binding site in amyloid beta peptide: XAS Study

    Science.gov (United States)

    Kremennaya, M. A.; Soldatov, M. A.; Stretsov, V. A.; Soldatov, A. V.

    2016-05-01

    There are two different motifs of X-ray absorption spectra for Cu(I) K-edge in amyloidpeptide which could be due to two different configurations of local Cu(I) environment. Two or three histidine ligands can coordinate copper ion in varying conformations. On the other hand, oxidation of amyloidpeptide could play an additional role in local copper environment. In order to explore the peculiarities of local atomic and electronic structure of Cu(I) binding sites in amyloidpeptide the x-ray absorption spectra were simulated for various Cu(I) environments including oxidized amyloid-β and compared with experimental data.

  18. Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes

    NARCIS (Netherlands)

    Lee, Jiyeon; Retamal, Claudio; Cuitino, Loreto; Caruano-Yzermans, Amy; Shin, Jung-Eun; van Kerkhof, Peter; Marzolo, Maria-Paz; Bu, Guojun

    2008-01-01

    Accumulation of extracellular amyloid beta peptide (A beta), generated from amyloid precursor protein (APP) processing by beta- and gamma-secretases, is toxic to neurons and is central to the pathogenesis of Alzheimer disease. Production of A beta from APP is greatly affected by the subcellular loca

  19. The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia

    Directory of Open Access Journals (Sweden)

    Brian A. Gordon

    2015-01-01

    Conclusions: The amount of amyloid deposition and white matter damage independently predicts cognitive impairment. This suggests a diagnostic utility of qualitative white matter scales in addition to measuring amyloid levels.

  20. Novel immunological approaches for the treatment of Alzheimer's disease

    OpenAIRE

    Priyanka Sabharwal; Thomas Wisniewski

    2014-01-01

    Alzheimer's disease (AD), the most prevalent form of dementia worldwide, can be deemed as the next global health epidemic. The biochemistry underlying deposition of amyloid beta (A β) and hyperphosphorylated tau aggregates in AD has been extensively studied. The oligomeric forms of Aβ that are derived from the normal soluble Aβ peptides are believed to be the most toxic. However, it is the fibrillar Aβ form that aggregates as amyloid plaques and cerebral amyloid angiopathy, which serve as pat...

  1. Non-fibrillar amyloidpeptide reduces NMDA-induced neurotoxicity, but not AMPA-induced neurotoxicity

    International Nuclear Information System (INIS)

    Amyloidpeptide (Aβ) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that Aβ has important physiological roles in addition to its pathological roles. We recently demonstrated that Aβ42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between Aβ42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar Aβ42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar Aβ42 on glutamate-induced neurotoxicity. Non-fibrillar Aβ42, but not fibrillar Aβ42, protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar Aβ42 decreased both neurotoxicity and increases in the intracellular Ca2+ concentration induced by N-methyl-D-aspartate (NMDA), but not by α-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar Aβ42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor.

  2. Metabolic changes may precede proteostatic dysfunction in a Drosophila model of amyloid beta peptide toxicity.

    Science.gov (United States)

    Ott, Stanislav; Vishnivetskaya, Anastasia; Malmendal, Anders; Crowther, Damian C

    2016-05-01

    Amyloid beta (Aβ) peptide aggregation is linked to the initiation of Alzheimer's disease; accordingly, aggregation-prone isoforms of Aβ, expressed in the brain, shorten the lifespan of Drosophila melanogaster. However, the lethal effects of Aβ are not apparent until after day 15. We used shibire(TS) flies that exhibit a temperature-sensitive paralysis phenotype as a reporter of proteostatic robustness. In this model, we found that increasing age but not Aβ expression lowered the flies' permissive temperature, suggesting that Aβ did not exert its lethal effects by proteostatic disruption. Instead, we observed that chemical challenges, in particular oxidative stressors, discriminated clearly between young (robust) and old (sensitive) flies. Using nuclear magnetic resonance spectroscopy in combination with multivariate analysis, we compared water-soluble metabolite profiles at various ages in flies expressing Aβ in their brains. We observed 2 genotype-linked metabolomic signals, the first reported the presence of any Aβ isoform and the second the effects of the lethal Arctic Aβ. Lethality was specifically associated with signs of oxidative respiration dysfunction and oxidative stress. PMID:27103517

  3. The effect of amyloid pathology and glucose metabolism on cortical volume loss over time in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Adriaanse, Sofie M. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); VU University Medical Center, Department of Radiology and Nuclear Medicine, Alzheimer Center, Neuroscience Campus Amsterdam, P.O. Box 7057, Amsterdam (Netherlands); Van Dijk, Koene R.A. [Harvard University, Department of Psychology, Center for Brain Science, Cambridge, MA (United States); Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA (United States); Ossenkoppele, Rik; Tolboom, Nelleke; Zwan, Marissa D.; Barkhof, Frederik; Berckel, Bart N.M. van [VU University Medical Center, Department of Radiology and Nuclear Medicine, Alzheimer Center, Neuroscience Campus Amsterdam, Amsterdam (Netherlands); Reuter, Martin [Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA (United States); Massachusetts Institute of Technology, Computer Science and Artificial Intelligence Laboratory, Division of Health Sciences and Technology, Cambridge, MA (United States); Yaqub, Maqsood; Boellaard, Ronald; Windhorst, Albert D.; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, Amsterdam (Netherlands); Flier, Wiesje M. van der; Scheltens, Philip [VU University Medical Center, Department of Neurology, Alzheimer Center, Neuroscience Campus Amsterdam, Amsterdam (Netherlands)

    2014-06-15

    The present multimodal neuroimaging study examined whether amyloid pathology and glucose metabolism are related to cortical volume loss over time in Alzheimer's disease (AD) patients and healthy elderly controls. Structural MRI scans of eleven AD patients and ten controls were available at baseline and follow-up (mean interval 2.5 years). Change in brain structure over time was defined as percent change of cortical volume within seven a-priori defined regions that typically show the strongest structural loss in AD. In addition, two PET scans were performed at baseline: [{sup 11}C]PIB to assess amyloid-β plaque load and [{sup 18}F]FDG to assess glucose metabolism. [{sup 11}C]PIB binding and [{sup 18}F]FDG uptake were measured in the precuneus, a region in which both amyloid deposition and glucose hypometabolism occur early in the course of AD. While amyloid-β plaque load at baseline was not related to cortical volume loss over time in either group, glucose metabolism within the group of AD patients was significantly related to volume loss over time (rho = 0.56, p < 0.05). The present study shows that in a group of AD patients amyloid-β plaque load as measured by [{sup 11}C]PIB behaves as a trait marker (i.e., all AD patients showed elevated levels of amyloid, not related to subsequent disease course), whilst hypometabolism as measured by [{sup 18}F]FDG changed over time indicating that it could serve as a state marker that is predictive of neurodegeneration. (orig.)

  4. Amyloid formation: functional friend or fearful foe?

    Science.gov (United States)

    Bergman, P; Roan, N R; Römling, U; Bevins, C L; Münch, J

    2016-08-01

    Amyloid formation has been most studied in the context of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, as well as in amyloidosis. However, it is becoming increasingly clear that amyloid is also present in the healthy setting; for example nontoxic amyloid formation is important for melanin synthesis and in innate immunity. Furthermore, bacteria have mechanisms to produce functional amyloid structures with important roles in bacterial physiology and interaction with host cells. Here, we will discuss some novel aspects of fibril-forming proteins in humans and bacteria. First, the amyloid-forming properties of the antimicrobial peptide human defensin 6 (HD6) will be considered. Intriguingly, unlike other antimicrobial peptides, HD6 does not kill bacteria. However, recent data show that HD6 can form amyloid structures at the gut mucosa with strong affinity for bacterial surfaces. These so-called nanonets block bacterial invasion by entangling the bacteria in net-like structures. Next, the role of functional amyloid fibrils in human semen will be discussed. These fibrils were discovered through their property to enhance HIV infection but they may also have other yet unknown functions. Finally, the role of amyloid formation in bacteria will be reviewed. The recent finding that bacteria can make amyloid in a controlled fashion without toxic effects is of particular interest and may have implications for human disease. The role of amyloid in health and disease is beginning to be unravelled, and here, we will review some of the most recent findings in this exciting area. PMID:27151743

  5. Interleukin-3 prevents neuronal death induced by amyloid peptide

    Directory of Open Access Journals (Sweden)

    Otth Carola

    2007-10-01

    Full Text Available Abstract Background Interleukin-3 (IL-3 is an important glycoprotein involved in regulating biological responses such as cell proliferation, survival and differentiation. Its effects are mediated via interaction with cell surface receptors. Several studies have demonstrated the expression of IL-3 in neurons and astrocytes of the hippocampus and cortices in normal mouse brain, suggesting a physiological role of IL-3 in the central nervous system. Although there is evidence indicating that IL-3 is expressed in some neuronal populations, its physiological role in these cells is poorly known. Results In this study, we demonstrated the expression of IL-3 receptor in cortical neurons, and analyzed its influence on amyloid β (Aβ-treated cells. In these cells, IL-3 can activate at least three classical signalling pathways, Jak/STAT, Ras/MAP kinase and the PI 3-kinase. Viability assays indicated that IL-3 might play a neuroprotective role in cells treated with Aβ fibrils. It is of interest to note that our results suggest that cell survival induced by IL-3 required PI 3-kinase and Jak/STAT pathway activation, but not MAP kinase. In addition, IL-3 induced an increase of the anti-apoptotic protein Bcl-2. Conclusion Altogether these data strongly suggest that IL-3 neuroprotects neuronal cells against neurodegenerative agents like Aβ.

  6. Involvement of receptor tyrosine kinase Tyro3 in amyloidogenic APP processing and β-amyloid deposition in Alzheimer's disease models.

    Directory of Open Access Journals (Sweden)

    Yan Zheng

    Full Text Available Alzheimer's disease (AD is the most common progressive neurodegenerative disease known to humankind. It is characterized by brain atrophy, extracellular amyloid plaques, and intracellular neurofibril tangles. β-Amyloid cascade is considered the major causative player in AD. Up until now, the mechanisms underlying the process of Aβ generation and accumulation in the brain have not been well understood. Tyro3 receptor belongs to the TAM receptor subfamily of receptor protein tyrosine kinases (RPTKs. It is specifically expressed in the neurons of the neocortex and hippocampus. In this study, we established a cell model stably expressing APPswe mutants and producing Aβ. We found that overexpression of Tyro3 receptor in the cell model significantly decreased Aβ generation and also down-regulated the expression of β-site amyloid precursor protein cleaving enzyme (BACE1. However, the effects of Tyro3 were inhibited by its natural ligand, Gas6, in a concentration-dependent manner. In order to confirm the role of Tyro3 in the progression of AD development, we generated an AD transgenic mouse model accompanied by Tyro3 knockdown. We observed a significant increase in the number of amyloid plaques in the hippocampus in the mouse model. More plaque-associated clusters of astroglia were also detected. The present study may help researchers determine the role of Tyro3 receptor in the neuropathology of AD.

  7. De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease.

    Science.gov (United States)

    Rovelet-Lecrux, A; Charbonnier, C; Wallon, D; Nicolas, G; Seaman, M N J; Pottier, C; Breusegem, S Y; Mathur, P P; Jenardhanan, P; Le Guennec, K; Mukadam, A S; Quenez, O; Coutant, S; Rousseau, S; Richard, A-C; Boland, A; Deleuze, J-F; Frebourg, T; Hannequin, D; Campion, D

    2015-09-01

    We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD. PMID:26194182

  8. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    Science.gov (United States)

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-01

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery. PMID:23926267

  9. Amyloid fibril formation of peptides derived from the C-terminus of CETP modulated by lipids

    Energy Technology Data Exchange (ETDEWEB)

    García-González, Victor [Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 México, DF (Mexico); Mas-Oliva, Jaime, E-mail: jmas@ifc.unam.mx [Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510 México, DF (Mexico); División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510 México, DF (Mexico)

    2013-04-26

    Highlights: •The secondary structure of a C-terminal peptide derived from CETP was studied. •Lipids modulate secondary structure changes of a C-terminal peptide derived from CETP. •Lysophosphatidic acid maintains a functional α-helix and prevents fibril formation. •Transfer of lipids by CETP is related to the presence of an α-helix at its C-end. -- Abstract: Cholesteryl-ester transfer protein (CETP) is a plasmatic protein involved in neutral lipid transfer between lipoproteins. Focusing on the last 12 C-terminus residues we have previously shown that mutation D{sub 470}N promotes a conformational change towards a β-secondary structure. In turn, this modification leads to the formation of oligomers and fibrillar structures, which cause cytotoxic effects similar to the ones provoked by amyloid peptides. In this study, we evaluated the role of specific lipid arrangements on the structure of peptide helix-Z (D{sub 470}N) through the use of thioflavin T fluorescence, peptide bond absorbance, circular dichroism and electron microscopy. The results indicate that the use of micelles formed with lysophosphatidylcholine and lysophosphatidic acid (LPA) under neutral pH induce a conformational transition of peptide helix-Z containing a β-sheet conformation to a native α-helix structure, therefore avoiding the formation of amyloid fibrils. In contrast, incubation with phosphatidic acid does not change the profile for the β-sheet conformation. When the electrostatic charge at the surface of micelles or vesicles is regulated through the use of lipids such as phospholipid and LPA, minimal changes and the presence of β-structures were recorded. Mixtures with a positive net charge diminished the percentage of β-structure and the amount of amyloid fibrils. Our results suggest that the degree of solvation determined by the presence of a free hydroxyl group on lipids such as LPA is a key condition that can modulate the secondary structure and the consequent formation of

  10. Mo polyoxometalate nanoclusters capable of inhibiting the aggregation of Aβ-peptide associated with Alzheimer's disease

    Science.gov (United States)

    Chen, Qingchang; Yang, Licong; Zheng, Chuping; Zheng, Wenjing; Zhang, Jingnan; Zhou, Yunshan; Liu, Jie

    2014-05-01

    A neuropathological hallmark of Alzheimer's disease (AD) is aggregation of a forty-residue peptide known as amyloid beta forty (Aβ40). While past work has indicated that blocking Aβ40 aggregation could be an effective strategy for the treatment of AD, developing therapies with this goal has been met with limited success. Polyoxometalates (POMs) have been previously investigated for their anti-viral and anti-tumoral properties and we report here that three representative POM nanoclusters have been synthesized for use against Aβ40 aggregation. Through the use of thioflavin T fluorescence, turbidity, circular dichroism spectroscopy, and transmission electron microscopy (TEM), we found that all three POM complexes can significantly inhibit both natural Aβ40 self-aggregation and metal-ion induced Aβ40 aggregation. We also evaluated the protective effect of POM complexes on Aβ40-induced neurotoxicity in cultured PC12 cells and found that treatment with POM complexes can elevate cell viability, decrease levels of intracellular reactive oxygen species, and stabilize mitochondrial membrane potential. These findings indicate that all three representative POM complexes are capable of inhibiting Aβ40 aggregation and subsequent neurotoxicity. While a complete mechanistic understanding remains to be elucidated, the synthesized POM complexes may work through a synergistic interaction with metal ions and Aβ40. These data indicate that POM complexes have high therapeutic potential for use against one of the primary neuropathological features of AD.A neuropathological hallmark of Alzheimer's disease (AD) is aggregation of a forty-residue peptide known as amyloid beta forty (Aβ40). While past work has indicated that blocking Aβ40 aggregation could be an effective strategy for the treatment of AD, developing therapies with this goal has been met with limited success. Polyoxometalates (POMs) have been previously investigated for their anti-viral and anti-tumoral properties

  11. Structural exploration and Förster theory modeling for the interpretation of gas-phase FRET measurements: Chromophore-grafted amyloidpeptides

    Science.gov (United States)

    Kulesza, Alexander; Daly, Steven; MacAleese, Luke; Antoine, Rodolphe; Dugourd, Philippe

    2015-07-01

    The distance-dependence of excitation energy transfer, e.g., being described by Förster theory (Förster resonance energy transfer (FRET)), allows the use of optical techniques for the direct observation of structural properties. Recently, this technique has been successfully applied in the gas phase. The detailed interpretation of the experimental FRET results, however, relies on the comparison with structural modeling. We therefore present a complete first-principles modeling approach that explores the gas-phase structure of chromophore-grafted peptides and achieves accurate predictions of FRET efficiencies. We apply the approach to amyloid-β 12-28 fragments, known to be involved in amyloid plaque formation connected to Alzheimer's disease. We sample structures of the peptides that are grafted with 5-carboxyrhodamine 575 (Rh575) and QSY-7 chromophores by means of replica-exchange molecular dynamics simulations upon an Amber-type forcefield parametrization as a function of the charge state. The generated ensembles provide chromophore-distance and -orientation distributions which are used with the spectral parameters of the Rh575/QSY-7 chromophores to model FRET-efficiencies for the systems. The theoretical values agree with the experimental average "action"-FRET efficiencies and motivate to use the herein reported parametrization, sampling, and FRET-modeling technique in future studies on the structural properties and aggregation-behavior of related systems.

  12. Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease

    OpenAIRE

    Lian, Hong; Litvinchuk, Alexandra; Chiang, Angie C.-A.; Aithmitti, Nadia; Jankowsky, Joanna L.; Zheng, Hui

    2016-01-01

    Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron–glia signaling pathway whereby Aβ acts as an upstream activator of astroglial nuclear factor kappa B (NF-κB), leading to the release of complement C3, which acts on the neuronal C3a receptor (C3aR) to influence dendritic morphology and cognitive function. Here we report that astrocytic complement activation also regulates Aβ dynamics in vitro and amyloid...

  13. Vitamin E but not 17B-estradiol protect against vascular toxicity induced by B-amyloid wild type and the Dutch amyploid variant

    OpenAIRE

    Mu??oz L??pez, Francisco Jos??, 1964-; Opazo, Carlos; Gil G??mez, Gabriel; Tapia, Gladys; Fern??ndez, Virginia; Valverde, M A; Nibaldo C Inestrosa

    2002-01-01

    Amyloid ??-peptide (A??) fibril deposition on cerebral vessels produces cerebral amyloid angiopathy that appears in the majority of Alzheimer's disease patients. An early onset of a cerebral amyloid angiopathy variant called hereditary cerebral hemorrhage with amyloidosis of the Dutch type is caused by a point mutation in A?? yielding A??Glu22???Gln. The present study addresses the effect of amyloid fibrils from both wild-type and mutated A?? on vascular cells, as well as the putative protect...

  14. Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Lin Nan

    2011-06-01

    Full Text Available Abstract Background Reactive microglia are associated with β-amyloid (Aβ deposit and clearance in Alzhiemer's Disease (AD. Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear Aβ deposits although they mainly exist in an "activated" state. Oligomeric Aβ (oAβ, a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar Aβ (fAβ. However, the role of the different Aβ forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear. Results We demonstrated that Aβ(1-42 fibrils, not Aβ(1-42 oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oAβ(1-42 not only attenuated fAβ(1-42-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fAβ(1-42. Compared with the fAβ(1-42 treatment, the oAβ(1-42 treatment resulted in a rapid and transient increase in interleukin 1β (IL-1β level and produced higher levels of tumor necrosis factor-α (TNF-α, nitric oxide (NO, prostaglandin E2 (PGE2 and intracellular superoxide anion (SOA. The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fAβ(1-42-induced microglia was decreased by IL-1β, lippolysaccharide (LPS and tert-butyl hydroperoxide (t-BHP. The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC, a nuclear factor-κB (NF-κB inhibitor, and N-acetyl-L-cysteine (NAC, a free radical scavenger. These results suggest that the oAβ-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oAβ(1-42 stimulation reduced the mRNA expression of CD36, integrin β1 (Itgb1, and Ig

  15. A synthetic peptide with the putative iron binding motif of amyloid precursor protein (APP does not catalytically oxidize iron.

    Directory of Open Access Journals (Sweden)

    Kourosh Honarmand Ebrahimi

    Full Text Available The β-amyloid precursor protein (APP, which is a key player in Alzheimer's disease, was recently reported to possess an Fe(II binding site within its E2 domain which exhibits ferroxidase activity [Duce et al. 2010, Cell 142: 857]. The putative ligands of this site were compared to those in the ferroxidase site of ferritin. The activity was indirectly measured using transferrin, which scavenges the Fe(III product of the reaction. A 22-residue synthetic peptide, named FD1, with the putative ferroxidase site of APP, and the E2 domain of APP were each reported to exhibit 40% of the ferroxidase activity of APP and of ceruloplasmin. It was also claimed that the ferroxidase activity of APP is inhibited by Zn(II just as in ferritin. We measured the ferroxidase activity indirectly (i by the incorporation of the Fe(III product of the ferroxidase reaction into transferrin and directly (ii by monitoring consumption of the substrate molecular oxygen. The results with the FD1 peptide were compared to the established ferroxidase activities of human H-chain ferritin and of ceruloplasmin. For FD1 we observed no activity above the background of non-enzymatic Fe(II oxidation by molecular oxygen. Zn(II binds to transferrin and diminishes its Fe(III incorporation capacity and rate but it does not specifically bind to a putative ferroxidase site of FD1. Based on these results, and on comparison of the putative ligands of the ferroxidase site of APP with those of ferritin, we conclude that the previously reported results for ferroxidase activity of FD1 and - by implication - of APP should be re-evaluated.

  16. Hydrodynamic effects on β-amyloid (16-22) peptide aggregation

    Science.gov (United States)

    Chiricotto, Mara; Melchionna, Simone; Derreumaux, Philippe; Sterpone, Fabio

    2016-07-01

    Computer simulations based on simplified representations are routinely used to explore the early steps of amyloid aggregation. However, when protein models with implicit solvent are employed, these simulations miss the effect of solvent induced correlations on the aggregation kinetics and lifetimes of metastable states. In this work, we apply the multi-scale Lattice Boltzmann Molecular Dynamics technique (LBMD) to investigate the initial aggregation phases of the amyloid Aβ16-22 peptide. LBMD includes naturally hydrodynamic interactions (HIs) via a kinetic on-lattice representation of the fluid kinetics. The peptides are represented by the flexible OPEP coarse-grained force field. First, we have tuned the essential parameters that control the coupling between the molecular and fluid evolutions in order to reproduce the experimental diffusivity of elementary species. The method is then deployed to investigate the effect of HIs on the aggregation of 100 and 1000 Aβ16-22 peptides. We show that HIs clearly impact the aggregation process and the fluctuations of the oligomer sizes by favouring the fusion and exchange dynamics of oligomers between aggregates. HIs also guide the growth of the leading largest cluster. For the 100 Aβ16-22 peptide system, the simulation of ˜300 ns allowed us to observe the transition from ellipsoidal assemblies to an elongated and slightly twisted aggregate involving almost the totality of the peptides. For the 1000 Aβ16-22 peptides, a system of unprecedented size at quasi-atomistic resolution, we were able to explore a branched disordered fibril-like structure that has never been described by other computer simulations, but has been observed experimentally.

  17. Fibrils from designed non-amyloid-related synthetic peptides induce AA-amyloidosis during inflammation in an animal model.

    Directory of Open Access Journals (Sweden)

    Per Westermark

    Full Text Available BACKGROUND: Mouse AA-amyloidosis is a transmissible disease by a prion-like mechanism where amyloid fibrils act by seeding. Synthetic peptides with no amyloid relationship can assemble into amyloid-like fibrils and these may have seeding capacity for amyloid proteins. PRINCIPAL FINDINGS: Several synthetic peptides, designed for nanotechnology, have been examined for their ability to produce fibrils with Congo red affinity and concomitant green birefringence, affinity for thioflavin S and to accelerate AA-amyloidosis in mice. It is shown that some amphiphilic fibril-forming peptides not only produced Congo red birefringence and showed affinity for thioflavin S, but they also shortened the lag phase for systemic AA-amyloidosis in mice when they were given intravenously at the time of inflammatory induction with silver nitride. Peptides, not forming amyloid-like fibrils, did not have such properties. CONCLUSIONS: These observations should caution researchers and those who work with synthetic peptides and their derivatives to be aware of the potential health concerns.

  18. Transcriptional regulation of human FE65, a ligand of Alzheimer's disease amyloid precursor protein, by Sp1.

    LENUS (Irish Health Repository)

    Yu, Hoi-Tin

    2010-03-01

    FE65 is a neuronal-enriched adaptor protein that binds to the Alzheimer\\'s disease amyloid precursor protein (APP). FE65 forms a transcriptionally active complex with the APP intracellular domain (AICD). The precise gene targets for this complex are unclear but several Alzheimer\\'s disease-linked genes have been proposed. Additionally, evidence suggests that FE65 influences APP metabolism. The mechanism by which FE65 expression is regulated is as yet unknown. To gain insight into the regulatory mechanism, we cloned a 1.6 kb fragment upstream of the human FE65 gene and found that it possesses particularly strong promoter activity in neurones. To delineate essential regions in the human FE65 promoter, a series of deletion mutants were generated. The minimal FE65 promoter was located between -100 and +5, which contains a functional Sp1 site. Overexpression of the transcription factor Sp1 potentiates the FE65 promoter activity. Conversely, suppression of the FE65 promoter was observed in cells either treated with an Sp1 inhibitor or in which Sp1 was knocked down. Furthermore, reduced levels of Sp1 resulted in downregulation of endogenous FE65 mRNA and protein. These findings reveal that Sp1 plays a crucial role in transcriptional control of the human FE65 gene.

  19. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

    Science.gov (United States)

    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 amyloidpeptide 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.

  20. Brain ischemia with Alzheimer phenotype dysregulates Alzheimer's disease-related proteins.

    Science.gov (United States)

    Ułamek-Kozioł, Marzena; Pluta, Ryszard; Bogucka-Kocka, Anna; Januszewski, Sławomir; Kocki, Janusz; Czuczwar, Stanisław J

    2016-06-01

    There are evidences for the influence of Alzheimer's proteins on postischemic brain injury. We present here an overview of the published evidence underpinning the relationships between β-amyloid peptide, hyperphosphorylated tau protein, presenilins, apolipoproteins, secretases and neuronal survival/death decisions after ischemia and development of postischemic dementia. The interactions of above molecules and their influence and contribution to final ischemic brain degeneration resulting in dementia of Alzheimer phenotype are reviewed. Generation and deposition of β-amyloid peptide and tau protein pathology are essential factors involved in Alzheimer's disease development as well as in postischemic brain dementia. Postischemic injuries demonstrate that ischemia may stimulate pathological amyloid precursor protein processing by upregulation of β- and γ-secretases and therefore are capable of establishing a vicious cycle. Functional postischemic brain recovery is always delayed and incomplete by an injury-related increase in the amount of the neurotoxic C-terminal of amyloid precursor protein and β-amyloid peptide. Finally, we present here the concept that Alzheimer's proteins can contribute to and/or precipitate postischemic brain neurodegeneration including dementia with Alzheimer's phenotype. PMID:26940197

  1. Cross-beta order and diversity in nanocrystals of an amyloid-forming peptide.

    Science.gov (United States)

    Diaz-Avalos, Ruben; Long, Chris; Fontano, Eric; Balbirnie, Melinda; Grothe, Robert; Eisenberg, David; Caspar, Donald L D

    2003-07-25

    The seven-residue peptide GNNQQNY from the N-terminal region of the yeast prion protein Sup35, which forms amyloid fibers, colloidal aggregates and highly ordered nanocrystals, provides a model system for characterizing the elusively protean cross-beta conformation. Depending on preparative conditions, orthorhombic and monoclinic crystals with similar lath-shaped morphology have been obtained. Ultra high-resolution (frames, have been mapped in reciprocal space. However, reliable integrated intensities cannot be obtained from these series, and dynamical electron diffraction effects present problems in data analysis. The diversity of ordered structures formed under similar conditions has made it difficult to obtain reproducible X-ray diffraction data from powder specimens; and overlapping Bragg reflections in the powder patterns preclude separated structure factor measurements for these data. Model protofilaments, consisting of tightly paired, half-staggered beta strands related by a screw axis, can be fit in the crystal lattices, but model refinement will require accurate structure factor measurements. Nearly anhydrous packing of this hydrophilic peptide can account for the insolubility of the crystals, since the activation energy for rehydration may be extremely high. Water-excluding packing of paired cross-beta peptide segments in thin protofilaments may be characteristic of the wide variety of anomalously stable amyloid aggregates. PMID:12860136

  2. Indexing amyloid peptide diffraction from serial femtosecond crystallography: new algorithms for sparse patterns

    Energy Technology Data Exchange (ETDEWEB)

    Brewster, Aaron S. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Sawaya, Michael R. [University of California, Los Angeles, CA 90095-1570 (United States); University of California, Los Angeles, CA 90095-1570 (United States); University of California, Los Angeles, CA 90095-1570 (United States); Rodriguez, Jose [University of California, Los Angeles, CA 90095-1570 (United States); University of California, Los Angeles, CA 90095-1570 (United States); Hattne, Johan; Echols, Nathaniel [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); McFarlane, Heather T. [University of California, Los Angeles, CA 90095-1570 (United States); University of California, Los Angeles, CA 90095-1570 (United States); Cascio, Duilio [University of California, Los Angeles, CA 90095-1570 (United States); University of California, Los Angeles, CA 90095-1570 (United States); University of California, Los Angeles, CA 90095-1570 (United States); Adams, Paul D. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); University of California, Berkeley, CA 94720 (United States); Eisenberg, David S. [University of California, Los Angeles, CA 90095-1570 (United States); University of California, Los Angeles, CA 90095-1570 (United States); University of California, Los Angeles, CA 90095-1570 (United States); Sauter, Nicholas K., E-mail: nksauter@lbl.gov [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States)

    2015-02-01

    Special methods are required to interpret sparse diffraction patterns collected from peptide crystals at X-ray free-electron lasers. Bragg spots can be indexed from composite-image powder rings, with crystal orientations then deduced from a very limited number of spot positions. Still diffraction patterns from peptide nanocrystals with small unit cells are challenging to index using conventional methods owing to the limited number of spots and the lack of crystal orientation information for individual images. New indexing algorithms have been developed as part of the Computational Crystallography Toolbox (cctbx) to overcome these challenges. Accurate unit-cell information derived from an aggregate data set from thousands of diffraction patterns can be used to determine a crystal orientation matrix for individual images with as few as five reflections. These algorithms are potentially applicable not only to amyloid peptides but also to any set of diffraction patterns with sparse properties, such as low-resolution virus structures or high-throughput screening of still images captured by raster-scanning at synchrotron sources. As a proof of concept for this technique, successful integration of X-ray free-electron laser (XFEL) data to 2.5 Å resolution for the amyloid segment GNNQQNY from the Sup35 yeast prion is presented.

  3. Effects of Amyloid Precursor Protein 17 Peptide on the Protection of Diabetic Encephalopathy and Improvement of Glycol Metabolism in the Diabetic Rat

    OpenAIRE

    Heng Meng; Duo Zhang; Haishan Yang

    2013-01-01

    Researchers have proposed that amyloid precursor protein 17 peptide (APP17 peptide), an active fragment of amyloid precursor protein (APP) in the nervous system, has therapeutic effects on neurodegeneration. Diabetic encephalopathy (DE) is a neurological disease caused by diabetes. Here we use multiple experimental approaches to investigate the effect of APP17 peptide on changes in learning behavior and glycol metabolism in rats. It was found that rats with DE treated by APP17 peptide showed ...

  4. Impairment of context memory by β-amyloid peptide in terrestrial snail

    Directory of Open Access Journals (Sweden)

    2008-09-01

    Full Text Available We examined influence of the β-amyloid peptide (25-35 neurotoxic fragment (βAP on Helix lucorum food-aversion learning. Testing with aversively conditioned carrot showed that 2, 5, and 14 days after training the βAP-injected group responded in a significantly larger number of cases and with a significantly smaller latency than the sham-injected control group. The results demonstrate that the amyloid peptide partially impairs the learning process. In an attempt to specify what component of memory is impaired we compared responses in a context in which the snails were aversively trained, and in a neutral context. It was found that the sham-injected learned snails significantly less frequently took the aversively conditioned food in the context in which the snails were shocked, while the βAP-injected snails remembered the aversive context 2 days after associative training, but were not able to distinguish two contexts 5, and 14 days after training. In a separate series of experiments a specific context was associated with electric shock, and changes in general responsiveness were tested in two contexts several days later. It was found that the βAP-injected snails significantly increased withdrawal responses in all tested contexts, while the sham-injected control animals selectively increased responsiveness only in the context in which they were reinforced with electric shocks. These results demonstrate that the β-amyloid peptide (25-35 interferes with the learning process, and may play a significant role in behavioral plasticity and memory by selectively impairing only one

  5. Penetratin Peptide-Functionalized Gold Nanostars: Enhanced BBB Permeability and NIR Photothermal Treatment of Alzheimer's Disease Using Ultralow Irradiance.

    Science.gov (United States)

    Yin, Tiantian; Xie, Wenjie; Sun, Jing; Yang, Licong; Liu, Jie

    2016-08-01

    The structural changes of amyloid-beta (Aβ) from nontoxic monomers into neurotoxic aggregates are implicated with pathogenesis of Alzheimer's disease (AD). Over the past decades, weak disaggregation ability and low permeability to the blood-brain barrier (BBB) may be the main obstacles for major Aβ aggregation blockers. Here, we synthesized penetratin (Pen) peptide loaded poly(ethylene glycol) (PEG)-stabilized gold nanostars (AuNS) modified with ruthenium complex (Ru@Pen@PEG-AuNS), and Ru(II) complex as luminescent probes for tracking drug delivery. We revealed that Ru@Pen@PEG-AuNS could obviously inhibit the formation of Aβ fibrils as well as dissociate preformed fibrous Aβ under the irradiation of near-infrared (NIR) due to the NIR absorption characteristic of AuNS. More importantly, this novel design could be applied in medicine as an appropriate nanovehicle, being highly biocompatible and hemocompatible. In addition, Ru@Pen@PEG-AuNS had excellent neuroprotective effect on the Aβ-induced cellular toxicity by applying NIR irradiation. Meanwhile, Pen peptide could effectively improve the delivery of nanoparticles to the brain in vitro and in vivo, which overcame the major limitation of Aβ aggregation blockers. These consequences illustrated that the enhanced BBB permeability and efficient photothermolysis of Ru@Pen@PEG-AuNS are promising agents in AD therapy. PMID:27411476

  6. Detection of amyloid in Alzheimer's disease with positron emission tomography using [{sup 11}C]AZD2184

    Energy Technology Data Exchange (ETDEWEB)

    Nyberg, Svante; Cselenyi, Zsolt; Julin, Per; Olsson, Hans; Svensson, Samuel [AstraZeneca R and D, Neuroscience Therapy Area, Soedertaelje (Sweden); Eriksdotter Joenhagen, Maria; Freund-Levi, Yvonne [Karolinska University Hospital Huddinge, NVS Department, Karolinska Institute, Huddinge (Sweden); Halldin, Christer; Andersson, Jan; Varnaes, Katarina [Karolinska Institutet, Karolinska University Hospital, PET Centre, Department of Clinical Neuroscience, Stockholm (Sweden); Farde, Lars [AstraZeneca R and D, Neuroscience Therapy Area, Soedertaelje (Sweden); Karolinska Institutet, Karolinska University Hospital, PET Centre, Department of Clinical Neuroscience, Stockholm (Sweden)

    2009-11-15

    Current positron emission tomography (PET) radioligands for detection of A{beta} amyloid in Alzheimer's disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [{sup 11}C]AZD2184 and report here the first clinical evaluation. Eight AD patients and four younger control subjects underwent 93-min PET measurements with [{sup 11}C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters. Brain uptake of [{sup 11}C]AZD2184 peaked within 1 min at 3-4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57. [{sup 11}C]AZD2184 is a promising radioligand for detailed mapping of A{beta} amyloid depositions in Alzheimer's disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium. (orig.)

  7. Increased efflux of amyloidpeptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis.

    Science.gov (United States)

    Paganetti, Paolo; Antoniello, Katia; Devraj, Kavi; Toni, Nicolas; Kieran, Dairin; Madani, Rime; Pihlgren, Maria; Adolfsson, Oskar; Froestl, Wolfgang; Schrattenholz, André; Liebner, Stefan; Havas, Daniel; Windisch, Manfred; Cirrito, John R; Pfeifer, Andrea; Muhs, Andreas

    2014-01-01

    The formation and accumulation of toxic amyloidpeptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Brain (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects. PMID:24072071

  8. Mild oxidative stress induces redistribution of BACE1 in non-apoptotic conditions and promotes the amyloidogenic processing of Alzheimer's disease amyloid precursor protein.

    Directory of Open Access Journals (Sweden)

    Jiang-Li Tan

    Full Text Available BACE1 is responsible for β-secretase cleavage of the amyloid precursor protein (APP, which represents the first step in the production of amyloid β (Aβ peptides. Previous reports, by us and others, have indicated that the levels of BACE1 protein and activity are increased in the brain cortex of patients with Alzheimer's disease (AD. The association between oxidative stress (OS and AD has prompted investigations that support the potentiation of BACE1 expression and enzymatic activity by OS. Here, we have established conditions to analyse the effects of mild, non-lethal OS on BACE1 in primary neuronal cultures, independently from apoptotic mechanisms that were shown to impair BACE1 turnover. Six-hour treatment of mouse primary cortical cells with 10-40 µM hydrogen peroxide did not significantly compromise cell viability but it did produce mild oxidative stress (mOS, as shown by the increased levels of reactive radical species and activation of p38 stress kinase. The endogenous levels of BACE1 mRNA and protein were not significantly altered in these conditions, whereas a toxic H2O2 concentration (100 µM caused an increase in BACE1 protein levels. Notably, mOS conditions resulted in increased levels of the BACE1 C-terminal cleavage product of APP, β-CTF. Subcellular fractionation techniques showed that mOS caused a major rearrangement of BACE1 localization from light to denser fractions, resulting in an increased distribution of BACE1 in fractions containing APP and markers for trans-Golgi network and early endosomes. Collectively, these data demonstrate that mOS does not modify BACE1 expression but alters BACE1 subcellular compartmentalization to favour the amyloidogenic processing of APP, and thus offer new insight in the early molecular events of AD pathogenesis.

  9. In vivo detection of amyloid-β deposits using heavy chain antibody fragments in a transgenic mouse model for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Rob J A Nabuurs

    Full Text Available This study investigated the in vivo properties of two heavy chain antibody fragments (V(HH, ni3A and pa2H, to differentially detect vascular or parenchymal amyloid-β deposits characteristic for Alzheimer's disease and cerebral amyloid angiopathy. Blood clearance and biodistribution including brain uptake were assessed by bolus injection of radiolabeled V(HH in APP/PS1 mice or wildtype littermates. In addition, in vivo specificity for Aβ was examined in more detail with fluorescently labeled V(HH by circumventing the blood-brain barrier via direct application or intracarotid co-injection with mannitol. All V(HH showed rapid renal clearance (10-20 min. Twenty-four hours post-injection (99mTc-pa2H resulted in a small yet significant higher cerebral uptake in the APP/PS1 animals. No difference in brain uptake were observed for (99mTc-ni3A or DTPA((111In-pa2H, which lacked additional peptide tags to investigate further clinical applicability. In vivo specificity for Aβ was confirmed for both fluorescently labeled V(HH, where pa2H remained readily detectable for 24 hours or more after injection. Furthermore, both V(HH showed affinity for parenchymal and vascular deposits, this in contrast to human tissue, where ni3A specifically targeted only vascular Aβ. Despite a brain uptake that is as yet too low for in vivo imaging, this study provides evidence that V(HH detect Aβ deposits in vivo, with high selectivity and favorable in vivo characteristics, making them promising tools for further development as diagnostic agents for the distinctive detection of different Aβ deposits.

  10. In vivo detection of amyloid-β deposits using heavy chain antibody fragments in a transgenic mouse model for Alzheimer's disease.

    Science.gov (United States)

    Nabuurs, Rob J A; Rutgers, Kim S; Welling, Mick M; Metaxas, Athanasios; de Backer, Maaike E; Rotman, Maarten; Bacskai, Brian J; van Buchem, Mark A; van der Maarel, Silvère M; van der Weerd, Louise

    2012-01-01

    This study investigated the in vivo properties of two heavy chain antibody fragments (V(H)H), ni3A and pa2H, to differentially detect vascular or parenchymal amyloid-β deposits characteristic for Alzheimer's disease and cerebral amyloid angiopathy. Blood clearance and biodistribution including brain uptake were assessed by bolus injection of radiolabeled V(H)H in APP/PS1 mice or wildtype littermates. In addition, in vivo specificity for Aβ was examined in more detail with fluorescently labeled V(H)H by circumventing the blood-brain barrier via direct application or intracarotid co-injection with mannitol. All V(H)H showed rapid renal clearance (10-20 min). Twenty-four hours post-injection (99m)Tc-pa2H resulted in a small yet significant higher cerebral uptake in the APP/PS1 animals. No difference in brain uptake were observed for (99m)Tc-ni3A or DTPA((111)In)-pa2H, which lacked additional peptide tags to investigate further clinical applicability. In vivo specificity for Aβ was confirmed for both fluorescently labeled V(H)H, where pa2H remained readily detectable for 24 hours or more after injection. Furthermore, both V(H)H showed affinity for parenchymal and vascular deposits, this in contrast to human tissue, where ni3A specifically targeted only vascular Aβ. Despite a brain uptake that is as yet too low for in vivo imaging, this study provides evidence that V(H)H detect Aβ deposits in vivo, with high selectivity and favorable in vivo characteristics, making them promising tools for further development as diagnostic agents for the distinctive detection of different Aβ deposits. PMID:22675537

  11. Radioiodinated benzimidazole derivatives as single photon emission computed tomography probes for imaging of β-amyloid plaques in Alzheimer's disease

    International Nuclear Information System (INIS)

    Five iodinated 2-phenyl-1H-benzo[d]imidazole derivatives were synthesized and evaluated as potential probes for β-amyloid (Aβ) plaques. One of the compounds, 4-(6-iodo-1H-benzo[d]imidazol-2-yl)-N,N-dimethylaniline (12), showed excellent affinity for Aβ1-42 aggregates (Ki=9.8 nM). Autoradiography with sections of postmortem Alzheimer's disease (AD) brain revealed that a radioiodinated probe [125I]12, labeled Aβ plaques selectively with low nonspecific binding. Biodistribution experiments with normal mice injected intravenously with [125I]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 Aβ plaques. In addition, [125I]12 labeled amyloid plaques in vivo in an AD transgenic model. The preliminary results strongly suggest that [125I]12 bears characteristics suitable for detecting amyloid plaques in vivo. When labeled with 123I, it may be a useful SPECT imaging agent for Aβ plaques in the brain of living AD patients.

  12. Amyloidpeptides time-dependent structural modifications: AFM and voltammetric characterization.

    Science.gov (United States)

    Enache, Teodor Adrian; Chiorcea-Paquim, Ana-Maria; Oliveira-Brett, Ana Maria

    2016-07-01

    The human amyloid beta (Aβ) peptides, Aβ1-40 and Aβ1-42, structural modifications, from soluble monomers to fully formed fibrils through intermediate structures, were investigated, and the results were compared with those obtained for the inverse Aβ40-1 and Aβ42-1, mutant Aβ1-40Phe(10) and Aβ1-40Nle(35), and rat Aβ1-40Rat peptide sequences. The aggregation was followed at a slow rate, in chloride free media and room temperature, and revealed to be a sequence-structure process, dependent on the physicochemical properties of each Aβ peptide isoforms, and occurring at different rates and by different pathways. The fibrilization process was investigated by atomic force microscopy (AFM), via changes in the adsorption morphology from: (i) initially random coiled structures of ∼0.6 nm height, corresponding to the Aβ peptide monomers in random coil or in α-helix conformations, to (ii) aggregates and protofibrils of 1.5-6.0 nm height and (iii) two types of fibrils, corresponding to the Aβ peptide in a β-sheet configuration. The reactivity of the carbon electrode surface was considered. The hydrophobic surface induced rapid changes of the Aβ peptide conformations, and differences between the adsorbed fibrils, formed at the carbon surface (beaded, thin, 2.0 nm height), were detected. Differential pulse voltammetry showed that, according to their primary structure, the Aβ peptides undergo oxidation in one or two steps, the first step corresponding to the tyrosine amino acids oxidation, and the second one to the histidine and methionine amino acids oxidation. The fibrilization process was electrochemically detected via the decrease of the Aβ peptide oxidation peak currents that occurred in a time dependent manner. PMID:27216391

  13. 99mTc-MAMA-chrysamine G, a probe for beta-amyloid protein of Alzheimer's disease

    International Nuclear Information System (INIS)

    Chrysamine G (CG), an analogue of Congo red, is known to bind in vitro to the β-amyloid protein (Aβ 10-43) and to homogenates of several regions of the brain of Alzheimer's disease (AD) patients. We synthesised a conjugate of 2-(acetamido)-CG with a bis-S-trityl protected monoamide-monoaminedithiol (MAMA-Tr2) tetraligand, which was efficiently deprotected and labelled with a 75% yield with technetium-99m, to obtain 99mTc-MAMA-CG. In mice, 99mTc-MAMA-CG was cleared mainly by the hepatobiliary system, resulting in a fast blood clearance. Brain uptake of 99mTc-MAMA-CG was low. Co-injection with the blood pool tracer iodine-125 human serum albumin (125I-HSA) demonstrated a brain/blood activity ratio for 99mTc-MAMA-CG that was significantly higher than that for 125I-HSA (t test for dependent samples, P99mTc-MAMA-CG to cross the blood-brain barrier. In vitro autoradiography demonstrated pronounced binding of 99mTc-MAMA-CG to β-amyloid deposits in autopsy sections of the parietal and occipital cortex of an AD patient as compared with controls. Adding 10 μM Congo red during incubation displaced the binding of 99mTc-MAMA-CG. Congo red staining and autoradiography identified the same lesions. 99mTc-MAMA-CG seems to bind selectively to β-amyloid deposition in human brain parenchyma and blood vessels in vitro and thus might be a lead compound for further development of a useful tracer agent for the in vivo diagnosis of Alzheimer's disease. (orig.)

  14. Protective effects of Lingguizhugan decoction on amyloid-beta peptide (25-35)-induced cell injury: Anti-inflammatory effects☆

    OpenAIRE

    Xi, Feifei; Sang, Feng; Zhou, Chunxiang; Ling, Yun

    2012-01-01

    In the present study, a human neuroblastoma cell line (SH-SY5Y) and BV-2 microglia were treated with amyloidpeptide (25–35), as a model of Alzheimer’s disease, to evaluate the protective effects of 10-3–10-8 g/mL Lingguizhugan decoction and to examine the underlying anti-inflammatory mechanism. Lingguizhugan decoction significantly enhanced the viability of SH-SY5Y cells with amyloidpeptide-induced injury, and lowered levels of interleukin-1β, interleukin-6, tumor necrosis factor-α and ...

  15. Amyloid-beta peptide degradation in cell cultures by mycoplasma contaminants

    Directory of Open Access Journals (Sweden)

    Davies Peter

    2008-06-01

    Full Text Available Abstract Background Cell cultures have become an indispensable tool in Alzheimer's disease research for studying amyloid-β (Aβ metabolism. It is estimated that up to 35% of cell cultures in current use are infected with various mycoplasma species. In contrast with common bacterial and fungal infections, contaminations of cell cultures with mycoplasmas represent a challenging issue in terms of detectability and prevention. Mycoplasmas are the smallest and simplest self-replicating bacteria and the consequences of an infection for the host cells are variable, ranging from no apparent effect to induction of apoptosis. Findings Here we present evidence that mycoplasmas from a cell culture contamination are able to efficiently and rapidly degrade extracellular Aβ. As a result, we observed no accumulation of Aβ in the conditioned medium of mycoplasma-positive cells stably transfected with the amyloid-β precursor protein (APP. Importantly, eradication of the mycoplasma contaminant – identified as M. hyorhinis – by treatments with a quinolone-based antibiotic, restored extracellular Aβ accumulation in the APP-transfected cells. Conclusion These data show that mycoplasmas degrade Aβ and thus may represent a significant source of variability when comparing extracellular Aβ levels in different cell lines. On the basis of these results, we recommend assessment of mycoplasma contaminations prior to extracellular Aβ level measurements in cultured cells.

  16. The AmyloidPeptide of Alzheimer’s Disease Binds CuI in a Linear Bis-His Coordination Environment: Insight into a Possible Neuroprotective Mechanism for the AmyloidPeptide

    Energy Technology Data Exchange (ETDEWEB)

    Shearer, J.; Szalai, V

    2008-01-01

    Oxidative stress has been suggested to contribute to neuronal apoptosis associated with Alzheimer's disease (AD). Copper may participate in oxidative stress through redox-cycling between its +2 and +1 oxidation states to generate reactive oxygen species (ROS). In vitro, copper binds to the amyloid-? peptide of AD, and in vivo, copper is associated with amyloid plaques characteristic of AD. As a result, the A?CuI complex may be a critical reactant involved in ROS associated with AD etiology. To characterize the A?CuI complex, we have pursued X-ray absorption (XAS) and electron paramagnetic resonance (EPR) spectroscopy of A?CuII and A?CuI (produced by ascorbate reduction of A?CuII). The A?CuII complex Cu K-edge XAS spectrum is indicative of a square-planar CuII center with mixed N/O ligation. Multiple scattering analysis of the extended X-ray absorption fine structure (EXAFS) data for A?CuII indicates that two of the ligands are imidazole groups of histidine ligands, indicating a (NIm)2(N/O)2 CuII ligation sphere for A?CuII. After reduction of the A?CuII complex with ascorbate, the edge region decreases in energy by 4 eV. The X-ray absorption near-edge spectrum region of A?CuI displays an intense pre-edge feature at 8984.1(2) eV. EXAFS data fitting yielded a two-coordinate geometry, with two imidazole ligands coordinated to CuI at 1.877(2) A in a linear geometry. Ascorbate reduction of A?CuII under inert atmosphere and subsequent air oxidation of A?CuI to regenerate A?CuII was monitored by low-temperature EPR spectroscopy. Slow reappearance of the A?CuII EPR signal indicates that O2 oxidation of the A?CuI complex is kinetically sluggish and A? damage is occurring following reoxidation of A?CuI by O2. Together, these results lead us to hypothesize that CuI is ligated by His13 and His14 in a linear coordination environment in ??, that A? may be playing a neuroprotective role, and that metal-mediated oxidative damage of A? occurs over multiple redox cycles.

  17. A new molecular model for Congo Red-β amyloid interaction: implications for diagnosis and inhibition of brain plaque formation in Alzheimer's disease

    Science.gov (United States)

    Zhang, Kristine A.; Li, Yat

    2015-08-01

    Alzheimer's disease (AD), an age-related neurodegenerative disorder, is the seventh leading cause of death in the United States. One strong pathological indicator of AD is senile plaques, which are aggregates of fibrils formed from amyloid β (Aβ) peptides. Thus, detection and inhibition of Aβ aggregation are critical for the prevention and treatment of AD. Congo red (CR) is one of the most widely used dye molecules for probing as well as inhabiting Aβ aggregation. However, the nature of interaction between CR and Aβ is not well understood. In this research, we systematically studied the interaction between CR and Aβ using a combination of optical techniques, including electronic absorption, fluorescence, Raman scattering, and circular dichroism, to provide detailed information with molecular specificity and high sensitivity. Compared to CR alone, interaction of the dye with Aβ results in a new absorption peak near 540 nm and significantly enhanced photoluminescence as well as Raman signal. Our results led us to propose a new model suggesting that CR exists primarily in a micellar form, resembling H-aggregates, in water and dissociates into monomers upon interaction with Aβ. This model has significant implications for the development of new strategies to detect and inhibit brain plaques for treatment of neurological diseases like AD.

  18. Curcumin-conjugated magnetic nanoparticles for detecting amyloid plaques in Alzheimer's disease mice using magnetic resonance imaging (MRI).

    Science.gov (United States)

    Cheng, Kwok Kin; Chan, Pui Shan; Fan, Shujuan; Kwan, Siu Ming; Yeung, King Lun; Wáng, Yì-Xiáng J; Chow, Albert Hee Lum; Wu, Ed X; Baum, Larry

    2015-03-01

    Diagnosis of Alzheimer's disease (AD) can be performed with the assistance of amyloid imaging. The current method relies on positron emission tomography (PET), which is expensive and exposes people to radiation, undesirable features for a population screening method. Magnetic resonance imaging (MRI) is cheaper and is not radioactive. Our approach uses magnetic nanoparticles (MNPs) made of superparamagnetic iron oxide (SPIO) conjugated with curcumin, a natural compound that specifically binds to amyloid plaques. Coating of curcumin-conjugated MNPs with polyethylene glycol-polylactic acid block copolymer and polyvinylpyrrolidone by antisolvent precipitation in a multi-inlet vortex mixer produces stable and biocompatible curcumin magnetic nanoparticles (Cur-MNPs) with mean diameter microscopy and atomic force microscopy, and their structure and chemistry were further characterized by X-ray diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectrometry, and Fourier transform infrared spectroscopy. Cur-MNPs exhibited no cytotoxicity in either Madin-Darby canine kidney (MDCK) or differentiated human neuroblastoma cells (SH-SY5Y). The Papp of Cur-MNPs was 1.03 × 10(-6) cm/s in an in vitro blood-brain barrier (BBB) model. Amyloid plaques could be visualized in ex vivo T2*-weighted magnetic resonance imaging (MRI) of Tg2576 mouse brains after injection of Cur-MNPs, and no plaques could be found in non-transgenic mice. Immunohistochemical examination of the mouse brains revealed that Cur-MNPs were co-localized with amyloid plaques. Thus, Cur-MNPs have the potential for non-invasive diagnosis of AD using MRI. PMID:25617135

  19. Curcumin Improves Amyloid β-Peptide (1-42) Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway

    OpenAIRE

    Lu Zhang; Yu Fang; Yuming Xu; Yajun Lian; Nanchang Xie; Tianwen Wu; Haifeng Zhang; Limin Sun; Ruifang Zhang; Zhenhua Wang

    2015-01-01

    Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects. Previous studies have suggested that curcumin reduces the levels of amyloid and oxidized proteins and prevents memory deficits and thus is beneficial to patients with Alzheimer's disease (AD). However, the molecular mechanisms underlying curcumin's effect on cognitive functions are not well-understood. In the present study, we examined the working ...

  20. Alzheimer disease : presenilin springs a leak

    NARCIS (Netherlands)

    Gandy, S.; Doeven, M.K.; Poolman, B.

    2006-01-01

    Presenilins are thought to contribute to Alzheimer disease through a protein cleavage reaction that produces neurotoxic amyloid-beta peptides. A new function for presenilins now comes to light - controlling the leakage of calcium out of the endoplasmic reticulum. Is this a serious challenge to the '

  1. Research Sheds Light on Mechanism of Alzheimer's Disease

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    @@ Scientists from the Shanghai Institute of Materia Medica (SIMM) under the CAS Shanghai Institutes for Biological Sciences have made significant progress in suggesting a possible mechanism for the accumulation of amyloid β-peptides (Aβs), which are believed to cause Alzheimer's disease. Aβs are fragments of a protein that is snipped from another protein called amyloid precursor protein (APP). In a healthy brain, these protein fragments would be broken down and eliminated. In Alzheimer's disease, unfortunately, the fragments accumulate to form hard, insoluble plaques, which are the characteristic lesions found in Alzheimer's patients and could dramatically inhibit several genes critical to memory and learning.

  2. Expression of secreted human single-chain fragment variable antibody against human amyloid beta peptide in Pichia pastoris

    Institute of Scientific and Technical Information of China (English)

    Jiong Cai; Fang Li; Shizhen Wang

    2008-01-01

    BACKGROUND: Studies have shown that monoclonal or polyclonal antibody injections ofamyloid β peptide arc effective in removing amyloid β peptide overload in the brain.OBJECTIVE: Based on successful screening of a human single-chain fragment variable antibody specific to amyloid β peptide, this paper aimed to express recombinant human single-chain variable antibody against amyloid β peptide.DESIGN, TIME AND SETTING: A single sample experiment was performed at the Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Hospital (Beijing, China) from January to July 2006.MATERIALS: Human single-chain fragment variable antibody gene against amyloid β peptide was screened from a human phage-display antibody library.METHODS: Human single-chain fragment variable antibody gene was mutated to eliminate a BamHI restriction site and cloned into a Teasy plasmid for pT-seFvAβ construction, which was identified by PCR amplification and endonuclease digestion. Plasmid pT-scFvA β was cut by EcoRl and Notl endonucleases, and the antibody gene was cloned into pPIC9K plasmid to construct pPIC9K-scFvA β expression vector, which was confirmed by gene sequencing. Linearized pPICgK-scFvA β was used to transform a Pichia pastoris GS115 cell line, and the recombinant was induced by 0.5 % methanol to express human single-chain fragment variable antibody specific to amyloid β peptide.MAIN OUTCOME MEASURES: Protein electrophoresis was used to identify PCR products, gene sequencing was uscd to verify the pPIC9K-scFvA sequence, and SDS-PAGE was used to detect recombinant expression of human single-chain fragment variable antibody specific to amyloid β peptide in Pichia pastoris.RESULTS: Gene sequencing confirmed pPICgK-scFvA β orientation. Rccomhinants were obtained by lineadzed pPIC9K-scFvA β transformation. After induction with 0.5% methanol, the recombinant yeast cells secreted proteins of 33-ku size

  3. Iron and aluminum interaction with amyloid-beta peptides associated with Alzheimer’s disease

    International Nuclear Information System (INIS)

    An elevation in the concentration of heavy metal ions in Alzheimer’s disease (AD) brain has been demonstrated in many studies. Aβ precipitation and toxicity in AD brains seem to be caused by abnormal interactions with neocortical metal ions, especially iron, copper, zinc, and aluminum [1–3]. There is increasing evidence that iron and aluminum ions are involved in the mechanisms that underlie the neurodegenerative diseases [4,5]. However, evidence was brought to demonstrate that some Aβ fragments, at physiological pH, are not able to form binary complexes with Fe(III) ions of sufficient stability to compete with metal hydroxide precipitation [6]. On the contrary, multiple metal ions are known to interact with Aβ peptides [7]. Consequently, we investigated here the interaction of Fe(II/III) and Al(III) ions with some amyloidpeptides and fragments that results in peptide aggregation and fibrillation [8,9]. Infrared spectroscopy, atomic force microscopy, scanning electron microscopy, electrophoresis and mass spectrometry demonstrated conformational changes of peptides in the presence of such metals

  4. Iron and aluminum interaction with amyloid-beta peptides associated with Alzheimer’s disease

    Energy Technology Data Exchange (ETDEWEB)

    Drochioiu, Gabi; Ion, Laura [Alexandru Ioan Cuza University of Iasi, 11 Carol I, Iasi 700506 (Romania); Murariu, Manuela; Habasescu, Laura [Petru Poni Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, Iasi 700487 (Romania)

    2014-10-06

    An elevation in the concentration of heavy metal ions in Alzheimer’s disease (AD) brain has been demonstrated in many studies. Aβ precipitation and toxicity in AD brains seem to be caused by abnormal interactions with neocortical metal ions, especially iron, copper, zinc, and aluminum [1–3]. There is increasing evidence that iron and aluminum ions are involved in the mechanisms that underlie the neurodegenerative diseases [4,5]. However, evidence was brought to demonstrate that some Aβ fragments, at physiological pH, are not able to form binary complexes with Fe(III) ions of sufficient stability to compete with metal hydroxide precipitation [6]. On the contrary, multiple metal ions are known to interact with Aβ peptides [7]. Consequently, we investigated here the interaction of Fe(II/III) and Al(III) ions with some amyloidpeptides and fragments that results in peptide aggregation and fibrillation [8,9]. Infrared spectroscopy, atomic force microscopy, scanning electron microscopy, electrophoresis and mass spectrometry demonstrated conformational changes of peptides in the presence of such metals.

  5. Increased expression and local accumulation of the Prion Protein, Alzheimerpeptides, superoxide dismutase 1, and Nitric oxide synthases 1 & 2 in muscle in a rabbit model of diabetes

    Directory of Open Access Journals (Sweden)

    Bitel Claudine L

    2010-09-01

    Full Text Available Abstract Background Muscle disease associated with different etiologies has been shown to produce localized accumulations of amyloid and oxidative stress-related proteins that are more commonly associated with neurodegeneration in the brain. In this study we examined changes in muscle tissue in a classic model of diabetes and hyperglycemia in rabbits to determine if similar dysregulation of Alzheimerpeptides, the prion protein (PrP, and superoxide dismutase 1 (SOD1, as well as nitric oxide synthases is produced in muscle in diabetic animals. This wild-type rabbit model includes systemic physiological expression of human-like Alzheimer precursor proteins and Aβ peptides that are considered key in Alzheimer protein studies. Results Diabetes was produced in rabbits by injection of the toxic glucose analogue alloxan, which selectively enters pancreatic beta cells and irreversibly decreases insulin production, similar to streptozotocin. Quadriceps muscle from rabbits 16 wks after onset of diabetes and hyperglycemia were analyzed with biochemical and in situ methods. Immunoblots of whole muscle protein samples demonstrated increased PrP, SOD1, as well as neuronal and inducible Nitric oxide synthases (NOS1 and NOS2 in diabetic muscle. In contrast, we detected little change in Alzheimer Aβ precursor protein expression, or BACE1 and Presenilin 1 levels. However, Aβ peptides measured by ELISA increased several fold in diabetic muscle, suggesting a key role for Aβ cleavage in muscle similar to Alzheimer neurodegeneration in this diabetes model. Histological changes in diabetic muscle included localized accumulations of PrP, Aβ, NOS1 and 2, and SOD1, and evidence of increased central nuclei and cell infiltration. Conclusions The present study provides evidence that several classic amyloid and oxidative stress-related disease proteins coordinately increase in overall expression and form localized accumulations in diabetic muscle. The present study

  6. Dynamic behavior of small heat shock protein inhibition on amyloid fibrillization of a small peptide (SSTSAA) from RNase A

    International Nuclear Information System (INIS)

    Highlights: ► Mechanism of small heat shock protein inhibition on fibril formation was studied. ► Peptide SSTSAA with modified ends was used for amyloid fibril formation. ► FRET signal was followed during the fibril formation. ► Mj HSP16.5 inhibits fibril formation when introduced in the lag phase. ► Mj HSP16.5 slows down fibril formation when introduced after the lag phase. -- Abstract: Small heat shock proteins, a class of molecular chaperones, are reported to inhibit amyloid fibril formation in vitro, while the mechanism of inhibition remains unknown. In the present study, we investigated the mechanism by which Mj HSP16.5 inhibits amyloid fibril formation of a small peptide (SSTSAA) from RNase A. A model peptide (dansyl-SSTSAA-W) was designed by introducing a pair of fluorescence resonance energy transfer (FRET) probes into the peptide, allowing for the monitoring of fibril formation by this experimental model. Mj HSP16.5 completely inhibited fibril formation of the model peptide at a molar ratio of 1:120. The dynamic process of fibril formation, revealed by FRET, circular dichroism, and electron microscopy, showed a lag phase of about 2 h followed by a fast growth period. The effect of Mj HSP16.5 on amyloid fibril formation was investigated by adding it into the incubation solution during different growth phases. Adding Mj HSP16.5 to the incubating peptide before or during the lag phase completely inhibited fibril formation. However, introducing Mj HSP16.5 after the lag phase only slowed down the fibril formation process by adhering to the already formed fibrils. These findings provide insight into the inhibitory roles of small heat shock proteins on amyloid fibril formation at the molecular level.

  7. Regulation of adenosine triphosphate-sensitive potassium channels suppresses the toxic effects of amyloid-beta peptide (25-35)

    Institute of Scientific and Technical Information of China (English)

    Min Kong; Maowen Ba; Hui Liang; Peng Shao; Tianxia Yu; Ying Wang

    2013-01-01

    In this study, we treated PC12 cells with 0-20 μM amyloidpeptide (25-35) for 24 hours to induce cytotoxicity, and found that 5-20 μM amyloidpeptide (25-35) decreased PC12 cell viability, but adenosine triphosphate-sensitive potassium channel activator diazoxide suppressed the decrease reactive oxygen species levels. These protective effects were reversed by the selective mitochondrial adenosine triphosphate-sensitive potassium channel blocker 5-hydroxydecanoate. An inducible nitric oxide synthase inhibitor, Nω-nitro-L-arginine, also protected PC12 cells from intracellular reactive oxygen species levels. However, the H2O2-degrading enzyme catalase could that the increases in both mitochondrial membrane potential and reactive oxygen species levels adenosine triphosphate-sensitive potassium channels and nitric oxide. Regulation of adenosine triphosphate-sensitive potassium channels suppresses PC12 cell cytotoxicity induced by amyloid

  8. A Cocoa Peptide Protects Caenorhabditis elegans from Oxidative Stress and β-Amyloid Peptide Toxicity

    OpenAIRE

    Martorell, Patricia; Bataller, Esther; Llopis, Silvia; Gonzalez, Núria; Álvarez, Beatriz; Montón, Fernando; Ortiz, Pepa; Ramón, Daniel; Genovés, Salvador

    2013-01-01

    Background Cocoa and cocoa-based products contain different compounds with beneficial properties for human health. Polyphenols are the most frequently studied, and display antioxidant properties. Moreover, protein content is a very interesting source of antioxidant bioactive peptides, which can be used therapeutically for the prevention of age-related diseases. Methodology/Principal Findings A bioactive peptide, 13L (DNYDNSAGKWWVT), was obtained from a hydrolyzed cocoa by-product by chromatog...

  9. Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets?

    OpenAIRE

    Moreth, Jens; Mavoungou, Chrystelle; Schindowski, Katharina

    2013-01-01

    Alzheimer’s disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. The dementia causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. AD is strongly associated with Amyloid-beta (Aβ) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising ta...

  10. Mechanisms of beta-amyloid neurotoxicity : Perspectives of pharmacotherapy

    NARCIS (Netherlands)

    Harkany, T; Abraham, [No Value; Konya, C; Nyakas, C; Zarandi, M; Penke, B; Luiten, PGM

    2000-01-01

    One of the characteristic neuropathological hallmarks of Alzheimer's disease (AD) is the extracellular accumulation of beta -amyloid peptides (A beta) in neuritic plaques, Experimental data indicate that different molecular forms of A beta affect a wide array of neuronal and glial functions and ther

  11. Spectroscopic investigation of Ginkgo biloba terpene trilactones and their interaction with amyloid peptide Aβ(25-35)

    Science.gov (United States)

    He, Jiangtao; Petrovic, Ana G.; Dzyuba, Sergei V.; Berova, Nina; Nakanishi, Koji; Polavarapu, Prasad L.

    2008-04-01

    The beneficial effects of Ginkgo biloba extract in the "treatment" of dementia are attributed to its terpene trilactone (TTL) constituents. The interactions between TTLs and amyloid peptide are believed to be responsible in preventing the aggregation of peptide. These interactions have been investigated using infrared vibrational absorption (VA) and circular dichroism (VCD) spectra. Four TTLs, namely ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC) and bilobalide (BB) and amyloid Aβ(25-35) peptide, as a model for the full length peptide, are used in this study. GA-monoether and GA-diether have also been synthesized and investigated to help understand the role of individual carbonyl groups in these interactions. The precipitation and solubility issues encountered with the mixture of ginkgolide + Aβ peptide for VA and VCD studies were overcome using binary ethanol-D 2O solvent mixture. The experimental VA and VCD spectra of GA, GB, GC and BB, GA-monoether and GA-diether have been analyzed using the corresponding spectra predicted with density functional theory. The time-dependent experimental VA and VCD spectra of Aβ(25-35) peptide and the corresponding experimental spectra in the presence of TTLs indicated that the effect of the TTLs in modulating the aggregation of Aβ(25-35) peptide is relatively small. Such small effects might indicate the absence of a specific interaction between the TTLs and Aβ(25-35) peptide as a major force leading to the reduced aggregation of amyloid peptides. It is possible that the therapeutic effect of G. biloba extract does not originate from direct interactions between TTLs and the Aβ(25-35) peptide and is more complex.

  12. Synthesis and evaluation of {sup 18}F-fluoroethylated benzothiazole derivatives for in vivo imaging of amyloid plaques in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Neumaier, B. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Max Planck Institute for Neurological Research, Klaus-Joachim-Zuelch Laboratories of the Max Planck Society and the Faculty of Medicine of the University of Cologne, Cologne (Germany)], E-mail: bernd.neumaier@nf.mpg.de; Deisenhofer, S. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Sommer, C. [Department of Neuropathology, University of Mainz (Germany); Solbach, C.; Reske, S.N. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Mottaghy, F. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Department of Nuclear Medicine, RWTH Aachen, Aachen (Germany)

    2010-06-15

    Amyloid aggregates play a major role in the development of Alzheimer's disease. Targeting these aggregates by PET probes enables non-invasively the detection and quantification of amyloid deposit distribution in human brains. Based on benzothiazole core structure a series of amyloid imaging agents were developed. Currently [{sup 11}C]2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B (PIB) is the most specific and widely used amyloid imaging ligand. But due to the short half life of {sup 11}C, longer lived {sup 18}F-labeled derivatives offer logistic advantages and higher contrast images. In this work, three different [{sup 18}F]fluoroethoxy-substituted benzothiazole derivatives ([{sup 18}F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole, [{sup 18}F]2-((2'-(2-fluoroethoxy)-4'-amino)phenyl)benzothiazole and [{sup 18}F]2-(3'-((2-fluoroethoxy)-4'-amino)phenyl)benzothiazole) were synthesized via [{sup 18}F]fluoroethylation. The latter two derivatives with fluoroethoxy-substitution on the aromatic amino group showed very low binding affinity for amyloid aggregates. In contrast [{sup 18}F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole with [{sup 18}F]fluoroethoxy-substitution in 6-position showed excellent amyloid imaging properties with respect to lipophilicity, brain entry and brain clearance in normal SCID mice, amyloid plaque binding affinity and specificity.

  13. Amyloid PET Screening for Enrichment of Early-Stage Alzheimer Disease Clinical Trials: Experience in a Phase 1b Clinical Trial.

    Science.gov (United States)

    Sevigny, Jeff; Suhy, Joyce; Chiao, Ping; Chen, Tianle; Klein, Gregory; Purcell, Derk; Oh, Joonmi; Verma, Ajay; Sampat, Mehul; Barakos, Jerome

    2016-01-01

    Amyloid positron emission tomography (PET) imaging is being investigated as a screening tool to identify amyloid-positive patients as an enrichment strategy for Alzheimer disease (AD) clinical trial enrollment. In a multicenter, phase 1b trial, patients meeting clinical criteria for prodromal or mild AD underwent florbetapir PET scanning at screening. PET, magnetic resonance imaging, and coregistered PET/magnetic resonance imaging scans were reviewed by 2 independent readers and binary visual readings tabulated. Semiquantitative values of cortical to whole cerebellar standard uptake value ratios were computed (threshold 1.10). Of 278 patients with an evaluable PET scan, 170 (61%) and 185 (67%) were amyloid-positive by visual reading and quantitative analysis, respectively; 39% were excluded from the study due to an amyloid-negative scan based on visual readings. More ApoE ε4 carriers than noncarriers were amyloid-positive (80% vs. 43%). Comparison of visual readings with quantitative results identified 21 discordant cases (92% agreement). Interreader and intrareader agreements from visual readings were 98% and 100%, respectively. Amyloid PET imaging is an effective and feasible screening tool for enrollment of amyloid-positive patients with early stages of AD into clinical trials. PMID:26885819

  14. GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP.

    Science.gov (United States)

    Ramanan, Vijay K; Risacher, Shannon L; Nho, Kwangsik; Kim, Sungeun; Shen, Li; McDonald, Brenna C; Yoder, Karmen K; Hutchins, Gary D; West, John D; Tallman, Eileen F; Gao, Sujuan; Foroud, Tatiana M; Farlow, Martin R; De Jager, Philip L; Bennett, David A; Aisen, Paul S; Petersen, Ronald C; Jack, Clifford R; Toga, Arthur W; Green, Robert C; Jagust, William J; Weiner, Michael W; Saykin, Andrew J

    2015-10-01

    Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process. PMID:26268530

  15. The interaction with gold suppresses fiber-like conformations of the amyloid β (16-22) peptide

    Science.gov (United States)

    Bellucci, Luca; Ardèvol, Albert; Parrinello, Michele; Lutz, Helmut; Lu, Hao; Weidner, Tobias; Corni, Stefano

    2016-04-01

    Inorganic surfaces and nanoparticles can accelerate or inhibit the fibrillation process of proteins and peptides, including the biomedically relevant amyloid β peptide. However, the microscopic mechanisms that determine such an effect are still poorly understood. By means of large-scale, state-of-the-art enhanced sampling molecular dynamics simulations, here we identify an interaction mechanism between the segments 16-22 of the amyloid β peptide, known to be fibrillogenic by itself, and the Au(111) surface in water that leads to the suppression of fiber-like conformations from the peptide conformational ensemble. Moreover, thanks to advanced simulation analysis techniques, we characterize the conformational selection vs. induced fit nature of the gold effect. Our results disclose an inhibition mechanism that is rooted in the details of the microscopic peptide-surface interaction rather than in general phenomena such as peptide sequestration from the solution.Inorganic surfaces and nanoparticles can accelerate or inhibit the fibrillation process of proteins and peptides, including the biomedically relevant amyloid β peptide. However, the microscopic mechanisms that determine such an effect are still poorly understood. By means of large-scale, state-of-the-art enhanced sampling molecular dynamics simulations, here we identify an interaction mechanism between the segments 16-22 of the amyloid β peptide, known to be fibrillogenic by itself, and the Au(111) surface in water that leads to the suppression of fiber-like conformations from the peptide conformational ensemble. Moreover, thanks to advanced simulation analysis techniques, we characterize the conformational selection vs. induced fit nature of the gold effect. Our results disclose an inhibition mechanism that is rooted in the details of the microscopic peptide-surface interaction rather than in general phenomena such as peptide sequestration from the solution. Electronic supplementary information (ESI

  16. Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer's disease-related microvascular cerebral amyloid angiopathy.

    Science.gov (United States)

    Merlini, Mario; Wanner, Debora; Nitsch, Roger M

    2016-05-01

    Alzheimer's disease (AD) is characterised by pathologic cerebrovascular remodelling. Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown. Therefore, we systematically quantified Braak tau stage- and cerebral amyloid angiopathy (CAA)-dependent alterations in the alpha-smooth muscle actin (α-SMA), collagen, and elastin content of leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP), including the sulci, of 17 clinically and pathologically diagnosed AD subjects (Braak stage IV-VI) and 28 non-demented control subjects (Braak stage I-IV). GFM and HIPP paraffin sections were stained for general collagen and elastin with the Verhoeff-van Gieson stain; α-SMA and CAA/amyloid β (Aβ) were detected using immunohistochemistry. Significant arterial elastin degradation was observed from Braak stage III onward and correlated with Braak tau pathology (ρ = 0.909, 95 % CI 0.370 to 0.990, p leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process unrelated to CAA and AD, which potentially may contribute to downstream CAA-dependent microvascular pathology in AD. PMID:26988843

  17. Reelin-immunoreactive neurons in entorhinal cortex layer II selectively express intracellular amyloid in early Alzheimer's disease.

    Science.gov (United States)

    Kobro-Flatmoen, Asgeir; Nagelhus, Anne; Witter, Menno P

    2016-09-01

    The onset of Alzheimer's disease (AD) is associated with subtle pathological changes including increased intracellular expression of amyloid-β (Aβ). A structure affected particularly early in the course of AD is the entorhinal cortex, where neuronal death in layer II is observed already at initial stages. Neurons in EC-layer II, particularly those that express the protein Reelin, give rise to projections to the hippocampal dentate gyrus and this projection shows severe loss of synaptic contacts during early-stage AD. Given this anatomical specificity, we sought to determine whether increased intracellular expression of Aβ is selectively associated with Reelin-immunoreactive neurons in layer II of the entorhinal cortex. Here we report that in a transgenic rat model, which mimics the onset and distribution of extracellular amyloid deposits seen in human AD subjects, expression of intracellular Aβ in entorhinal layer II selectively occurs in Reelin-immunoreactive neurons during the early, pre-plaque stage. This Reelin-Aβ association is also present in human subjects with AD-related pathological changes, even in early disease stages. These findings strongly indicate that Reelin-immunoreactive neurons in entorhinal layer II play a crucial role during the initial stages of AD, and may therefore lead to refined hypotheses concerning the origin of this devastating condition. PMID:27195475

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Mitochondria-Targeted Antioxidant SS31 Prevents Amyloid Beta-Induced Mitochondrial Abnormalities and Synaptic Degeneration in Alzheimer's Disease.

    Science.gov (United States)

    Calkins, Marcus J; Manczak, Maria; Reddy, P Hemachandra

    2012-01-01

    In neuronal systems, the health and activity of mitochondria and synapses are tightly coupled. For this reason, it has been postulated that mitochondrial abnormalities may, at least in part, drive neurodegeneration in conditions such as Alzheimer's disease (AD). Mounting evidence from multiple Alzheimer's disease cell and mouse models and postmortem brains suggest that loss of mitochondrial integrity may be a key factor that mediates synaptic loss. Therefore, the prevention or rescue of mitochondrial dysfunction may help delay or altogether prevent AD-associated neurodegeneration. Since mitochondrial health is heavily dependent on antioxidant defenses, researchers have begun to explore the use of mitochondria-targeted antioxidants as therapeutic tools to prevent neurodegenerative diseases. This review will highlight advances made using a model mitochondria-targeted antioxidant peptide, SS31, as a potential treatment for AD. PMID:23226091

  20. The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer's disease

    OpenAIRE

    Portelius, Erik; Fortea, Juan; Molinuevo, Jose Luis; Gustavsson, Mikael K; Andreasson, Ulf; Sanchez-Valle, Raquel

    2012-01-01

    There are several familial forms of Alzheimer's disease (AD) most of which are caused by mutations in the genes that encode the presenilin enzymes involved in the production of amyloid-β (Aβ) from the amyloid precursor protein (APP). In AD, Aβ forms fibrils that are deposited in the brain as plaques. Much of the fibrillar Aβ found in the plaques consists of the 42 amino acid form of Aβ (Aβ1-–2) and it is now widely accepted that Aβ is related to the pathogenesis of AD and that Aβ may both imp...

  1. In vivo PET imaging of beta-amyloid deposition in mouse models of Alzheimer's disease with a high specific activity PET imaging agent [18F]flutemetamol

    OpenAIRE

    Snellman, Anniina; Rokka, Johanna; Lopez-Picon, Francisco R; Eskola, Olli; Salmona, Mario; Forloni, Gianluigi; Scheinin, Mika; Solin, Olof; Rinne, Juha O; Haaparanta-Solin, Merja

    2014-01-01

    Background: The purpose of the study was to evaluate the applicability of 18F-labelled amyloid imaging positron emission tomography (PET) agent [18F]flutemetamol to detect changes in brain beta-amyloid (Aβ) deposition in vivo in APP23, Tg2576 and APPswe-PS1dE9 mouse models of Alzheimer's disease. We expected that the high specific activity of [18F]flutemetamol would make it an attractive small animal Aβ imaging agent. Methods: [18F]flutemetamol uptake in the m...

  2. Rescue of amyloid-Beta-induced inhibition of nicotinic acetylcholine receptors by a peptide homologous to the nicotine binding domain of the alpha 7 subtype.

    Directory of Open Access Journals (Sweden)

    Arthur A Nery

    Full Text Available Alzheimer's disease (AD is characterized by brain accumulation of the neurotoxic amyloidpeptide (Aβ and by loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs. Recent evidence indicates that memory loss and cognitive decline in AD correlate better with the amount of soluble Aβ than with the extent of amyloid plaque deposits in affected brains. Inhibition of nAChRs by soluble Aβ40 is suggested to contribute to early cholinergic dysfunction in AD. Using phage display screening, we have previously identified a heptapeptide, termed IQ, homologous to most nAChR subtypes, binding with nanomolar affinity to soluble Aβ40 and blocking Aβ-induced inhibition of carbamylcholine-induced currents in PC12 cells expressing α7 nAChRs. Using alanine scanning mutagenesis and whole-cell current recording, we have now defined the amino acids in IQ essential for reversal of Aβ40 inhibition of carbamylcholine-induced responses in PC12 cells, mediated by α7 subtypes and other endogenously expressed nAChRs. We further investigated the effects of soluble Aβ, IQ and analogues of IQ on α3β4 nAChRs recombinantly expressed in HEK293 cells. Results show that nanomolar concentrations of soluble Aβ40 potently inhibit the function of α3β4 nAChRs, and that subsequent addition of IQ or its analogues does not reverse this effect. However, co-application of IQ makes the inhibition of α3β4 nAChRs by Aβ40 reversible. These findings indicate that Aβ40 inhibits different subtypes of nAChRs by interacting with specific receptor domains homologous to the IQ peptide, suggesting that IQ may be a lead for novel drugs to block the inhibition of cholinergic function in AD.

  3. Investigation of the inhibitory effects of TiO{sub 2} on the β-amyloid peptide aggregation

    Energy Technology Data Exchange (ETDEWEB)

    Ahmed, Mukhtar H., E-mail: ahmed-m@email.ulster.ac.uk [School of Chemical Science, National Centre for Sensor Research, Dublin City University, Dublin 9 (Ireland); Nanotechnology Integrated Bioengineering Centre, University of Ulster, Jordanstown, BT37 0QB Belfast (United Kingdom); Byrne, John A. [Nanotechnology Integrated Bioengineering Centre, University of Ulster, Jordanstown, BT37 0QB Belfast (United Kingdom); Keyes, Tia E. [School of Chemical Science, National Centre for Sensor Research, Dublin City University, Dublin 9 (Ireland)

    2014-06-01

    TiO{sub 2} thin films are of great interest as biocompatible coatings and also as photocatalytic self-cleaning and antimicrobial coatings. In this work we used β-amyloid as a model for infectious protein to investigate the attachment and photocatalytic degradation. TiO{sub 2} films were prepared on stainless steel substrates using magnetron sputtering. The films were characterised before and after exposure to β-amyloid (1–42), using XRD, Raman spectroscopy, XPS and AFM. The TiO{sub 2} film was mostly composed of the anatase phase with a relatively high surface roughness. The presence of Raman peaks at 1668 cm{sup −1} and 1263 cm{sup −1}, with the XPS spectral feature for nitrogen at 400 eV, confirmed the adsorption of amyloid on surface. Following exposure of the β-amyloid contaminated TiO{sub 2} to UV-B irradiation a slight shift of amide modes was observed. Furthermore, the amide I spectra show an overall decrease in α-helix content with presence of a minor peak around 1591 cm{sup −1}, which is related to tryptophanyl and tyrosinyl radicals, which can lead to conformational change of β-amyloid. The C1s band at 292.2 eV suggests the formation of free carboxylic acid. The loss in the crucial structure of β-amyloid leads to reduce the fibril formation, thought to be induced through a photocatalytic process. - Highlights: • TiO{sub 2} thin films synthesised and characterised • Absorption study using β-amyloid (1–42) • Investigation of peptide configuration via Raman, AFM and XPS spectroscopies • β-Amyloid was subsequently degraded by photocatalytic activity of TiO{sub 2}.

  4. Transfer of Copper from an Amyloid to a Natural Copper-Carrier Peptide with a Specific Mediating Ligand.

    Science.gov (United States)

    Nguyen, Michel; Bijani, Christian; Martins, Nathalie; Meunier, Bernard; Robert, Anne

    2015-11-16

    The oxidative stress that arises from the catalytic reduction of dioxygen by Cu(II/I)-loaded amyloids is the major pathway for neuron death that occurs in Alzheimer's disease. In this work, we show that bis-8(aminoquinoline) ligands, copper(II) specific chelators, are able to catalytically extract Cu(II) from Cu-Aβ1-16 and then completely release Cu(I) in the presence of glutathione to provide a Cu(I)-glutathione complex, a biological intermediate that is able to deliver copper to apo forms of copper-protein complexes. These data demonstrate that bis-8(aminoquinolines) can perform the transfer of copper ions from the pathological Cu-amyloid complexes to regular copper-protein complexes. These copper-specific ligands assist GSH to recycle Cu(I) in an AD brain and consequently slow down oxidative damage that is due to copper dysregulation in Alzheimer's disease. Under the same conditions, we have shown that the copper complex of PBT2, a mono(8-hydroxyquinoline) previously used as a drug candidate, does not efficiently release copper in the presence of GSH. In addition, we report that GSH itself was unable to fully abstract copper ions from Cu-β-amyloid complexes. PMID:26420347

  5. 670 nm laser light and EGCG complementarily reduce amyloid-{beta} aggregates in human neuroblastoma cells: basis for treatment of Alzheimer's disease?

    OpenAIRE

    Sommer, A.P.; Bieschke, J.; Friedrich, R.P.; Zhu, D.; Wanker, E. E.; Fecht, H.J.; Mereles, D; Hunstein, W

    2012-01-01

    Objective: The aim of the present study is to present the results of in vitro experiments with possible relevance in the treatment of Alzheimer's disease (AD). Background Data: Despite intensive research efforts, there is no treatment for AD. One root cause of AD is the extra- and intracellular deposition of amyloid-beta (A{beta}) fibrils in the brain. Recently, it was shown that extracellular A{beta} can enter brain cells, resulting in neurotoxicity. Methods: After internalization of A{beta}...

  6. Neurogenic Responses to Amyloid-Beta Plaques in the Brain of Alzheimer's Disease-Like Transgenic (pPDGF-APPSw,Ind) Mice

    OpenAIRE

    Gan, Li; Qiao, Shuhong; Lan, Xun; Chi, Liying; Luo, Chun; Lien, Lindsey; Liu, Qing Yan; Liu, Rugao

    2007-01-01

    Formation and accumulation of amyloid-beta (Aβ) plaques are associated with declined memory and other neurocognitive function in Alzheimer's Disease (AD) patients. However, the effects of Aβ plaques on neural progenitor cells (NPCs) and neurogenesis from NPCs remain largely unknown. The existing data on neurogenesis in AD patients and AD-like animal models remain controversial. For this reason, we utilized the nestin second-intron enhancer controlled LacZ (pNes-LacZ) reporter transgenic mice ...

  7. Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

    OpenAIRE

    Evin G; Barakat A

    2014-01-01

    Genevieve Evin,1,2 Adel Barakat21Oxidation Biology Laboratory, Mental Health Research Institute, Florey Institute of Neuroscience and Mental Health, University of Melbourne, 2Department of Pathology, University of Melbourne, Parkville, VIC, AustraliaAbstract: Alzheimer's disease (AD) is the major cause of dementia in the elderly and an unmet clinical challenge. A variety of therapies that are currently under development are directed to the amyloid cascade. Indeed, the accumulation and tox...

  8. Computational model for astroglial cell function in Alzheimer's disease

    OpenAIRE

    Eeva Mäkiraatikka; Amit K Nahata; Jalonen, Tuula O.

    2008-01-01

    Neuritic plaques, consisting mostly of aggregated amyloidpeptide, are some of the pathological findings in brains of Alzheimer's disease patients. The aggregated amyloid-β disturbs the cellular homeostasis, which can be monitored by e.g. measuring changes in the intracellular Ca2+ concentrations [Ca2+]. As an intracellular second messenger, Ca2+ functions as a mediator in transporting extracellular signals into the cell. Normally, the Ca2+ concentration in the cytosol is kept...

  9. Inflammation as a therapeutic target for Alzheimer s disease

    OpenAIRE

    Hjorth, Erik

    2010-01-01

    Alzheimer s disease (AD) is a progressive neurodegenerative disorder which is characterised by impairment of memory and learning. The impairment is caused by neuronal death which originates in the parts of the brain that execute memory functions: the entorhinal cortex and hippocampus. The neuronal death is believed to be caused by the amyloid- (A) peptide which is prone to oligomerisation and aggregation into insoluble amyloid plaques (AP). The levels of soluble A and the nu...

  10. Impairment of consciousness in Alzheimer's disease the amyloid water-filled nanotubes manifest quantum optical coherence interfering with the normal QBD?

    CERN Document Server

    Georgiev, D D

    2002-01-01

    Recent discovery by Perutz et al. of the physical structure of the amyloid that accumulates in neurons in certain neurodegenerative diseases like Alzheimer's disease or Huntington's disease, suggests novel mechanism of consciousness impairment, different from the neuronal loss, which is the end stage of the pathogenic process. Amyloid is shown to be water-filled nanotubes made of polymerized pathologically-changed proteins. It is hypothesized that the water inside the new-formed nanotubes can manifest optical coherent laser-like excitations and superradiance similarly to the processes taking part in the normal brain microtubules as shown by Jibu et al. The interfering with the macroscopic quantum effects within the normal microtubules can lead to impairment of conscious experience. Experimental data in favor of quantum theory of consciousness can be obtained from the research of the amyloid nanotubes.

  11. Inflammatory process in Alzheimer's Disease

    OpenAIRE

    MARCO ANTONIO MERAZ RIOS; DANIRA TORAL-RIOS; DIANA FRANCO-BOCANEGRA; VICTORIA CAMPOS-PEÑA

    2013-01-01

    Alzheimer Disease (AD) is a neurodegenerative disorder and the most common form of dementia. Histopathologically is characterized by the presence of two major hallmarks, the intracellular neurofibrillary tangles (NFTs) and extracellular neuritic plaques (NPs) surrounded by activated astrocytes and microglia. NFTs consist of paired helical filaments of truncated tau protein that is abnormally hyperphosphorylated. The main component in the NP is the amyloidpeptide (Aβ), a small fragment of 4...

  12. DCP-LA neutralizes mutant amyloid beta peptide-induced impairment of long-term potentiation and spatial learning.

    Science.gov (United States)

    Nagata, Tetsu; Tomiyama, Takami; Tominaga, Takemi; Mori, Hiroshi; Yaguchi, Takahiro; Nishizaki, Tomoyuki

    2010-01-01

    Long-term potentiation (LTP) was monitored from the CA1 region of the intact rat hippocampus by delivering high frequency stimulation (HFS) to the Schaffer collateral commissural pathway. Intraventricular injection with mutant amyloid beta(1-42) peptide lacking glutamate-22 (Abeta(1-42)E22Delta), favoring oligomerization, 10 min prior to HFS, inhibited expression of LTP, with the potency more than wild-type amyloid beta(1-42) peptide. Intraperitoneal injection with the linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) 70 min prior to HFS neutralized mutant Abeta(1-42)E22Delta peptide-induced LTP inhibition. In the water maze test, continuous intraventricular injection with mutant Abeta(1-42)E22Delta peptide for 14 days prolonged the acquisition latency as compared with that for control, with the potency similar to wild-type Abeta(1-42) peptide, and intraperitoneal injection with DCP-LA shortened the prolonged latency to control levels. The results of the present study indicate that DCP-LA neutralizes mutant Abeta(1-42)E22Delta peptide-induced impairment of LTP and spatial learning. PMID:19716848

  13. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology

    Directory of Open Access Journals (Sweden)

    Ferretti Maria

    2012-04-01

    Full Text Available Abstract Background A growing body of evidence indicates that inflammation is one of the earliest neuropathological events in Alzheimer's disease. Accordingly, we have recently shown the occurrence of an early, pro-inflammatory reaction in the hippocampus of young, three-month-old transgenic McGill-Thy1-APP mice in the absence of amyloid plaques but associated with intracellular accumulation of amyloid beta petide oligomers. The role of such a pro-inflammatory process in the progression of the pathology remained to be elucidated. Methods and results To clarify this we administered minocycline, a tetracyclic derivative with anti-inflammatory and neuroprotective properties, to young, pre-plaque McGill-Thy1-APP mice for one month. The treatment ended at the age of three months, when the mice were still devoid of plaques. Minocycline treatment corrected the up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 observed in young transgenic placebo mice. Furthermore, the down-regulation of inflammatory markers correlated with a reduction in amyloid precursor protein levels and amyloid precursor protein-related products. Beta-site amyloid precursor protein cleaving enzyme 1 activity and levels were found to be up-regulated in transgenic placebo mice, while minocycline treatment restored these levels to normality. The anti-inflammatory and beta-secretase 1 effects could be partly explained by the inhibition of the nuclear factor kappa B pathway. Conclusions Our study suggests that the pharmacological modulation of neuroinflammation might represent a promising approach for preventing or delaying the development of Alzheimer's disease neuropathology at its initial, pre-clinical stages. The results open new vistas to the interplay between inflammation and amyloid pathology.

  14. Cerebrospinal fluid amyloid beta42/phosphorylated tau ratio discriminates between Alzheimer's disease and vascular dementia.

    NARCIS (Netherlands)

    Jong, D. de; Jansen, R.W.M.M.; Kremer, H.P.H.; Verbeek, M.M.

    2006-01-01

    BACKGROUND: The differentiation of Alzheimer's disease (AD) from vascular dementia (VaD) is hampered by clinical diagnostic criteria with disappointing sensitivity and specificity. The objective of this study was to investigate whether cerebrospinal fluid (CSF) levels of total tau protein (t-tau), a

  15. Amyloid β-protein, Cystatin C and Cathepsin B as Biomarkers of Alzheimer's Disease

    OpenAIRE

    Sundelöf, Johan

    2010-01-01

    It is suggested that Alzheimer’s disease (AD) is caused by an imbalance between production, degradation and clearance of the amyloid-β (Aβ) protein. This imbalance leads to aggregation of Aβ and tau proteins and neurodegeneration in the brain. Today there is increasing evidence that the balance between the protease cathepsin B and the protease inhibitor cystatin C affects the tendency for Aβ to aggregate. The primary aim of this thesis was to investigate Aβ, cystatin C and cathepsin B levels ...

  16. General amyloid inhibitors? A critical examination of the inhibition of IAPP amyloid formation by inositol stereoisomers.

    Directory of Open Access Journals (Sweden)

    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.

  17. Retrieval of the Alzheimer's amyloid precursor protein from the endosome to the TGN is S655 phosphorylation state-dependent and retromer-mediated

    Directory of Open Access Journals (Sweden)

    Gandy Sam

    2010-10-01

    Full Text Available Abstract Background Retrograde transport of several transmembrane proteins from endosomes to the trans-Golgi network (TGN occurs via Rab 5-containing endosomes, mediated by clathrin and the recently characterized retromer complex. This complex and one of its putative sorting receptor components, SorLA, were reported to be associated to late onset Alzheimer's disease (AD. The pathogenesis of this neurodegenerative disorder is still elusive, although accumulation of amyloidogenic Abeta is a hallmark. This peptide is generated from the sucessive β- and γ- secretase proteolysis of the Alzheimer's amyloid precursor protein (APP, events which are associated with endocytic pathway compartments. Therefore, APP targeting and time of residence in endosomes would be predicted to modulate Abeta levels. However, the formation of an APP- and retromer-containing protein complex with potential functions in retrieval of APP from the endosome to the TGN had, to date, not been demonstrated directly. Further, the motif(s in APP that regulate its sorting to the TGN have not been characterized. Results Through the use of APP-GFP constructs, we show that APP containing endocytic vesicles targeted for the TGN, are also immunoreactive for clathrin-, Rab 5- and VPS35. Further, they frequently generate protruding tubules near the TGN, supporting an association with a retromer-mediated pathway. Importantly, we show for the first time, that mimicking APP phosphorylation at S655, within the APP 653YTSI656 basolateral motif, enhances APP retrieval via a retromer-mediated process. The phosphomimetic APP S655E displays decreased APP lysosomal targeting, enhanced mature half-life, and decreased tendency towards Abeta production. VPS35 downregulation impairs the phosphorylation dependent APP retrieval to the TGN, and decreases APP half-life. Conclusions We reported for the first time the importance of APP phosphorylation on S655 in regulating its retromer-mediated sorting to

  18. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  19. DBA/2J genetic background exacerbates spontaneous lethal seizures but lessens amyloid deposition in a mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Harriet M Jackson

    Full Text Available Alzheimer's disease (AD is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs and neuronal dysfunction. Early onset AD (EOAD is commonly caused by mutations in amyloid precursor protein (APP or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2. In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APPswe and PSEN1de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1de9 has not been tested. Our study shows that DBA/2J.APPswePSEN1de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APPswePSEN1de9 mice-70% of DBA/2J.APPswePSEN1de9 mice die between 2-3 months of age. Of the DBA/2J.APPswePSEN1de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APPswePSEN1de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity.

  20. Inhibitory Effect of Curcumin-Cu(II) and Curcumin-Zn(II) Complexes on Amyloid-Beta Peptide Fibrillation

    OpenAIRE

    Rona Banerjee

    2014-01-01

    Mononuclear complexes of Curcumin with Cu(II) and Zn(II) have been synthesized and, characterized and their effects on the fibrillization and aggregation of amyloid-beta (Aβ) peptide have been studied. FTIR spectroscopy and atomic force microscopy (AFM) observations demonstrate that the complexes can inhibit the transition from less structured oligomers to β-sheet rich protofibrils which act as seeding factors for further fibrillization. The metal complexes also impart more improved inhibitor...

  1. A common landscape for membrane-active peptides

    OpenAIRE

    Last, Nicholas B.; Schlamadinger, Diana E.; Miranker, Andrew D.

    2013-01-01

    Three families of membrane-active peptides are commonly found in nature and are classified according to their initial apparent activity. Antimicrobial peptides are ancient components of the innate immune system and typically act by disruption of microbial membranes leading to cell death. Amyloid peptides contribute to the pathology of diverse diseases from Alzheimer's to type II diabetes. Preamyloid states of these peptides can act as toxins by binding to and permeabilizing cellular membranes...

  2. Cilostazol Upregulates Autophagy via SIRT1 Activation: Reducing AmyloidPeptide and APP-CTFβ Levels in Neuronal Cells.

    Directory of Open Access Journals (Sweden)

    Hye Rin Lee

    Full Text Available Autophagy is a vital pathway for the removal of β-amyloid peptide (Aβ and the aggregated proteins that cause Alzheimer's disease (AD. We previously found that cilostazol induced SIRT1 expression and its activity in neuronal cells, and thus, we hypothesized that cilostazol might stimulate clearances of Aβ and C-terminal APP fragment β subunit (APP-CTFβ by up-regulating autophagy.When N2a cells were exposed to soluble Aβ1-42, protein levels of beclin-1, autophagy-related protein5 (Atg5, and SIRT1 decreased significantly. Pretreatment with cilostazol (10-30 μM or resveratrol (20 μM prevented these Aβ1-42 evoked suppressions. LC3-II (a marker of mammalian autophagy levels were significantly increased by cilostazol, and this increase was reduced by 3-methyladenine. To evoke endogenous Aβ overproduction, N2aSwe cells (N2a cells stably expressing human APP containing the Swedish mutation were cultured in medium with or without tetracycline (Tet+ for 48 h and then placed in Tet- condition. Aβ and APP-CTFβ expressions were increased after 12~24 h in Tet- condition, and these increased expressions were significantly reduced by pretreating cilostazol. Cilostazol-induced reductions in the expressions of Aβ and APP-CTFβ were blocked by bafilomycin A1 (a blocker of autophagosome to lysosome fusion. After knockdown of the SIRT1 gene (to ~40% in SIRT1 protein, cilostazol failed to elevate the expressions of beclin-1, Atg5, and LC3-II, indicating that cilostazol increases these expressions by up-regulating SIRT1. Further, decreased cell viability induced by Aβ was prevented by cilostazol, and this inhibition was reversed by 3-methyladenine, indicating that the protective effect of cilostazol against Aβ induced neurotoxicity is, in part, ascribable to the induction of autophagy. In conclusion, cilostazol modulates autophagy by increasing the activation of SIRT1, and thereby enhances Aβ clearance and increases cell viability.

  3. Pharmacokinetic properties of tandem d-peptides designed for treatment of Alzheimer's disease.

    Science.gov (United States)

    Leithold, Leonie H E; Jiang, Nan; Post, Julia; Niemietz, Nicole; Schartmann, Elena; Ziehm, Tamar; Kutzsche, Janine; Shah, N Jon; Breitkreutz, Jörg; Langen, Karl-Josef; Willuweit, Antje; Willbold, Dieter

    2016-06-30

    Peptides are more and more considered for the development of drug candidates. However, they frequently exhibit severe disadvantages such as instability and unfavourable pharmacokinetic properties. Many peptides are rapidly cleared from the organism and oral bioavailabilities as well as in vivo half-lives often remain low. In contrast, some peptides consisting solely of d-enantiomeric amino acid residues were shown to combine promising therapeutic properties with high proteolytic stability and enhanced pharmacokinetic parameters. Recently, we have shown that D3 and RD2 have highly advantageous pharmacokinetic properties. Especially D3 has already proven promising properties suitable for treatment of Alzheimer's disease. Here, we analyse the pharmacokinetic profiles of D3D3 and RD2D3, which are head-to-tail tandem d-peptides built of D3 and its derivative RD2. Both D3D3 and RD2D3 show proteolytic stability in mouse plasma and organ homogenates for at least 24h and in murine and human liver microsomes for 4h. Notwithstanding their high affinity to plasma proteins, both peptides are taken up into the brain following i.v. as well as i.p. administration. Although both peptides contain identical d-amino acid residues, they are arranged in a different sequence order and the peptides show differences in pharmacokinetic properties. After i.p. administration RD2D3 exhibits lower plasma clearance and higher bioavailability than D3D3. We therefore concluded that the amino acid sequence of RD2 leads to more favourable pharmacokinetic properties within the tandem peptide, which underlines the importance of particular sequence motifs, even in short peptides, for the design of further therapeutic d-peptides. PMID:27086111

  4. Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit.

    Directory of Open Access Journals (Sweden)

    Gary W Arendash

    Full Text Available Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF

  5. Multiple mechanisms of iron-induced amyloid beta-peptide accumulation in SHSY5Y cells: protective action of negletein.

    Science.gov (United States)

    Banerjee, Priyanjalee; Sahoo, Arghyadip; Anand, Shruti; Ganguly, Anirban; Righi, Giuliana; Bovicelli, Paolo; Saso, Luciano; Chakrabarti, Sasanka

    2014-12-01

    The increased accumulation of iron in the brain in Alzheimer's disease (AD) is well documented, and excess iron is strongly implicated in the pathogenesis of the disease. The adverse effects of accumulated iron in AD brain may include the oxidative stress, altered amyloid beta-metabolism and the augmented toxicity of metal-bound amyloid beta 42. In this study, we have shown that exogenously added iron in the form of ferric ammonium citrate (FAC) leads to considerable accumulation of amyloid precursor protein (APP) without a corresponding change in the concerned gene expression in cultured SHSY5Y cells during exposure up to 48 h. This phenomenon is also associated with increased β-secretase activity and augmented release of amyloid beta 42 in the medium. Further, the increase in β-secretase activity, in SHSY5Y cells, upon exposure to iron apparently involves reactive oxygen species (ROS) and NF-κB activation. The synthetic flavone negletein (5,6-dihydroxy-7-methoxyflavone), which is a known chelator for iron, can significantly prevent the effects of FAC on APP metabolism in SHSY5Y cells. Further, this compound inhibits the iron-dependent formation of ROS and also blocks the iron-induced oligomerization of amyloid beta 42 in vitro. In concentrations used in this study, negletein alone appears to have only marginal toxic effects on cell viability, but, on the other hand, the drug is capable of ameliorating the iron-induced loss of cell viability considerably. Our results provide the initial evidence of potential therapeutic effects of negletein, which should be explored in suitable animal models of AD. PMID:25249289

  6. Antimicrobial peptide (Cn-AMP2) from liquid endosperm of Cocos nucifera forms amyloid-like fibrillar structure.

    Science.gov (United States)

    Gour, Shalini; Kaushik, Vibha; Kumar, Vijay; Bhat, Priyanka; Yadav, Subhash C; Yadav, Jay K

    2016-04-01

    Cn-AMP2 is an antimicrobial peptide derived from liquid endosperm of coconut (Cocos nucifera). It consists of 11 amino acid residues and predicted to have high propensity for β-sheet formation that disposes this peptide to be amyloidogenic. In the present study, we have examined the amyloidogenic propensities of Cn-AMP2 in silico and then tested the predictions under in vitro conditions. The in silico study revealed that the peptide possesses high amyloidogenic propensity comparable with Aβ. Upon solubilisation and agitation in aqueous buffer, Cn-AMP2 forms visible aggregates that display bathochromic shift in the Congo red absorbance spectra, strong increase in thioflavin T fluorescence and fibrillar morphology under transmission electron microscopy. All these properties are typical of an amyloid fibril derived from various proteins/peptides including Aβ. PMID:27028204

  7. Cellular and proteomic studies of the mitochondrial ABAD/Aβ complex : investigating its role in Alzheimer's disease

    OpenAIRE

    Taylor, Margaret Alexandra

    2012-01-01

    The focus of this thesis is to investigate the intracellular protein-peptide complex 3-hydroxyacyl-CoA dehydrogenase (HADH), also known as ABAD (amyloid- binding alcohol dehydrogenase) and amyloid-beta peptide (Aβ). This complex has been identified in the development of Alzheimer's disease (AD), and this study tries to identify if ABAD is a useful biomarker for genetic risk profiling strategies for the early diagnosis of Alzheimer’s disease, or a suitable target for disease-...

  8. Characterization of D-enantiomeric peptides binding to monomeric Amyloid beta (1-42) identified by a competitive mirror image phage display

    OpenAIRE

    Rudolph, Stephan; Kutzsche, Janine; Klein, Antonia Nicole; Frenzel, Daniel; Willbold, Dieter

    2014-01-01

    Alzheimer's disease (AD) is the most prominent type of dementia in elderly people. Until now there is no curative therapy available.Amyloid beta (Aβ) is assumed to play a major role in the development and progression of the disease. Freely diffusible, toxic Aβ oligomers seem to have a major toxicological impact.

  9. Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients

    International Nuclear Information System (INIS)

    The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD). In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [11C]AZD2995 and [11C]AZD2184 in three healthy control subjects and seven AD patients. AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [3H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [11C]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 [11C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus. Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [11C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [11C]AZD2995. However, the very low nonspecific binding of [11C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. 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.)

  10. Acute stress increases interstitial fluid amyloid-β via corticotropin-releasing factor and neuronal activity

    OpenAIRE

    Kang, Jae-Eun; Cirrito, John R.; Dong, Hongxin; John G. Csernansky; Holtzman, David M.

    2007-01-01

    Aggregation of the amyloid-β (Aβ) peptide in the extracellular space of the brain is critical in the pathogenesis of Alzheimer's disease. Aβ is produced by neurons and released into the brain interstitial fluid (ISF), a process regulated by synaptic activity. To determine whether behavioral stressors can regulate ISF Aβ levels, we assessed the effects of chronic and acute stress paradigms in amyloid precursor protein transgenic mice. Isolation stress over 3 months increased Aβ levels by 84%. ...

  11. Orally administrated cinnamon extract reduces β-amyloid oligomerization and corrects cognitive impairment in Alzheimer's disease animal models.

    Directory of Open Access Journals (Sweden)

    Anat Frydman-Marom

    Full Text Available An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of β-amyloid polypeptide (Aβ play a key role in Alzheimer's disease (AD pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Aβ plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Aβ oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt, which markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Aβ oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Aβ species formation in AD through the utilization of a compound that is currently in use in human diet.

  12. Subtle learning and memory impairment in an idiopathic rat model of Alzheimer's disease utilizing cholinergic depletions and β-amyloid.

    Science.gov (United States)

    Deibel, S H; Weishaupt, N; Regis, A M; Hong, N S; Keeley, R J; Balog, R J; Bye, C M; Himmler, S M; Whitehead, S N; McDonald, R J

    2016-09-01

    Alzheimer's disease (AD) is a disease of complex etiology, involving multiple risk factors. When these risk factors are presented concomitantly, cognition and brain pathology are more severely compromised than if those risk factors were presented in isolation. Reduced cholinergic tone and elevated amyloid-beta (Aβ) load are pathological hallmarks of AD. The present study sought to investigate brain pathology and alterations in learning and memory when these two factors were presented together in rats. Rats received either sham surgeries, cholinergic depletions of the medial septum, intracerebroventricular Aβ25-35 injections, or both cholinergic depletion and Aβ25-35 injections (Aβ+ACh group). The Aβ+ACh rats were unimpaired in a striatal dependent visual discrimination task, but had impaired acquisition in the standard version of the Morris water task. However, these rats displayed normal Morris water task retention and no impairment in acquisition of a novel platform location during a single massed training session. Aβ+ACh rats did not have exacerbated brain pathology as indicated by activated astroglia, activated microglia, or accumulation of Aβ. These data suggest that cholinergic depletions and Aβ injections elicit subtle cognitive deficits when behavioural testing is conducted shortly after the presentation of these factors. These factors might have altered hippocampal synaptic plasticity and thus resemble early AD pathology. PMID:27208489

  13. Monoclonal antibodies against β-amyloid (Aβ) for the treatment of Alzheimer's disease: the Aβ target at a crossroads.

    Science.gov (United States)

    Panza, Francesco; Frisardi, Vincenza; Imbimbo, Bruno P; Seripa, Davide; Solfrizzi, Vincenzo; Pilotto, Alberto

    2011-06-01

    Several second-generation active β-amyloid (Aβ) vaccines and passive Aβ immunotherapies are under clinical investigation with the aim of boosting Aβ clearance from the brain of the Alzheimer's disease (AD) patients. However, the preliminary cognitive efficacy of bapineuzumab, a humanized anti-Aβ monoclonal antibody, appears uncertain. Moreover, the occurrence of vasogenic edema and, more rarely, brain microhemorrhages, especially in apolipoprotein E ϵ4 carriers, have led to abandoning of the highest dose of the drug. Solanezumab, another humanized anti-Aβ monoclonal antibody, was shown to neutralize soluble Aβ oligomers, which is believed to be the more neurotoxic Aβ species. Phase II studies showed a good safety profile of solanezumab while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. However, the preliminary equivocal cognitive results obtained with bapineuzumab as well as the detrimental cognitive effects observed with semagacestat, a potent γ-secretase inhibitor, raise the possibility that targeting Aβ may not be clinically efficacious in AD. The results of four ongoing large Phase III trials on bapineuzumab and two Phase III trials on solanezumab will tell us if passive anti-Aβ immunization is able to alter the course of this devastating disease, and if Aβ is still a viable target for anti-AD drugs. PMID:21501112

  14. Highly Sensitive Near-Infrared Fluorophores for in Vivo Detection of Amyloid-β Plaques in Alzheimer's Disease.

    Science.gov (United States)

    Fu, Hualong; Cui, Mengchao; Zhao, Liu; Tu, Peiyu; Zhou, Kaixiang; Dai, Jiapei; Liu, Boli

    2015-09-10

    Alzheimer's disease (AD) is pathologically characterized by the accumulation of β-amyloid (Aβ) deposits in the parenchymal and cortical brain. In this work, we designed, synthesized, and evaluated a series of near-infrared (NIR) probes with electron donor-acceptor end groups interacting through a π-conjugated system for the detection of Aβ deposits in the brain. Among these probes, 3b and 3c had excellent fluorescent properties (emission maxima > 650 nm and high quantum yields) and displayed high sensitivity and high affinities to Aβ aggregates (3b, Kd = 8.8 nM; 3c, Kd = 1.9 nM). Both 3b and 3c could readily penetrate the blood-brain barrier with high initial brain uptake and fast to moderate washout from the brain. In vivo NIR imaging revealed that 3b and 3c could efficiently differentiate transgenic and wild-type mice. In summary, our research provides new hints for developing smarter and more activatable NIR probes targeting Aβ. PMID:26262759

  15. Orally administrated cinnamon extract reduces β-amyloid oligomerization and corrects cognitive impairment in Alzheimer's disease animal models.

    Science.gov (United States)

    Frydman-Marom, Anat; Levin, Aviad; Farfara, Dorit; Benromano, Tali; Scherzer-Attali, Roni; Peled, Sivan; Vassar, Robert; Segal, Daniel; Gazit, Ehud; Frenkel, Dan; Ovadia, Michael

    2011-01-01

    An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of β-amyloid polypeptide (Aβ) play a key role in Alzheimer's disease (AD) pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Aβ plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Aβ oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt), which markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Aβ oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Aβ species formation in AD through the utilization of a compound that is currently in use in human diet. PMID:21305046

  16. Cognitive-enhancing activities of the polyprenol preparation Ropren® in gonadectomized β-amyloid (25-35) rat model of Alzheimer's disease.

    Science.gov (United States)

    Fedotova, Julia; Soultanov, Vagif; Nikitina, Tamara; Roschin, Victor; Ordyan, Natalia; Hritcu, Lucian

    2016-04-01

    The present preclinical study was designed to examine the effects of prolonged Ropren® administration (8.6mg/kg, orally, once daily, 28days) in a β-amyloid (25-35) rat model of Alzheimer's disease following gonadectomy. The experimental model was created by intracerebroventricular injection of β-amyloid (25-35) into gonadectomized (GDX) rats and GDX rats with testosterone propionate (TP, 0.5mg/kg, subcutaneous, once daily, 28days) supplementation. Ropren® was administered to the GDX rats and GDX rats treated with TP. Memory performance was assessed using the passive avoidance and the Morris water maze tests and the spontaneous locomotor activity was assessed using the open field test. Treatment with Ropren® significantly improved and restored the cognitive ability of GDX rats with β-amyloid (25-35)-induced amnesia in the passive avoidance test and Morris water maze. Co-administration of Ropren® with TP exerted a markedly synergistic memory-enhancing effect in the GDX rats with β-amyloid (25-35)-induced amnesia on the same models of memory testing. Ropren® administered alone or together with TP significantly enhanced crossing, frequency of rearing and grooming of the GDX rats with β-amyloid (25-35)-induced amnesia in the open field test. These results indicate that Ropren® has a marked memory-enhancing action in the experimental model of Alzheimer's disease in male rats with altered levels of androgens. PMID:26821186

  17. 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.

  18. Curcumin Improves Amyloid β-Peptide (1-42 Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway.

    Directory of Open Access Journals (Sweden)

    Lu Zhang

    Full Text Available Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects. Previous studies have suggested that curcumin reduces the levels of amyloid and oxidized proteins and prevents memory deficits and thus is beneficial to patients with Alzheimer's disease (AD. However, the molecular mechanisms underlying curcumin's effect on cognitive functions are not well-understood. In the present study, we examined the working memory and spatial reference memory in rats that received a ventricular injection of amyloid-β1-42 (Aβ1-42, representing a rodent model of Alzheimer's disease (AD. The rats treated with Aβ1-42 exhibited obvious cognitive deficits in behavioral tasks. Chronic (seven consecutive days, once per day but not acute (once a day curcumin treatments (50, 100, and 200 mg/kg improved the cognitive functions in a dose-dependent manner. In addition, the beneficial effect of curcumin is accompanied by increased BDNF levels and elevated levels of phosphorylated ERK in the hippocampus. Furthermore, the cognition enhancement effect of curcumin could be mimicked by the overexpression of BDNF in the hippocampus and blocked by either bilateral hippocampal injections with lentiviruses that express BDNF shRNA or a microinjection of ERK inhibitor. These findings suggest that chronic curcumin ameliorates AD-related cognitive deficits and that upregulated BDNF-ERK signaling in the hippocampus may underlie the cognitive improvement produced by curcumin.

  19. Validation of a Commercial Chemiluminescence Immunoassay for the Simultaneous Measurement of Three Different AmyloidPeptides in Human Cerebrospinal Fluid and Application to a Clinical Cohort.

    Science.gov (United States)

    Klafki, Hans-W; Hafermann, Henning; Bauer, Chris; Haussmann, Ute; Kraus, Inga; Schuchhardt, Johannes; Muck, Stephan; Scherbaum, Norbert; Wiltfang, Jens

    2016-09-01

    A comprehensive assay validation campaign of a commercially available chemiluminescence multiplex immunoassay for the simultaneous measurement of the amyloidpeptides Aβ38, Aβ40, and Aβ42 in human cerebrospinal fluid (CSF) is presented. The assay quality parameters we addressed included impact of sample dilution, parallelism, lower limits of detection, lower limits of quantification, intra- and inter-assay repeatability, analytical spike recoveries, and between laboratory reproducibility of the measurements. The assay performed well in our hands and fulfilled a number of predefined acceptance criteria. The CSF levels of Aβ40 and Aβ42 determined in a clinical cohort (n = 203) were statistically significantly correlated with available ELISA data of Aβ1-40 (n = 158) and Aβ1-42 (n = 179) from a different laboratory. However, Bland-Altman method comparison indicated systematic differences between the assays. The data presented here furthermore indicate that the CSF concentration of Aβ40 can surrogate total CSF Aβ and support the hypothesis that the Aβ42/Aβ40 ratio outperforms CSF Aβ42 alone as a biomarker for Alzheimer's disease due to a normalization to total Aβ levels. PMID:27567847

  20. Neutron Scattering Studies of the Interplay of Amyloid β Peptide(1-40) and An Anionic Lipid 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol.

    Science.gov (United States)

    Rai, Durgesh K; Sharma, Veerendra K; Anunciado, Divina; O'Neill, Hugh; Mamontov, Eugene; Urban, Volker; Heller, William T; Qian, Shuo

    2016-01-01

    The interaction between lipid bilayers and Amyloid β peptide (Aβ) plays a critical role in proliferation of Alzheimer's disease (AD). AD is expected to affect one in every 85 humans by 2050, and therefore, deciphering the interplay of Aβ and lipid bilayers at the molecular level is of profound importance. In this work, we applied an array of neutron scattering methods to study the structure and dynamics of Aβ(1-40) interacting 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) bilayers. In the structural investigations of lipid bilayer's response to Aβ binding, Small Angle Neutron Scattering and Neutron Membrane Diffraction revealed that the Aβ anchors firmly to the highly charged DMPG bilayers in the interfacial region between water and hydrocarbon chain, and it doesn't penetrate deeply into the bilayer. This association mode is substantiated by the dynamics studies with high resolution Quasi-Elastic Neutron Scattering experiments, showing that the addition of Aβ mainly affects the slower lateral motion of lipid molecules, especially in the fluid phase, but not the faster internal motion. The results revealed that Aβ associates with the highly charged membrane in surface with limited impact on the structure, but the altered membrane dynamics could have more influence on other membrane processes. PMID:27503057

  1. Influence of dendrimer's structure on its activity against amyloid fibril formation

    International Nuclear Information System (INIS)

    Inhibition of fibril assembly is a potential therapeutic strategy in neurodegenerative disorders such as prion and Alzheimer's diseases. Highly branched, globular polymers-dendrimers-are novel promising inhibitors of fibril formation. In this study, the effect of polyamidoamine (PAMAM) dendrimers (generations 3rd, 4th, and 5th) on amyloid aggregation of the prion peptide PrP 185-208 and the Alzheimer's peptide Aβ 1-28 was examined. Amyloid fibrils were produced in vitro and their formation was monitored using the dye thioflavin T (ThT). Fluorescence studies were complemented with electron microscopy. The results show that the higher the dendrimer generation, the larger the degree of inhibition of the amyloid aggregation process and the more effective are dendrimers in disrupting the already existing fibrils. A hypothesis on dendrimer-peptide interaction mechanism is presented based on the dendrimers' molecular structure

  2. Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice

    OpenAIRE

    Rat, Dorothea; Schmitt, Ulrich; Tippmann, Frank; Dewachter, Ilse; Theunis, Clara; Wieczerzak, Ewa; Postina, Rolf; Van Leuven, Fred Van; Fahrenholz, Falk; Kojro, Elzbieta

    2011-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) has neuroprotective and neurotrophic properties and is a potent alpha-secretase activator. As PACAP peptides and their specific receptor PAC1 are localized in central nervous system areas affected by Alzheimer's disease (AD), this study aims to examine the role of the natural peptide PACAP as a valuable approach in AD therapy. We investigated the effect of PACAP in the brain of an AD transgenic mouse model. The long-term intranasal da...

  3. A role for heme in Alzheimer's disease: Heme binds amyloid β and has altered metabolism

    OpenAIRE

    Atamna, Hani; Frey, William H.

    2004-01-01

    Heme is a common factor linking several metabolic perturbations in Alzheimer's disease (AD), including iron metabolism, mitochondrial complex IV, heme oxygenase, and bilirubin. Therefore, we determined whether heme metabolism was altered in temporal lobes obtained at autopsy from AD patients and age-matched nondemented subjects. AD brain demonstrated 2.5-fold more heme-b (P < 0.01) and 26% less heme-a (P = 0.16) compared with controls, resulting in a highly significant 2.9-fold decrease in he...

  4. Ceria/POMs hybrid nanoparticles as a mimicking metallopeptidase for treatment of neurotoxicity of amyloidpeptide.

    Science.gov (United States)

    Guan, Yijia; Li, Meng; Dong, Kai; Gao, Nan; Ren, Jinsong; Zheng, Yongchen; Qu, Xiaogang

    2016-08-01

    Protein misfolding to amyloid aggregates is the hallmark for neurodegenerative disease. While much attention has been paid to screen natural proteases that can degrade amyloidpeptides (Aβ), it is difficult to apply them in the clinics with the intractable problem of immunogenicity in living organisms. Herein, we rationally designed an artificial nanozyme, Ceria/Polyoxometalates hybrid (CeONP@POMs) with both proteolytic and superoxide dismutase (SOD) activities. Our results indicated that CeONP@POMs could efficiently degrade Aβ aggregates and reduce intracellular reactive oxygen species (ROS). More importantly, CeONP@POMD could not only promote PC12 cell proliferation and can cross blood-brain barrier (BBB), but also inhibit Aβ-induced BV2 microglial cell activation which was demonstrated by immunoluorescence assay and flow cytometry measurements. In vivo studies further indicated that CeONP@POMD as nanozyme possessed good biocompatibility, evidenced by a detailed study of their biodistribution, body weight change, and in vivo toxicology. Therefore, our results pave the way for design of multifunctional artificial nanozyme for treatment of neurotoxicity of amyloidpeptide. PMID:27179436

  5. The architecture of amyloid-like peptide fibrils revealed by X-ray scattering, diffraction and electron microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Langkilde, Annette E., E-mail: annette.langkilde@sund.ku.dk [University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen (Denmark); Morris, Kyle L.; Serpell, Louise C. [University of Sussex, Falmer, Brighton (United Kingdom); Svergun, Dmitri I. [European Molecular Biology Laboratory, Hamburg Outstation, 22607 Hamburg (Germany); Vestergaard, Bente [University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen (Denmark)

    2015-04-01

    The aggregation process and the fibril state of an amyloidogenic peptide suggest monomer addition to be the prevailing mechanism of elongation and a model of the peptide packing in the fibrils has been obtained. Structural analysis of protein fibrillation is inherently challenging. Given the crucial role of fibrils in amyloid diseases, method advancement is urgently needed. A hybrid modelling approach is presented enabling detailed analysis of a highly ordered and hierarchically organized fibril of the GNNQQNY peptide fragment of a yeast prion protein. Data from small-angle X-ray solution scattering, fibre diffraction and electron microscopy are combined with existing high-resolution X-ray crystallographic structures to investigate the fibrillation process and the hierarchical fibril structure of the peptide fragment. The elongation of these fibrils proceeds without the accumulation of any detectable amount of intermediate oligomeric species, as is otherwise reported for, for example, glucagon, insulin and α-synuclein. Ribbons constituted of linearly arranged protofilaments are formed. An additional hierarchical layer is generated via the pairing of ribbons during fibril maturation. Based on the complementary data, a quasi-atomic resolution model of the protofilament peptide arrangement is suggested. The peptide structure appears in a β-sheet arrangement reminiscent of the β-zipper structures evident from high-resolution crystal structures, with specific differences in the relative peptide orientation. The complexity of protein fibrillation and structure emphasizes the need to use multiple complementary methods.

  6. Electrochemical quantification of the Alzheimer’s disease amyloid-β (1–40 using amyloid-β fibrillization promoting peptide

    Directory of Open Access Journals (Sweden)

    Satoshi Fujii

    2015-12-01

    Full Text Available Amyloidpeptide (Aβ is believed to be an important biomarker for the early diagnosis of Alzheimer’s disease. Therefore, practical and reliable methods to assay Aβ levels have been coveted. In this study, a rapid, sensitive, and selective electrochemical method for Aβ(1–40 detection using Cu2+ redox cycling on peptide-modified gold electrodes was developed. A 19-residue peptide that can promote Aβ fibrillization (AFPP was immobilized onto a gold electrode. After incubating an Aβ solution with the modified electrode for 1 h, a Cu2+ solution was added and cyclic voltammetry measurements were conducted. The voltammetric response was found to be proportional to the Aβ(1–40 concentration in the 0.1–5 μM range, and a detection limit of 18 nM was achieved. Washing with sodium hydroxide and ethylenediaminetetraacetate solutions easily reinitialized the modified electrode. Results obtained using the reinitialized electrode showed good reproducibility. Furthermore, when another amyloidogenic and Cu2+-binding protein amylin was used as the target, no voltammetric response was observed. These results indicate that the AFPP-modified electrode provides a promising, label-free, sensitive, selective, cost-effective, and easy method for the quantification of Aβ.

  7. SS31, a Small Molecule Antioxidant Peptide, Attenuates β-Amyloid Elevation, Mitochondrial/Synaptic Deterioration and Cognitive Deficit in SAMP8 Mice.

    Science.gov (United States)

    Jia, Yan-Li; Sun, Su-Juan; Chen, Jing-Hong; Jia, Qian; Huo, Tian-Tian; Chu, Li-Fang; Bai, Jiang-Tao; Yu, Ye-Jing; Yan, Xiao-Xin; Wang, Jian-Hua

    2016-01-01

    Mitochondrial dysfunction, oxidative stress and β -amyloid (Aβ) formation are thought to cause neuronal and synaptic degeneration underlying cognitive decline in Alzheimer's disease (AD). The senescence-accelerated mouse-prone 8 (SAMP8) mice have been used as an animal model for mechanistic and translational research for AD. In the present study we characterized mitochondrial and synaptic alterations in SAMP8 mice relative to SAMR1control mice and explored a protective effect of the small molecule peptide SS31, a cell membrane penetrant antioxidant, on mitochondrial and synaptic protein integrity as well as cognitive performance. Electron microscopic analysis revealed mitochondrial/synaptic deterioration in 10 months-old SAMP8 relative to SAMR1 mice, with the changes in the former rescued following 8 weeks treatment with SS31 (5 mg/kg/day, i.p.). Elevation of Aβ42, mitochondrial fission protein (DLP1, Fis1) and matrix protein cyclophilin D (CypD), and reductions of mitochondrial fusion protein (Mfn2) and synaptic (i.e. synaptophysin, postsynaptic density protein 95 and growth associated protein 43) proteins, were detected in hippocampal lysates in SAMP8 mice relative to SAMR1. The above altered protein expressions in the SAMP8 mouse brain were restored with the SS31 treatment. Moreover, the SS31 treatment rescued learning and memory deficits detected in 10 month-old SAMP8 mice. Together, the findings suggest that this mitochondria-targeting antioxidant peptide may be of potential utility for AD therapy, with its pharmacological efficacy involves lowering of central Aβ levels and protection of mitochondrial homeostasis and synaptic integrity, which may help slow down cognitive decline. PMID:26679857

  8. Imaging noradrenergic influence on amyloid pathology in mouse models of Alzheimer's disease

    International Nuclear Information System (INIS)

    Molecular imaging aims towards the non-invasive characterization of disease-specific molecular alterations in the living organism in vivo. In that, molecular imaging opens a new dimension in our understanding of disease pathogenesis, as it allows the non-invasive determination of the dynamics of changes on the molecular level. The imaging technology being employed includes magnetic resonance imaging (MRI) and nuclear imaging as well as optical-based imaging technologies. These imaging modalities are employed together or alone for disease phenotyping, development of imaging-guided therapeutic strategies and in basic and translational research. In this study, we review recent investigations employing positron emission tomography and MRI for phenotyping mouse models of Alzheimers' disease by imaging. We demonstrate that imaging has an important role in the characterization of mouse models of neurodegenerative diseases. (orig.)

  9. Imaging noradrenergic influence on amyloid pathology in mouse models of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Winkeler, A.; Waerzeggers, Y.; Klose, A.; Monfared, P.; Thomas, A.V.; Jacobs, A.H. [Max Planck Institute for Neurological Research with Klaus-Joachim-Zuelch-Laboratories of the Max Planck Society and the Faculty of Medicine of the University of Cologne, Laboratory for Gene Therapy and Molecular Imaging, Cologne (Germany); Centre for Molecular Medicine Cologne (CMMC), Cologne (Germany); Schubert, M. [Centre for Molecular Medicine Cologne (CMMC), Cologne (Germany); Heneka, M.T. [Centre for Molecular Medicine Cologne (CMMC), Cologne (Germany); University of Muenster, Department of Neurology, Muenster (Germany)

    2008-03-15

    Molecular imaging aims towards the non-invasive characterization of disease-specific molecular alterations in the living organism in vivo. In that, molecular imaging opens a new dimension in our understanding of disease pathogenesis, as it allows the non-invasive determination of the dynamics of changes on the molecular level. The imaging technology being employed includes magnetic resonance imaging (MRI) and nuclear imaging as well as optical-based imaging technologies. These imaging modalities are employed together or alone for disease phenotyping, development of imaging-guided therapeutic strategies and in basic and translational research. In this study, we review recent investigations employing positron emission tomography and MRI for phenotyping mouse models of Alzheimers' disease by imaging. We demonstrate that imaging has an important role in the characterization of mouse models of neurodegenerative diseases. (orig.)

  10. Cellular uptake of PLGA nanoparticles targeted with anti-amyloid and anti-transferrin receptor antibodies for Alzheimer's disease treatment.

    Science.gov (United States)

    Loureiro, Joana A; Gomes, Bárbara; Fricker, Gert; Coelho, Manuel A N; Rocha, Sandra; Pereira, Maria Carmo

    2016-09-01

    During the last few decades, relevant efforts have been reported to design nanocarriers for drug transport through the blood brain barrier (BBB). New drugs, such as peptide iAβ5, capable to inhibit the aggregates associated with Alzheimeŕs disease (AD) are being tested but the most frequent drawback is to reach the brain in the desired concentrations due to the low BBB permeability-surface area. Our approach, as a proof of concept to improve drug transport through the BBB, is based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles with surface functionalized with anti-transferrin receptor monoclonal antibody (OX26) and anti-Aβ (DE2B4) to deliver encapsulated iAβ5 into the brain. Porcine brain capillary endothelial cells (PBCECs) were used as a BBB model to evaluate the system efficacy and toxicity. The uptake of immune nanoparticles with a controlled delivery of the peptide iAβ5 was substantially increased compared to the nanoparticles (NPs) without monoclonal antibody functionalization. PMID:27131092

  11. A novel approach to the identification and quantitative elemental analysis of amyloid deposits-Insights into the pathology of Alzheimer's disease

    International Nuclear Information System (INIS)

    There is considerable interest in the role of metals such as iron, copper, and zinc in amyloid plaque formation in Alzheimer's disease. However to convincingly establish their presence in plaques in vivo, a sensitive technique is required that is both quantitatively accurate and avoids isolation of plaques or staining/fixing brain tissue, since these processes introduce contaminants and redistribute elements within the tissue. Combining the three ion beam techniques of scanning transmission ion microscopy, Rutherford back scattering spectrometry and particle induced X-ray emission in conjunction with a high energy (MeV) proton microprobe we have imaged plaques in freeze-dried unstained brain sections from CRND-8 mice, and simultaneously quantified iron, copper, and zinc. Our results show increased metal concentrations within the amyloid plaques compared with the surrounding tissue: iron (85 ppm compared with 42 ppm), copper (16 ppm compared to 6 ppm), and zinc (87 ppm compared to 34 ppm).

  12. Molecular Dynamics Study on the Inhibition Mechanisms of Drugs CQ1-3 for Alzheimer Amyloid-β40 Aggregation Induced by Cu(2.).

    Science.gov (United States)

    Dong, Mingyan; Li, Haoyue; Hu, Dingkun; Zhao, Wei; Zhu, Xueying; Ai, Hongqi

    2016-05-18

    The aggregation of amyloid-β (Aβ) peptide induced by Cu(2+) is a key factor in development of Alzheimer's disease (AD), and metal ion chelation therapy enables treatment of AD. Three CQi (i = 1, 2, and 3 with R = H, Cl, and NO2, respectively) drugs had been verified experimentally to be much stronger inhibitors than the pioneer clioquinol (CQ) in both disaggregation of Aβ40 aggregate and reduction of toxicity induced by Cu(2+) binding at low pH. Due to the multiple morphologies of Cu(2+)-Aβ40 complexes produced at different pH states, we performed a series of molecular dynamics simulations to explain the structural changes and morphology characteristics as well as intrinsic disaggregation mechanisms of three Cu(2+)-Aβ40 models in the presence of any of the three CQi drugs at both low and high pH states. Three inhibition mechanisms for CQi were proposed as "insertion", "semi-insertion", and "surface" mechanisms, based on the morphologies of CQi-model x (CQi-x, x = 1, 2, and 3) and the strengths of binding between CQi and the corresponding model x. The insertion mechanism was characterized by the morphology with binding strength of more than 100 kJ/mol and by CQi being inserted or embedded into the hydrophobic cavity of model x. In those CQi-x morphologies with lower binding strength, CQi only attaches on the surface or inserts partly into Aβ peptide. Given the evidence that the binding strength is correlated positively with the effectiveness of drug to inhibit Aβ aggregation and thus to reduce toxicity, the data of binding strength presented here can provide a reference for one to screen drugs. From the point of view of binding strength, CQ2 is the best drug. Because of the special role of Asp23 in both Aβ aggregation and stabilizing the Aβ fibril, the generation of a H-bond between CQ3 and Asp23 of the Aβ40 peptide is believed to be responsible for CQ3 having the strongest disaggregation capacity. Therefore, besides strong binding, stronger propensity to

  13. Restraint stress and repeated CRF receptor activation in the amygdala both increase amyloid β precursor protein (APP) and amyloid-β (Aβ) peptide but have divergent effects on BDNF and pre-synaptic proteins in the prefrontal cortex of rats

    OpenAIRE

    Ray, Balmiki; Gaskins, Denise L.; Sajdyk, Tammy J.; Spence, John P.; Fitz, Stephanie D.; Shekhar, Anantha; Lahiri, Debomoy K.

    2011-01-01

    Both environmental stress and anxiety may represent important risk factors for Alzheimer's disease (AD) pathogenesis. Previous studies demonstrate that restraint stress is associated with increased amyloid beta (Aβ) and decreased brain-derived neurotrophic factor (BDNF) levels in the brain. Aβ deposition, synaptic loss, and neurodegeneration define major hallmarks of AD, and BDNF is responsible for the maintenance of neurons. In contrast to restraint stress, repeated injections of sub-anxioge...

  14. The new β amyloid-derived peptide Aβ1-6A2V-TAT(D) prevents Aβ oligomer formation and protects transgenic C. elegans from Aβ toxicity.

    Science.gov (United States)

    Diomede, Luisa; Romeo, Margherita; Cagnotto, Alfredo; Rossi, Alessandro; Beeg, Marten; Stravalaci, Matteo; Tagliavini, Fabrizio; Di Fede, Giuseppe; Gobbi, Marco; Salmona, Mario

    2016-04-01

    One attractive pharmacological strategy for Alzheimer's disease (AD) is to design small peptides to interact with amyloid-β (Aβ) protein reducing its aggregation and toxicity. Starting from clinical observations indicating that patients coding a mutated Aβ variant (AβA2V) in the heterozygous state do not develop AD, we developed AβA2V synthetic peptides, as well as a small peptide homologous to residues 1-6. These hindered the amyloidogenesis of Aβ and its neurotoxicity in vitro, suggesting a basis for the design of a new small peptide in D-isomeric form, linked to the arginine-rich TAT sequence [Aβ1-6A2V-TAT(D)], to allow translocation across biological membranes and the blood-brain barrier. Aβ1-6A2V-TAT(D) was resistant to protease degradation, stable in serum and specifically able to interfere with Aβ aggregation in vitro, reducing the appearance of toxic soluble species and protecting transgenic C. elegans from toxicity related to the muscular expression of human Aβ. These observations offer a proof of concept for future pharmacological studies in mouse models of AD, providing a foundation for the design of AβA2V-based peptidomimetic molecules for therapeutic purposes. PMID:26792398

  15. Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer's disease and ROCK1 depletion reduces amyloid-β levels in brain.

    Science.gov (United States)

    Henderson, Benjamin W; Gentry, Erik G; Rush, Travis; Troncoso, Juan C; Thambisetty, Madhav; Montine, Thomas J; Herskowitz, Jeremy H

    2016-08-01

    Alzheimer's disease (AD) is the leading cause of dementia and mitigating amyloid-β (Aβ) levels may serve as a rational therapeutic avenue to slow AD progression. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb Aβ levels, and mechanisms that underlie ROCK2's effects on Aβ production are defined. How ROCK1 affects Aβ generation remains a critical barrier. Here, we report that ROCK1 protein levels were elevated in mild cognitive impairment due to AD (MCI) and AD brains compared to controls. Aβ42 oligomers marginally increased ROCK1 and ROCK2 protein levels in neurons but strongly induced phosphorylation of Lim kinase 1 (LIMK1), suggesting that Aβ42 activates ROCKs. RNAi depletion of ROCK1 or ROCK2 suppressed endogenous Aβ40 production in neurons, and Aβ40 levels were reduced in brains of ROCK1 heterozygous knock-out mice compared to wild-type littermate controls. ROCK1 knockdown decreased amyloid precursor protein (APP), and treatment with bafilomycin accumulated APP levels in neurons depleted of ROCK1. These observations suggest that reduction of ROCK1 diminishes Aβ levels by enhancing APP protein degradation. Collectively, these findings support the hypothesis that both ROCK1 and ROCK2 are therapeutic targets to combat Aβ production in AD. Mitigating amyloid-β (Aβ) levels is a rational strategy for Alzheimer's disease (AD) treatment, however, therapeutic targets with clinically available drugs are lacking. We hypothesize that Aβ accumulation in mild cognitive impairment because of AD (MCI) and AD activates the RhoA/ROCK pathway which in turn fuels production of Aβ. Escalation of this cycle over the course of many years may contribute to the buildup of amyloid pathology in MCI and/or AD. PMID:27246255

  16. Butyrylcholinesterase is Associated with β-Amyloid Plaques in the Transgenic APPSWE/PSEN1dE9 Mouse Model of Alzheimer Disease

    OpenAIRE

    Darvesh, Sultan; Cash, Meghan K.; Reid, G. Andrew; Martin, Earl; Mitnitski, Arnold; Geula, Changiz

    2012-01-01

    Histochemical analysis of Alzheimer disease (AD) brain tissues indicates that butyrylcholinesterase (BuChE) is present in β-amyloid (Aβ) plaques. The role of BuChE in AD pathology is unknown but an animal model developing similar BuChE-associated Aβ plaques could provide insights. The APPSWE/PSEN1dE9 mouse (ADTg), which develops Aβ plaques, was examined to determine if BuChE associates with these plaques, as in AD. We found that in mature ADTg mice, BuChE activity associated with Aβ plaques. ...

  17. 1α,25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-β phagocytosis and inflammation in Alzheimer's disease patients

    OpenAIRE

    Mizwicki, MT; Liu, G; Fiala, M.; Magpantay, L.; J. Sayre; Siani, A.; Mahanian, M; Weitzman, R; Hayden, EY; Rosenthal, MJ; Nemere, I; Ringman, J; Teplow, DB

    2013-01-01

    As immune defects in amyloid-β (Aβ) phagocytosis and degradation underlie Aβ deposition and inflammation in Alzheimer's disease (AD) brain, better understanding of the relation between Aβ phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD patients and controls: 1α,25(OH)2-vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-Aβ by AD macrophages...

  18. Korrelation klinischer Parameter mit der Anreicherung eines in-vivo Indikators für Amyloid bei Patienten mit Demenz bei Alzheimer-Krankheit

    OpenAIRE

    Grimmer, Timo

    2009-01-01

    In der vorgelegten Arbeit ist zunächst die Hypothese geprüft worden, dass zwischen dem klinischen Schweregrad des dementiellen Syndroms, eingeschätzt an Hand der CDR, und der zerebralen Aufnahme des Radiopharmakons PIB als Maß für die Menge des abgelagerten cerebralen Amyloid-Proteins, bei Patienten mit Alzheimer-Krankheit ein positiver Zusammenhang bestehe. Ein statistisch signifikanter Zusammenhang zwischen diesen beiden Maßen ist gezeigt worden. Die Stärke des Zusammenhangs liegt in einer ...

  19. Amyloid β Protein Aggravates Neuronal Senescence and Cognitive Deficits in 5XFAD Mouse Model of Alzheimer's Disease

    Science.gov (United States)

    Wei, Zhen; Chen, Xiao-Chun; Song, Yue; Pan, Xiao-Dong; Dai, Xiao-Man; Zhang, Jing; Cui, Xiao-Li; Wu, Xi-Lin; Zhu, Yuan-Gui

    2016-01-01

    Background: Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in the AD brains, Aβ accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model. Methods: The 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aβ (oAβ) (1–42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence. Results: In 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as Iba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAβ (1–42) induced the production of senescence-related protein p16, but not p53 in vitro, which was in line with the in vivo manifestation. Conclusions: oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population. PMID

  20. Systematic review of the relationship between amyloid-β levels and measures of transgenic mouse cognitive deficit in Alzheimer's disease.

    Science.gov (United States)

    Foley, Avery M; Ammar, Zeena M; Lee, Robert H; Mitchell, Cassie S

    2015-01-01

    Amyloid-β (Aβ) is believed to directly affect memory and learning in Alzheimer's disease (AD). It is widely suggested that there is a relationship between Aβ40 and Aβ42 levels and cognitive performance. In order to explore the validity of this relationship, we performed a meta-analysis of 40 peer-reviewed, published AD transgenic mouse studies that quantitatively measured Aβ levels in brain tissue after assessing cognitive performance. We examined the relationship between Aβ levels (Aβ40, Aβ42, or the ratio of Aβ42 to Aβ40) and cognitive function as measured by escape latency times in the Morris water maze or exploratory preference percentage in the novel object recognition test. Our systematic review examined five mouse models (Tg2576, APP, PS1, 3xTg, APP(OSK)-Tg), gender, and age. The overall result revealed no statistically significant correlation between quantified Aβ levels and experimental measures of cognitive function. However, enough of the trends were of the same sign to suggest that there probably is a very weak qualitative trend visible only across many orders of magnitude. In summary, the results of the systematic review revealed that mice bred to show elevated levels of Aβ do not perform significantly worse in cognitive tests than mice that do not have elevated Aβ levels. Our results suggest two lines of inquiry: 1) Aβ is a biochemical "side effect" of the AD pathology; or 2) learning and memory deficits in AD are tied to the presence of qualitatively "high" levels of Aβ but are not quantitatively sensitive to the levels themselves. PMID:25362040

  1. Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice

    Science.gov (United States)

    Rhein, Virginie; Song, Xiaomin; Wiesner, Andreas; Ittner, Lars M.; Baysang, Ginette; Meier, Fides; Ozmen, Laurence; Bluethmann, Horst; Dröse, Stefan; Brandt, Ulrich; Savaskan, Egemen; Czech, Christian; Götz, Jürgen; Eckert, Anne

    2009-01-01

    Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ)-containing plaques, neurofibrillary tangles, and neuron and synapse loss. Tangle formation has been reproduced in P301L tau transgenic pR5 mice, whereas APPswPS2N141I double-transgenic APP152 mice develop Aβ plaques. Cross-breeding generates triple transgenic (tripleAD) mice that combine both pathologies in one model. To determine functional consequences of the combined Aβ and tau pathologies, we performed a proteomic analysis followed by functional validation. Specifically, we obtained vesicular preparations from tripleAD mice, the parental strains, and nontransgenic mice, followed by the quantitative mass-tag labeling proteomic technique iTRAQ and mass spectrometry. Within 1,275 quantified proteins, we found a massive deregulation of 24 proteins, of which one-third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Notably, deregulation of complex I was tau dependent, whereas deregulation of complex IV was Aβ dependent, both at the protein and activity levels. Synergistic effects of Aβ and tau were evident in 8-month-old tripleAD mice as only they showed a reduction of the mitochondrial membrane potential at this early age. At the age of 12 months, the strongest defects on OXPHOS, synthesis of ATP, and reactive oxygen species were exhibited in the tripleAD mice, again emphasizing synergistic, age-associated effects of Aβ and tau in perishing mitochondria. Our study establishes a molecular link between Aβ and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics. PMID:19897719

  2. Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein-specific antibodies.

    Science.gov (United States)

    Höfling, Corinna; Morawski, Markus; Zeitschel, Ulrike; Zanier, Elisa R; Moschke, Katrin; Serdaroglu, Alperen; Canneva, Fabio; von Hörsten, Stephan; De Simoni, Maria-Grazia; Forloni, Gianluigi; Jäger, Carsten; Kremmer, Elisabeth; Roßner, Steffen; Lichtenthaler, Stefan F; Kuhn, Peer-Hendrik

    2016-10-01

    Alzheimer's disease (AD) is histopathologically characterized by neurodegeneration, the formation of intracellular neurofibrillary tangles and extracellular Aβ deposits that derive from proteolytic processing of the amyloid precursor protein (APP). As rodents do not normally develop Aβ pathology, various transgenic animal models of AD were designed to overexpress human APP with mutations favouring its amyloidogenic processing. However, these mouse models display tremendous differences in the spatial and temporal appearance of Aβ deposits, synaptic dysfunction, neurodegeneration and the manifestation of learning deficits which may be caused by age-related and brain region-specific differences in APP transgene levels. Consequentially, a comparative temporal and regional analysis of the pathological effects of Aβ in mouse brains is difficult complicating the validation of therapeutic AD treatment strategies in different mouse models. To date, no antibodies are available that properly discriminate endogenous rodent and transgenic human APP in brains of APP-transgenic animals. Here, we developed and characterized rat monoclonal antibodies by immunohistochemistry and Western blot that detect human but not murine APP in brains of three APP-transgenic mouse and one APP-transgenic rat model. We observed remarkable differences in expression levels and brain region-specific expression of human APP among the investigated transgenic mouse lines. This may explain the differences between APP-transgenic models mentioned above. Furthermore, we provide compelling evidence that our new antibodies specifically detect endogenous human APP in immunocytochemistry, FACS and immunoprecipitation. Hence, we propose these antibodies as standard tool for monitoring expression of endogenous or transfected APP in human cells and APP expression in transgenic animals. PMID:27470171

  3. Nanoformulated alpha-mangostin ameliorates Alzheimer's disease neuropathology by elevating LDLR expression and accelerating amyloid-beta clearance.

    Science.gov (United States)

    Yao, Lei; Gu, Xiao; Song, Qingxiang; Wang, Xiaolin; Huang, Meng; Hu, Meng; Hou, Lina; Kang, Ting; Chen, Jun; Chen, Hongzhuan; Gao, Xiaoling

    2016-03-28

    Alzheimer's disease (AD), the most common form of dementia, is now representing one of the largest global healthcare challenges. However, an effective therapy is still lacking. Accumulation of amyloid-beta (Aβ) in the brain is supposed to trigger pathogenic cascades that eventually lead to AD. Therefore, Aβ clearance strategy is being actively pursued as a promising disease modifying therapy. Here, we found that α-mangostin (α-M), a polyphenolic xanthone derivative from mangosteen, up-regulated low density lipoprotein receptor (LDLR) expression in microglia and liver cells, and efficiently facilitated Aβ clearance. However, the in vivo application of α-M is limited due to its hydrophobic nature, poor aqueous solubility and stability, and thus low bioavailability and accumulation in the target organs. To overcome this limitation, α-M was encapsulated into the core of poly(ethylene glycol)-poly(l-lactide) (PEG-PLA) nanoparticles [NP(α-M)]. Such nanoencapsulation improved the biodistribution of α-M in both the brain and liver, enhanced the brain clearance of (125)I-radiolabeled Aβ1-42 in an LDLR-dependent manner, reduced Aβ deposition, attenuated neuroinflammatory responses, ameliorated neurologic changes and reversed behavioral deficits in AD model mice. These findings justified the concept that polyphenol-mediated modulation of LDLR expression might serve as a safe and efficient disease-modifying therapy for AD by accelerating Aβ clearance. It also demonstrated the powerful capacity of nanotechnology in modulating the biodistribution behavior of drug to improve its therapeutic efficacy in AD. PMID:26836197

  4. Neuronal histamine and cognitive symptoms in Alzheimer's disease.

    Science.gov (United States)

    Zlomuzica, Armin; Dere, Dorothea; Binder, Sonja; De Souza Silva, Maria Angelica; Huston, Joseph P; Dere, Ekrem

    2016-07-01

    Alzheimer's disease is a neurodegenerative disorder characterized by extracellular amyloid plaque deposits, mainly composed of amyloid-beta peptide and intracellular neurofibrillary tangles consisting of aggregated hyperphosphorylated tau protein. Amyloid-beta represents a neurotoxic proteolytic cleavage product of amyloid precursor protein. The progressive cognitive decline that is associated with Alzheimer's disease has been mainly attributed to a deficit in cholinergic neurotransmission due to the continuous degeneration of cholinergic neurons e.g. in the basal forebrain. There is evidence suggesting that other neurotransmitter systems including neuronal histamine also contribute to the development and maintenance of Alzheimer's disease-related cognitive deficits. Pathological changes in the neuronal histaminergic system of such patients are highly predictive of ensuing cognitive deficits. Furthermore, histamine-related drugs, including histamine 3 receptor antagonists, have been demonstrated to alleviate cognitive symptoms in Alzheimer's disease. This review summarizes findings from animal and clinical research on the relationship between the neuronal histaminergic system and cognitive deterioration in Alzheimer's disease. The significance of the neuronal histaminergic system as a promising target for the development of more effective drugs for the treatment of cognitive symptoms is discussed. Furthermore, the option to use histamine-related agents as neurogenesis-stimulating therapy that counteracts progressive brain atrophy in Alzheimer's disease is considered. This article is part of a Special Issue entitled 'Histamine Receptors'. PMID:26025658

  5. Generation of amyloid-β is reduced by the interaction of calreticulin with amyloid precursor protein, presenilin and nicastrin.

    Directory of Open Access Journals (Sweden)

    Nina Stemmer

    Full Text Available Dysregulation of the proteolytic processing of amyloid precursor protein by γ-secretase and the ensuing generation of amyloid-β is associated with the pathogenesis of Alzheimer's disease. Thus, the identification of amyloid precursor protein binding proteins involved in regulating processing of amyloid precursor protein by the γ-secretase complex is essential for understanding the mechanisms underlying the molecular pathology of the disease. We identified calreticulin as novel amyloid precursor protein interaction partner that binds to the γ-secretase cleavage site within amyloid precursor protein and showed that this Ca(2+- and N-glycan-independent interaction is mediated by amino acids 330-344 in the C-terminal C-domain of calreticulin. Co-immunoprecipitation confirmed that calreticulin is not only associated with amyloid precursor protein but also with the γ-secretase complex members presenilin and nicastrin. Calreticulin was detected at the cell surface by surface biotinylation of cells overexpressing amyloid precursor protein and was co-localized by immunostaining with amyloid precursor protein and presenilin at the cell surface of hippocampal neurons. The P-domain of calreticulin located between the N-terminal N-domain and the C-domain interacts with presenilin, the catalytic subunit of the γ-secretase complex. The P- and C-domains also interact with nicastrin, another functionally important subunit of this complex. Transfection of amyloid precursor protein overexpressing cells with full-length calreticulin leads to a decrease in amyloid-β42 levels in culture supernatants, while transfection with the P-domain increases amyloid-β40 levels. Similarly, application of the recombinant P- or C-domains and of a synthetic calreticulin peptide comprising amino acid 330-344 to amyloid precursor protein overexpressing cells result in elevated amyloid-β40 and amyloid-β42 levels, respectively. These findings indicate that the interaction of

  6. Effect of curcumin and Cu 2+/Zn 2+ ions on the fibrillar aggregates formed by the amyloid peptide and other peptides at the organic-aqueous interface

    Science.gov (United States)

    Sanghamitra, Nusrat J. M.; Varghese, Neenu; Rao, C. N. R.

    2010-08-01

    Characteristic features of a perilous neuro-degenerative disease such as the Alzhiemer's disease is fibrillar plaque formation by the amyloid (Aβ) peptide. We have modelled the formation and disintegration of fibrils by studying the aggregate structures formed by Aβ structural motif diphenylalanine as well as insulin and bovine serum albumin at the organic-aqueous interface. Even small concentrations of curcumin in the organic medium or Cu 2+ and Zn 2+ ions in the aqueous medium are found to break down the fibrillar structures.

  7. Effect of cholesterol and amyloidpeptide on structure and function of mixed-lipid films and pulmonary surfactant BLES: an atomic force microscopy study.

    Science.gov (United States)

    Hane, Francis; Drolle, Elizabeth; Leonenko, Zoya

    2010-12-01

    Pulmonary surfactant forms a thin molecular film inside mammalian lung alveoli and lowers the surface tension of the air/fluid interface to reduce the work of breathing. Upon compression functional surfactant forms characteristic multilayer structures, which indicate surfactant surface activity. We showed that cholesterol adversely affects both structural and surface-active properties of BLES surfactant and DPPC/DOPG lipid films. Incorporation of small concentrations of fibril-forming peptide amyloid-β 1-40 helps to counteract the distractive effect of cholesterol by improving characteristic multilayer formation that occurs upon compression. In contrast to many negative effects of amyloid-forming peptides reported earlier, we report a positive effect of amyloidpeptide on surfactant function, which may aid in the designing of novel surfactant formulations. PMID:20493966

  8. Molecular dynamics studies of the inhibitory mechanism of copper(Ⅱ) on aggregation of amyloid β-peptide

    Institute of Scientific and Technical Information of China (English)

    Yong Jiao; Pin Yang

    2007-01-01

    The inhibitory mechanism of copper(Ⅱ) on the aggregation of amyloid β-peptide (Aβ) was investigated by molecular dynamics simulations. The binding mode of copper(Ⅱ) with Aβ is characterized by the imidazole nitrogen atom, Nπ, of the histidine residue H13,acting as the anchoring site, and the backbone's deprotoned amide nitrogen atoms as the main binding sites. Drove by the coordination bonds and their induced hydrogen bond net, the conformations of Aβ converted from β-sheet non-β-sheet conformations, which destabilized the aggregation of Aβ into fibrils.

  9. Depression and Plasma Amyloid β Peptides in the Elderly with and without the Apolipoprotein E4 Allele

    OpenAIRE

    Sun, Xiaoyan; Chiu, Chi Chia; Liebson, Elizabeth; Crivello, Natalia A.; Wang, Lixia; Caunch, Joshua; Folstein, Marshal; Rosenberg, Irwin; Mwamburi, D. Mkaya; Peter, Inga; Qiu, Wei Qiao

    2009-01-01

    Depression associated with low plasma Amyloidpeptide 42 (Aβ42) leading to a high ratio of Aβ40/Aβ42, a biomarker of Alzheimer’s disease (AD), may represent a unique depression subtype. The relationship between low plasma Aβ42 in depression and the major risk factor of AD, Apolipoprotein E4 (ApoE4), is unknown. With the goal of clarifying this relationship, we analyzed 1060 homebound elders with ApoE characterization and depression status in a cross-sectional study. Plasma Aβ40 and Aβ42 wer...

  10. Cryogenic solid state NMR studies of fibrils of the Alzheimer’s disease amyloidpeptide: perspectives for DNP

    International Nuclear Information System (INIS)

    Dynamic Nuclear Polarization solid-state NMR holds the potential to enable a dramatic increase in sensitivity by exploiting the large magnetic moment of the electron. However, applications to biological solids are hampered in uniformly isotopically enriched biomacromolecules due to line broadening which yields a limited spectral resolution at cryogenic temperatures. We show here that high magnetic fields allow to overcome the broadening of resonance lines often experienced at liquid nitrogen temperatures. For a fibril sample of the Alzheimer’s disease β-amyloid peptide, we find similar line widths at low temperature and at room temperature. The presented results open new perspectives for structural investigations in the solid-state

  11. Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

    OpenAIRE

    Bayer, Thomas A; Schäfer, Stephanie; Simons, Andreas; Kemmling, André; Kamer, Thomas; Tepests, Ralf; Eckert, Anne; Schüssel, Katrin; Eikenberg, Oliver; Sturchler-Pierrat, Christine; Abramowski, Dorothee; Staufenbiel, Matthias; Multhaup, Gerd

    2003-01-01

    The Cu-binding β-amyloid precursor protein (APP), and the amyloidpeptide have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced Cu homeostasis with a causative or diagnostic link to Alzheimer's disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in Aβ levels in APP-transfected cells in vitro. To investigate the...

  12. New Alzheimer amyloid beta responsive genes identified in human neuroblastoma cells by hierarchical clustering.

    Directory of Open Access Journals (Sweden)

    Markus Uhrig

    Full Text Available Alzheimer's disease (AD is characterized by neuronal degeneration and cell loss. Abeta(42, in contrast to Abeta(40, is thought to be the pathogenic form triggering the pathological cascade in AD. In order to unravel overall gene regulation we monitored the transcriptomic responses to increased or decreased Abeta(40 and Abeta(42 levels, generated and derived from its precursor C99 (C-terminal fragment of APP comprising 99 amino acids in human neuroblastoma cells. We identified fourteen differentially expressed transcripts by hierarchical clustering and discussed their involvement in AD. These fourteen transcripts were grouped into two main clusters each showing distinct differential expression patterns depending on Abeta(40 and Abeta(42 levels. Among these transcripts we discovered an unexpected inverse and strong differential expression of neurogenin 2 (NEUROG2 and KIAA0125 in all examined cell clones. C99-overexpression had a similar effect on NEUROG2 and KIAA0125 expression as a decreased Abeta(42/Abeta(40 ratio. Importantly however, an increased Abeta(42/Abeta(40 ratio, which is typical of AD, had an inverse expression pattern of NEUROG2 and KIAA0125: An increased Abeta(42/Abeta(40 ratio up-regulated NEUROG2, but down-regulated KIAA0125, whereas the opposite regulation pattern was observed for a decreased Abeta(42/Abeta(40 ratio. We discuss the possibilities that the so far uncharacterized KIAA0125 might be a counter player of NEUROG2 and that KIAA0125 could be involved in neurogenesis, due to the involvement of NEUROG2 in developmental neural processes.

  13. New Alzheimer Amyloid β Responsive Genes Identified in Human Neuroblastoma Cells by Hierarchical Clustering

    Science.gov (United States)

    Uhrig, Markus; Ittrich, Carina; Wiedmann, Verena; Knyazev, Yuri; Weninger, Annette; Riemenschneider, Matthias; Hartmann, Tobias

    2009-01-01

    Alzheimer's disease (AD) is characterized by neuronal degeneration and cell loss. Aβ42, in contrast to Aβ40, is thought to be the pathogenic form triggering the pathological cascade in AD. In order to unravel overall gene regulation we monitored the transcriptomic responses to increased or decreased Aβ40 and Aβ42 levels, generated and derived from its precursor C99 (C-terminal fragment of APP comprising 99 amino acids) in human neuroblastoma cells. We identified fourteen differentially expressed transcripts by hierarchical clustering and discussed their involvement in AD. These fourteen transcripts were grouped into two main clusters each showing distinct differential expression patterns depending on Aβ40 and Aβ42 levels. Among these transcripts we discovered an unexpected inverse and strong differential expression of neurogenin 2 (NEUROG2) and KIAA0125 in all examined cell clones. C99-overexpression had a similar effect on NEUROG2 and KIAA0125 expression as a decreased Aβ42/Aβ40 ratio. Importantly however, an increased Aβ42/Aβ40 ratio, which is typical of AD, had an inverse expression pattern of NEUROG2 and KIAA0125: An increased Aβ42/Aβ40 ratio up-regulated NEUROG2, but down-regulated KIAA0125, whereas the opposite regulation pattern was observed for a decreased Aβ42/Aβ40 ratio. We discuss the possibilities that the so far uncharacterized KIAA0125 might be a counter player of NEUROG2 and that KIAA0125 could be involved in neurogenesis, due to the involvement of NEUROG2 in developmental neural processes. PMID:19707560

  14. New Alzheimer amyloid beta responsive genes identified in human neuroblastoma cells by hierarchical clustering.

    Science.gov (United States)

    Uhrig, Markus; Ittrich, Carina; Wiedmann, Verena; Knyazev, Yuri; Weninger, Annette; Riemenschneider, Matthias; Hartmann, Tobias

    2009-01-01

    Alzheimer's disease (AD) is characterized by neuronal degeneration and cell loss. Abeta(42), in contrast to Abeta(40), is thought to be the pathogenic form triggering the pathological cascade in AD. In order to unravel overall gene regulation we monitored the transcriptomic responses to increased or decreased Abeta(40) and Abeta(42) levels, generated and derived from its precursor C99 (C-terminal fragment of APP comprising 99 amino acids) in human neuroblastoma cells. We identified fourteen differentially expressed transcripts by hierarchical clustering and discussed their involvement in AD. These fourteen transcripts were grouped into two main clusters each showing distinct differential expression patterns depending on Abeta(40) and Abeta(42) levels. Among these transcripts we discovered an unexpected inverse and strong differential expression of neurogenin 2 (NEUROG2) and KIAA0125 in all examined cell clones. C99-overexpression had a similar effect on NEUROG2 and KIAA0125 expression as a decreased Abeta(42)/Abeta(40) ratio. Importantly however, an increased Abeta(42)/Abeta(40) ratio, which is typical of AD, had an inverse expression pattern of NEUROG2 and KIAA0125: An increased Abeta(42)/Abeta(40) ratio up-regulated NEUROG2, but down-regulated KIAA0125, whereas the opposite regulation pattern was observed for a decreased Abeta(42)/Abeta(40) ratio. We discuss the possibilities that the so far uncharacterized KIAA0125 might be a counter player of NEUROG2 and that KIAA0125 could be involved in neurogenesis, due to the involvement of NEUROG2 in developmental neural processes. PMID:19707560

  15. Hydrogen sulfide inhibits beta-amyloid peptide-induced apoptosis in PC12 cells and the underlying mechanisms

    Institute of Scientific and Technical Information of China (English)

    Xiuqin Chen; Jingtian Li; Jinhui Zou; Bailing Li; Meng Wang

    2008-01-01

    BACKGROUND: Studies have demonstrated that hydrogen sulfide (H2S) levels are 55% lower in brains of Alzheimer's disease (AD) patients than in age-matched normal individuals, which suggests that H2S might be involved in some aspects of AD pathogenesis.OBJECTIVE: To observe the protective mechanisms of varied concentrations of H2S against β -amyloid-peptide (A β) induced apoptosis in pheochromoytoma (PC12) cells, and to analyze the pathway of action.DESIGN, TIME AND SETTING: A controlled, observational, in vitro experiment was performed at Nenrophysiology Laboratory in Zhougshan Medical School, Sun Yat-sen University between July 2006 and May 2007.MATERIALS: PC12 cells were provided by the Animal Experimental Center of Medical School of Sun Yat-sen University. Glybenclamide, rhodamine123, and dihydrorhodamine123 were purchased from Sigma (USA).METHODS: PCI2 cells were incubated at 37℃ in a 5% CO2-enriched incubator with RPMI-1640 medium, supplemented with 5% horse-serum and 10% fetal bovine serum. Cells in logarithmic growth curves received different treatment: The PC12 cells were maintains at 37℃ with the original medium, then incubated in A β 25-35, sodium hydrosulfide (NariS), glybenclamide, NailS+ A β 25-35, or pretreated with glybenelamide 30 minutes prior to administration of and A β 25-35, respectively. MAIN OUTCOME MEASURES: (1) The survival rate of PC12 cells was detected by MTT assay and Hoechst staining. (2) The apoptosis rate of PC12 cells was detected utilizing flow cytometry with propidium iodide staining, and morphological changes of apoptotic cells were observed. (3) The mitochondrial membrane potential was detected by Rhodamine 123-combined flow cytometry. (4) The intracellular reactive oxygen species content was detected by dihydrorhodamine123-combined flow cytometry. RESULTS: A β 25-35 induced significantly decreased viability and increased percentage of apoptosis in PC 12 cells, as well as dissipated mitochondrial membrane potential

  16. Aggregation properties of a short peptide that mediates amyloid fibril formation in model proteins unrelated to disease

    Indian Academy of Sciences (India)

    Nitin Chaudhary; Shashi Singh; Ramakrishnan Nagaraj

    2011-09-01

    Short peptides have been identified from amyloidogenic proteins that form amyloid fibrils in isolation. The hexapeptide stretch 21DIDLHL26 has been shown to be important in the self-assembly of the Src homology 3 (SH3) domain of p85 subunit of bovine phosphatidylinositol-3-kinase (PI3-SH3). The SH3 domain of chicken brain -spectrin, which is otherwise non-amyloidogenic, is rendered amyloidogenic if 22EVTMKK27 is replaced by DIDLHL. In this article, we describe the aggregation behaviour of DIDLHL-COOH and DIDLHL-CONH2. Our results indicate that DIDLHL-COOH and DIDLHL-CONH2 aggregate to form spherical structures at pH 5 and 6. At pH 5, in the presence of mica, DIDLHL-CONH2 forms short fibrous structures. The presence of NaCl along with mica results in fibrillar structures. At pH 6, DIDLHL-CONH2 forms largely spherical aggregates. Both the peptides are unstructured in solution but adopt -conformation on drying. The aggregates formed by DIDLHL-COOH and DIDLHL-CONH2 are formed during drying process and their structures are modulated by the presence of mica and salt. Our study suggests that a peptide need not have intrinsic amyloidogenic propensity to facilitate the selfassembly of the full-length protein. The propensity of peptides to form self-assembled structures that are non-amyloidogenic could be important in potentiating the self-assembly of full-length proteins into amyloid fibrils.

  17. First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression.

    Science.gov (United States)

    Cummings, Damian M; Liu, Wenfei; Portelius, Erik; Bayram, Sevinç; Yasvoina, Marina; Ho, Sui-Hin; Smits, Hélène; Ali, Shabinah S; Steinberg, Rivka; Pegasiou, Chrysia-Maria; James, Owain T; Matarin, Mar; Richardson, Jill C; Zetterberg, Henrik; Blennow, Kaj; Hardy, John A; Salih, Dervis A; Edwards, Frances A

    2015-07-01

    Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-β. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloidpeptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloidpeptides in a mouse model of increasing amyloid-β ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloidpeptides were above the limit of detection, including amyloid-β40, amyloid-β38 and amyloid-β42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-β levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-β40 rose by ∼7-fold, but amyloid-β42 rose by 25-fold, increasing the amyloid-β42:amyloid-β40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P < 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P < 0.001, n = 7). Hence synaptic changes occur when the amyloid-β levels and amyloid-β42:amyloid-β40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly

  18. Novel β-amyloid aggregation inhibitors possessing a turn mimic.

    Science.gov (United States)

    Hamada, Yoshio; Miyamoto, Naoko; Kiso, Yoshiaki

    2015-04-01

    Amyloid β peptide, the main component of senile plaques found in the brain of Alzheimer disease (AD) patients, is a molecular target for AD therapeutic intervention. A number of potential AD therapeutics have been reported, including inhibitors of β-secretase, γ-secretase, and Aβ aggregation, and anti-amyloid agents, such as neprilysin, insulin degrading enzyme (IDE), and Aβ antibodies. Recently, we reported potent small-sized β-secretase (BACE1) inhibitors, which could serve as anti-AD drugs. However AD is a progressive disorder, where dementia symptoms gradually worsen over several decades, and therefore may require many years to get cured. One possible way to achieve a greater therapeutic effect is through simultaneous administration of multiple drugs, similar to those used in Highly Active Anti-Retroviral Therapy (HAART) used to treat AIDS. In order to overcome AD, we took a drug discovery approach to evaluate, novel β-amyloid aggregation inhibitors. Previously, we reported that a tong-type compound possessing a turn mimic as the inhibitor of HIV-1 protease dimerization. Oligomerized amyloid β peptides contain a turn structure within the molecule. Here, we designed and synthesized novel β-amyloid aggregation inhibitors with a turn-mimic template, based on the turn conformer of the oligomerized amyloid β peptides. PMID:25736996

  19. Quantitative longitudinal interrelationships between brain metabolism and amyloid deposition during a 2-year follow-up in patients with early Alzheimer's disease

    International Nuclear Information System (INIS)

    Similar regional anatomical distributions were reported for fibrillary amyloid deposition [measured by 11C-Pittsburgh compound B (PIB) positron emission tomography (PET)] and brain hypometabolism [measured by 18F-fluorodeoxyglucose (FDG) PET] in numerous Alzheimer's disease (AD) studies. However, there is a lack of longitudinal studies evaluating the interrelationships of these two different pathological markers in the same AD population. Our most recent AD study suggested that the longitudinal pattern of hypometabolism anatomically follows the pattern of amyloid deposition with temporal delay, which indicates that neuronal dysfunction may spread within the anatomical pattern of amyloid pathology. Based on this finding we now hypothesize that in early AD patients quantitative longitudinal decline in hypometabolism may be related to the amount of baseline amyloid deposition during a follow-up period of 2 years. Fifteen patients with mild probable AD underwent baseline (T1) and follow-up (T2) examination after 24 ± 2.1 months with [18F]FDG PET, [11C]PIB PET, structural T1-weighted MRI and neuropsychological testing [Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery]. Longitudinal cognitive measures and quantitative PET measures of amyloid deposition and metabolism [standardized uptake value ratios (SUVRs)] were obtained using volume of interest (VOI)-based approaches in the frontal-lateral-retrosplenial (FLR) network and in predefined bihemispheric brain regions after partial volume effect (PVE) correction of PET data. Statistical group comparisons (SUVRs and cognitive measures) between patients and 15 well-matched elderly controls who had undergone identical imaging procedures once as well as Pearson's correlation analyses within patients were performed. Group comparison revealed significant cognitive decline and increased mean PIB/decreased FDG SUVRs in the FLR network as well as in several AD-typical regions in patients

  20. Quantitative longitudinal interrelationships between brain metabolism and amyloid deposition during a 2-year follow-up in patients with early Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Foerster, Stefan [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Technische Universitaet Muenchen, TUM-Neuroimaging Center (TUM-NIC), Munich (Germany); Technische Universitaet Muenchen (TUM), Klinik und Poliklinik fuer Nuklearmedizin, Klinikum rechts der Isar, Munich (Germany); Yousefi, Behrooz H.; Wester, Hans-Juergen; Klupp, Elisabeth [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Rominger, Axel [Ludwig Maximilians Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Foerstl, Hans; Kurz, Alexander; Grimmer, Timo [Technische Universitaet Muenchen, Department of Psychiatry and Psychotherapy, Munich (Germany); Drzezga, Alexander [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Technische Universitaet Muenchen, TUM-Neuroimaging Center (TUM-NIC), Munich (Germany)

    2012-12-15

    Similar regional anatomical distributions were reported for fibrillary amyloid deposition [measured by {sup 11}C-Pittsburgh compound B (PIB) positron emission tomography (PET)] and brain hypometabolism [measured by {sup 18}F-fluorodeoxyglucose (FDG) PET] in numerous Alzheimer's disease (AD) studies. However, there is a lack of longitudinal studies evaluating the interrelationships of these two different pathological markers in the same AD population. Our most recent AD study suggested that the longitudinal pattern of hypometabolism anatomically follows the pattern of amyloid deposition with temporal delay, which indicates that neuronal dysfunction may spread within the anatomical pattern of amyloid pathology. Based on this finding we now hypothesize that in early AD patients quantitative longitudinal decline in hypometabolism may be related to the amount of baseline amyloid deposition during a follow-up period of 2 years. Fifteen patients with mild probable AD underwent baseline (T1) and follow-up (T2) examination after 24 {+-} 2.1 months with [{sup 18}F]FDG PET, [{sup 11}C]PIB PET, structural T1-weighted MRI and neuropsychological testing [Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery]. Longitudinal cognitive measures and quantitative PET measures of amyloid deposition and metabolism [standardized uptake value ratios (SUVRs)] were obtained using volume of interest (VOI)-based approaches in the frontal-lateral-retrosplenial (FLR) network and in predefined bihemispheric brain regions after partial volume effect (PVE) correction of PET data. Statistical group comparisons (SUVRs and cognitive measures) between patients and 15 well-matched elderly controls who had undergone identical imaging procedures once as well as Pearson's correlation analyses within patients were performed. Group comparison revealed significant cognitive decline and increased mean PIB/decreased FDG SUVRs in the FLR network as well as

  1. Neuropathology of Alzheimer's Disease

    Science.gov (United States)

    Perl, Daniel P.

    2010-01-01

    Alois Alzheimer first pointed out that the disease which would later bear his name has a distinct and recognizable neuropathological substrate. Since then, much has been added to our understanding of the pathological lesions associated with the condition. The 2 primary cardinal lesions associated with Alzheimer's disease are the neurofibrillary tangle and the senile plaque. The neurofibrillary tangle consists of abnormal accumulations of abnormally phosphorylated tau within the perikaryal cytoplasm of certain neurons. The senile plaque consists of a central core of beta-amyloid, a 4-kD peptide, surrounded by abnormally configured neuronal processes or neurites. Other neuropathological lesions are encountered in cases of Alzheimer's disease, but the disease is defined and recognized by these 2 cardinal lesions. Other lesions include poorly understood changes such as granulovacuolar degeneration and eosinophilic rod-like bodies (Hirano bodies). The loss of synaptic components is a change that clearly has a significant impact on cognitive function and represents another important morphological alteration. It is important to recognize that distinguishing between Alzheimer's disease, especially in its early stages, and normal aging may be very difficult, particularly if one is examining the brains of patients who died at an advanced old age. It is also noted that instances of pure forms of Alzheimer's disease, in the absence of other coexistent brain disease processes, such as infarctions or Parkinson's disease–related lesions, are relatively uncommon, and this must be taken into account by researchers who employ postmortem brain tissues for research. PMID:20101720

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

    International Nuclear Information System (INIS)

    Complementing clinical findings with those generated by biomarkers - such as β-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 ([18F]BAY 94-9172) is a novel β-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 μg. 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 β-amyloid load''. Visual analysis of the PET data revealed nine of the ten AD, but only one of the ten HC brains to be β-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 β-amyloid load yielded the closest correlation with

  3. Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer’s disease

    OpenAIRE

    Wang, Chiou-Miin; deVries, Sarah; Camboni, Marybeth; Glass, Matthew; Martin, Paul T.

    2010-01-01

    Vaccination has become an important therapeutic approach to the treatment of Alzheimer’s disease (AD), however, immunization with Aβ amyloid can have unwanted, potentially lethal, side effects. Here we demonstrate an alternative peptide-mimotope vaccine strategy using the SDPM1 peptide. SDPM1 is a 20 amino acid peptide bounded by cysteines that binds tetramer forms of Aβ1–40- and Aβ1–42-amyloid and blocks subsequent Aβ amyloid aggregation. Immunization of mice with SDPM1 induced peptide mimot...

  4. Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism

    Directory of Open Access Journals (Sweden)

    Anckarsäter Henrik

    2010-06-01

    Full Text Available Abstract Background The metabolism of amyloid precursor protein (APP and β-amyloid (Aβ is widely studied in Alzheimer's disease, where Aβ deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB. Methods The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy and 22 healthy controls. CSF was analysed for the β-amyloid peptides Aβ38, Aβ40 and Aβ42, and the amyloid precursor protein (APP isoforms α-sAPP and β-sAPP. CSF total-tau (T-tau, phosphorylated tau (P-tau and neurofilament protein (NFL were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers. Results In the cross-sectional study, LNB patients had lower levels of CSF α-sAPP, β-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF α-sAPP, β-sAPP and P-tau at baseline, which all increased towards normal at follow-up. Conclusions Amyloid metabolism is altered in LNB. CSF levels of α-sAPP, β-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.

  5. Effects of Amyloid Precursor Protein 17 Peptide on the Protection of Diabetic Encephalopathy and Improvement of Glycol Metabolism in the Diabetic Rat

    Directory of Open Access Journals (Sweden)

    Heng Meng

    2013-01-01

    Full Text Available Researchers have proposed that amyloid precursor protein 17 peptide (APP17 peptide, an active fragment of amyloid precursor protein (APP in the nervous system, has therapeutic effects on neurodegeneration. Diabetic encephalopathy (DE is a neurological disease caused by diabetes. Here we use multiple experimental approaches to investigate the effect of APP17 peptide on changes in learning behavior and glycol metabolism in rats. It was found that rats with DE treated by APP17 peptide showed reversed behavioral alternation. The [18F]-FDG-PET images and other results all showed that the APP17 peptide could promote glucose metabolism in the brain of the DE rat model. Meanwhile, the insulin signaling was markedly increased as shown by increased phosphorylation of Akt and enhanced GLUT4 activation. Compared with the DE group, the activities of SOD, GSH-Px, and CAT in the rat hippocampal gyrus were increased, while MDA decreased markedly in the DE + APP17 peptide group. No amyloid plaques in the cortex and the hippocampus were detected in either group, indicating that the experimental animals in the current study were not suffering from Alzheimer’s disease. These results indicate that APP17 peptide could be used to treat DE effectively.

  6. Nucleic Acid Aptamers as Novel Class of Therapeutics to Mitigate Alzheimer's Disease Pathology

    DEFF Research Database (Denmark)

    K. Tannenberg, Rudi; Al. Shamaileh, Hadi; Lauridsen, Lasse Holm; R. Kanwar, Jagat; R. Dodd, Peter; N. Veedu, Rakesh

    2013-01-01

    Deposition of amyloid-beta (A beta) peptides in the brain is a central event in the pathogenesis of Alzheimer's disease (AD), which makes A beta peptides a crucial target for therapeutic intervention. Significant efforts have been made towards the development of ligands that bind to A beta peptides...... with a goal of early detection of amyloid aggregation and the neutralization of A toxicity. Short single-stranded oligonucleotide aptamers bind with high affinity and specificity to their targets. Aptamers that specifically bind to A beta monomers, specifically the 40 and 42 amino acid species (A beta...

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  8. Alzheimer's disease-related amyloid-β induces synaptotoxicity in human iPS cell-derived neurons.

    Science.gov (United States)

    Nieweg, K; Andreyeva, A; van Stegen, B; Tanriöver, G; Gottmann, K

    2015-01-01

    Human induced pluripotent stem cell (iPSC)-derived neurons have been proposed to be a highly valuable cellular model for studying the pathomechanisms of Alzheimer's disease (AD). Studies employing patient-specific human iPSCs as models of familial and sporadic forms of AD described elevated levels of AD-related amyloid-β (Aβ). However, none of the present AD iPSC studies could recapitulate the synaptotoxic actions of Aβ, which are crucial early events in a cascade that eventually leads to vast brain degeneration. Here we established highly reproducible, human iPSC-derived cortical cultures as a cellular model to study the synaptotoxic effects of Aβ. We developed a highly efficient immunopurification procedure yielding immature neurons that express markers of deep layer cortical pyramidal neurons and GABAergic interneurons. Upon long-term cultivation, purified cells differentiated into mature neurons exhibiting the generation of action potentials and excitatory glutamatergic and inhibitory GABAergic synapses. Most interestingly, these iPSC-derived human neurons were strongly susceptible to the synaptotoxic actions of Aβ. Application of Aβ for 8 days led to a reduction in the overall FM4-64 and vGlut1 staining of vesicles in neurites, indicating a loss of vesicle clusters. A selective analysis of presynaptic vesicle clusters on dendrites did not reveal a significant change, thus suggesting that Aβ impaired axonal vesicle clusters. In addition, electrophysiological patch-clamp recordings of AMPA receptor-mediated miniature EPSCs revealed an Aβ-induced reduction in amplitudes, indicating an impairment of postsynaptic AMPA receptors. A loss of postsynaptic AMPA receptor clusters was confirmed by immunocytochemical stainings for GluA1. Incubation with Aβ for 8 days did not result in a significant loss of neurites or cell death. In summary, we describe a highly reproducible cellular AD model based on human iPSC-derived cortical neurons that enables the

  9. The detection of β-amyloid plaques in an Alzheimer's disease rat model with DDNP-SPIO

    International Nuclear Information System (INIS)

    Aim: To detect the β-amyloid plaques (Aβ) in a rat model of Alzheimer's disease (AD) using superparamagnetic iron oxide nanoparticles coated with 1,1-dicyano-2-[6-(dimethylamino)-naphthalene-2-yl] propene carboxyl derivative (DDNP-SPIO). Materials and methods: DDNP-SPIO was prepared in a previous trial. The binding affinity of DDNP-SPIO to Aβ was tested using fluorescence spectrophotometry in vitro. In vivo, five AD rats and five non-AD rats were intravenously injected with DDNP-SPIO at a dose of 76 μmol Fe/kg. Coronal T2*-weighted images were collected at baseline and repeated at 10, 30, and 60 min post-injection. Enhancement features of the two groups were analysed. After imaging, brain specimens were resected for Congo red and Prussian blue staining to assess the binding of DDNP-SPIO to Aβ deposits. Results: In vitro experiments indicated that the DDNP-SPIO nanoparticles displayed high binding affinities towards Aβ with a Kd value of 29.4 nmol/l. A significant decrease in SI was detected in the hippocampal area of AD rats after intravenous injection of the nanoparticles, but not in non-AD rats. The measurement of the percentage signal loss decreased to 52% in AD rats. In non-AD rats, only 10% signal loss was observed. There was a significant difference between the two groups (t = 4.533, p < 0.05). The signal decrease resulted from the binding of the DDNP-SPIO nanoparticles to the Aβ plaques, which was identified with Congo red and Prussian blue staining. Conclusion: The DDNP-SPIO nanoparticles could potentially be used for visualizing Aβ plaques, which may be helpful for diagnosing the early stages of AD and monitoring the effects of drug therapy. - Highlights: • A new targeted nanoparticle (DDNP-SPIO) for MRI detection of Aβ was synthesized • The DDNP-SPIO nanoparticles has the ability to detect the Aβ deposites in AD rats • The DDNP-SPIO nanoparticles could potentially be used for visualizing Aβ plaques, which may be helpful for

  10. Alzheimer's disease and amyloid beta-peptide deposition in the brain: a matter of 'aging'?

    DEFF Research Database (Denmark)

    Moro, Maria Luisa; Collins, Matthew J; Cappellini, Enrico

    2010-01-01

    Biomolecules can experience aging processes that limit their long-term functionality in organisms. Typical markers of protein aging are spontaneous chemical modifications, such as AAR (amino acid racemization) and AAI (amino acid isomerization), mainly involving aspartate and asparagine residues...... changes associated with molecular aging also have significant long-term consequences for Abeta folding and turnover. New fast, reproducible and accurate methods for the screening of protein aging markers in biological samples may contribute to improve diagnostic and therapeutic approaches in AD....

  11. Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-β1-42 peptide in mice.

    Science.gov (United States)

    Souza, Leandro Cattelan; Jesse, Cristiano R; Antunes, Michelle S; Ruff, Jossana Rodrigues; de Oliveira Espinosa, Dieniffer; Gomes, Nathalie Savedra; Donato, Franciele; Giacomeli, Renata; Boeira, Silvana Peterini

    2016-08-01

    Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by a progressive cognitive decline along with various neuropsychiatric symptoms, including depression and anxiety. Increasing evidence has been proposed the activation of the tryptophan-degrading indoleamine-2,3-dyoxigenase (IDO), the rate-limiting enzyme of kynurerine pathway (KP), as a pathogenic factor of amyloid-beta (Aβ)-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of Aβ1-42 peptide (400pmol/mice; 3μl/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of Aβ1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that Aβ1-42 induced memory impairment in the object recognition test. Aβ1-42 also induced emotional alterations, such as depressive and anxiety-like behaviors, as evaluated in the tail suspension and elevated-plus maze tests, respectively. We observed an increase in levels of proinflammatory cytokines in the Aβ1-42-treated mice, which led to an increase in IDO activity in the prefrontal cortex (PFC) and the hippocampus (HC). The IDO activation subsequently increased kynurerine production and the kynurenine/tryptophan ratio and decreased the levels of neurotrophic factors in the PFC and HC, which contributed to Aβ-associated behavioral disturbances. The inhibition of IDO activation by IDO inhibitor 1-methyltryptophan (1-MT), prevented the development of behavioral and neurochemical alterations. These data demonstrate that brain IDO activation plays a key role in mediating the memory and emotional disturbances in an experimental model based on Aβ-induced neuroinflammation. PMID:26965653

  12. Quantification of molecular interactions between ApoE, amyloid-beta (Aβ) and laminin: Relevance to accumulation of Aβ in Alzheimer's disease.

    Science.gov (United States)

    Zekonyte, Jurgita; Sakai, Kenji; Nicoll, James A R; Weller, Roy O; Carare, Roxana O

    2016-05-01

    Accumulation of amyloid-β (Aβ) in plaques in the brain and in artery walls as cerebral amyloid angiopathy indicates a failure of elimination of Aβ from the brain with age and Alzheimer's disease. A major pathway for elimination of Aβ and other soluble metabolites from the brain is along basement membranes within the walls of cerebral arteries that represent the lymphatic drainage pathways for the brain. The motive force for the elimination of Aβ along this perivascular pathway appears to be the contrary (reflection) wave that follows the arterial pulse wave. Following injection into brain parenchyma, Aβ rapidly drains out of the brain along basement membranes in the walls of cerebral arteries; such drainage is impaired in apolipoprotein E ε4 (ApoE4) mice. For drainage of Aβ to occur in a direction contrary to the pulse wave, some form of attachment to basement membrane would be required to prevent reflux of Aβ back into the brain during the passage of the subsequent pulse wave. In this study, we show first that apolipoprotein E co-localizes with Aβ in basement membrane drainage pathways in the walls of arteries. Secondly, we show by Atomic Force Microscopy that attachment of ApoE4/Aβ complexes to basement membrane laminin is significantly weaker than ApoE3/Aβ complexes. These results suggest that perivascular elimination of ApoE4/Aβ complexes would be less efficient than with other isoforms of apolipoprotein E, thus endowing a higher risk for Alzheimer's disease. Therapeutic correction for ApoE4/Aβ/laminin interactions may increase the efficiency of elimination of Aβ in the prevention of Alzheimer's disease. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26327683

  13. Designer Self-Assemble Peptides Maximize the Therapeutic Benefits of Neural Stem Cell Transplantation for Alzheimer's Disease via Enhancing Neuron Differentiation and Paracrine Action.

    Science.gov (United States)

    Cui, Guo-hong; Shao, Shui-jin; Yang, Jia-jun; Liu, Jian-ren; Guo, Hai-dong

    2016-03-01

    The neuropathological hallmarks of Alzheimer's disease (AD) include the presence of extracellular amyloidpeptide (Aβ) in the form of amyloid plaques and neuronal loss. Neural stem cell (NSC) is being scrutinized as a promising cell replacement therapy for various neurodegenerative diseases. However, the unfavorable niche at the site of degenerative disease is hostile to the survival and differentiation of transplanted cells. Here, we undertook in vitro and in vivo works to examine whether a designer self-assemble peptide (DSP), which contains one functional domain Tyr-Ile-Gly-Ser-Arg (YIGSR) derived from laminin, promotes the survival and neuronal differentiation of NSC and behavioral improvement. We found that DSP could undergo spontaneous assembly into well-ordered nanofibers, and it not only facilitated the cell viability in normal culture condition, but also decreased the number of apoptotic cells induced by Aβ in vitro. NSC seeded in DSP showed much more neuronal differentiation than that seeded in self-assemble peptide (SP) or alone. In the AD model, NSC transplantation in DSP-treated AD rats demonstrated much more obvious cognitive rescue with restoration of learning/memory function compared with NSC transplantation in SP, NSC alone, or DSP alone treated ones. Interestingly, DSP enhanced the survival and neuronal differentiation of transplanted NSC. Apoptosis levels in the CA1 region and Aβ level in the hippocampus were significantly decreased in the group of NSC transplantation in DSP. Moreover, synaptic function, indicated by the expression of pre-synaptic protein synapsin-1, was restored and the secretion of anti-inflammatory and neurotrophic factors were increased, such as IL-10, brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and insulin-like growth factor 1 (IGF-1), while the expression of pro-inflammatory factors were decreased, such as TNF-α and IL-1β. These data firstly unveiled that the biomaterial DSP can

  14. Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3β pathway in an amyloid β protein induced alzheimer disease mouse model.

    Science.gov (United States)

    Qi, Liqin; Ke, Linfang; Liu, Xiaohong; Liao, Lianming; Ke, Sujie; Liu, Xiaoying; Wang, Yanping; Lin, Xiaowei; Zhou, Yu; Wu, Lijuan; Chen, Zhou; Liu, Libin

    2016-07-15

    Type 2 diabetes mellitus is a risk factor for Alzheimer's disease (AD). The glucagon-like peptide-1 analog liraglutide, a novel long-lasting incretin hormone, has been used to treat type 2 diabetes mellitus. In addition, liraglutide has been shown to be neurotrophic and neuroprotective. Here, we investigated the effects of liraglutide on amyloid β protein (Aβ)-induced AD in mice and explored its mechanism of action. The results showed that subcutaneous administration of liraglutide (25nmol/day), once daily for 8 weeks, prevented memory impairments in the Y Maze and Morris Water Maze following Aβ1-42 intracerebroventricular injection, and alleviated the ultra-structural changes of pyramidal neurons and chemical synapses in the hippocampal CA1 region. Furthermore, liraglutide reduced Aβ1-42-induced tau phosphorylation via the protein kinase B and glycogen synthase kinase-3β pathways. Thus liraglutide may alleviate cognitive impairment in AD by at least decreasing the phosphorylation of tau. PMID:27131827

  15. Critical analysis of the use of β-site amyloid precursor protein-cleaving enzyme 1 inhibitors in the treatment of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Evin G

    2014-01-01

    Full Text Available Genevieve Evin,1,2 Adel Barakat21Oxidation Biology Laboratory, Mental Health Research Institute, Florey Institute of Neuroscience and Mental Health, University of Melbourne, 2Department of Pathology, University of Melbourne, Parkville, VIC, AustraliaAbstract: Alzheimer's disease (AD is the major cause of dementia in the elderly and an unmet clinical challenge. A variety of therapies that are currently under development are directed to the amyloid cascade. Indeed, the accumulation and toxicity of amyloid-β (Aβ is believed to play a central role in the etiology of the disease, and thus rational interventions are aimed at reducing the levels of Aβ in the brain. Targeting β-site amyloid precursor protein-cleaving enzyme (BACE-1 represents an attractive strategy, as this enzyme catalyzes the initial and rate-limiting step in Aβ production. Observation of increased levels of BACE1 and enzymatic activity in the brain, cerebrospinal fluid, and platelets of patients with AD and mild cognitive impairment supports the potential benefits of BACE1 inhibition. Numerous potent inhibitors have been generated, and many of these have been proved to lower Aβ levels in the brain of animal models. Over 10 years of intensive research on BACE1 inhibitors has now culminated in advancing half a dozen of these drugs into human trials, yet translating the in vitro and cellular efficacy of BACE1 inhibitors into preclinical and clinical trials represents a challenge. This review addresses the promises and also the potential problems associated with BACE1 inhibitors for AD therapy, as the complex biological function of BACE1 in the brain is becoming unraveled.Keywords: amyloid, dementia, secretase, aspartyl protease, neuregulin

  16. Monodisperse carboxyl-functionalized poly(ethylene glycol)-coated magnetic poly(glycidyl methacrylate) microspheres: application to the immunocapture of .beta.-amyloid peptides

    Czech Academy of Sciences Publication Activity Database

    Horák, Daniel; Hlídková, Helena; Hiraoui, M.; Taverna, M.; Proks, Vladimír; Mázl Chánová, Eliška; Smadja, C.; Kučerová, Z.

    2014-01-01

    Roč. 14, č. 11 (2014), s. 1590-1599. ISSN 1616-5187 R&D Projects: GA MŠk 7E12053 EU Projects: European Commission(XE) 246513 - NADINE Institutional support: RVO:61389013 Keywords : β-amyloid peptides * CE-LIF detection * functionalization Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.851, year: 2014

  17. The Role of Neurotransmitters in Protection against Amyloid-β Toxicity by KiSS-1 Overexpression in SH-SY5Y Neurons

    OpenAIRE

    Chilumuri, Amrutha; Milton, Nathaniel G. N.

    2013-01-01

    Recent studies have suggested that the kisspeptin (KP) and kissorphin (KSO) peptides have neuroprotective actions against the Alzheimer's amyloid- β (A β ) peptide. Overexpression of the human KiSS-1 gene that codes for KP and KSO peptides in SH-SY5Y neurons has also been shown to inhibit A β neurotoxicity. The in vivo actions of KP include activation of neuroendocrine and neurotransmitter systems. The present study used antagonists of KP, neuropeptide FF (NPFF), opioids, oxytocin, estrogen, ...

  18. Fibpredictor: a computational method for rapid prediction of amyloid fibril structures.

    Science.gov (United States)

    Tabatabaei Ghomi, Hamed; Topp, Elizabeth M; Lill, Markus A

    2016-09-01

    Amyloid fibrils are important in diseases such as Alzheimer's disease and Parkinson's disease, and are also a common instability in peptide and protein drug products. Despite their importance, experimental structures of amyloid fibrils in atomistic detail are rare. To address this limitation, we have developed a novel, rapid computational method to predict amyloid fibril structures (Fibpredictor). The method combines β-sheet model building, β-sheet replication, and symmetry operations with side-chain prediction and statistical scoring functions. When applied to nine amyloid fibrils with experimentally determined structures, the method predicted the correct structures of amyloid fibrils and enriched those among the top-ranked structures. These models can be used as the initial heuristic structures for more complicated computational studies. Fibpredictor is available at http://nanohub.org/resources/fibpredictor . PMID:27502172

  19. Tritium-labeled (E,E)-2,5-Bis(4’-hydroxy-3’-carboxystyryl)benzene as a Probe for β-Amyloid Fibrils

    OpenAIRE

    Matveev, Sergey V.; Kwiatkowski, Stefan; Sviripa, Vitaliy M.; Fazio, Robert C.; Watt, David S.; LeVine, Harry

    2014-01-01

    Accumulation of Aβ in the brains of Alzheimer disease (AD) patients reflects an imbalance between Aβ production and clearance from their brains. Alternative cleavage of amyloid precursor protein (APP) by processing proteases generates soluble APP fragments including the neurotoxic amyloid Aβ40 and Aβ42 peptides that assemble into fibrils and form plaques. Plaque-buildup occurs over an extended time-frame, and the early detection and modulation of plaque formation are areas of active research....

  20. Early stages of amyloid fibril formation studied by liquid-state NMR: the peptide hormone glucagon

    DEFF Research Database (Denmark)

    Svane, Anna Sigrid Pii; Jahn, Kasper; Deva, Taru; Malmendal, Anders; Otzen, Daniel; Dittmer, Jens; Nielsen, Niels Chr

    2008-01-01

    the course of the fibril formation process. Kinetic information is extracted from the time course of the residual free glucagon signal decay. This suggests that glucagon amyloids form by a nucleated growth mechanism in which trimers (rather than monomers) of glucagon interact directly with the growing...

  1. Polymorphism of amyloid fibrils formed by a peptide from the yeast prion protein Sup35: AFM and Tip-Enhanced Raman Scattering studies.

    Science.gov (United States)

    Krasnoslobodtsev, Alexey V; Deckert-Gaudig, Tanja; Zhang, Yuliang; Deckert, Volker; Lyubchenko, Yuri L

    2016-06-01

    Aggregation of prion proteins is the cause of various prion related diseases. The infectious form of prions, amyloid aggregates, exist as multiple strains. The strains are thought to represent structurally different prion protein molecules packed into amyloid aggregates, but the knowledge on the structure of different types of aggregates is limited. Here we report on the use of AFM (Atomic Force Microscopy) and TERS (Tip-Enhanced Raman Scattering) to study morphological heterogeneity and access underlying conformational features of individual amyloid aggregates. Using AFM we identified the morphology of amyloid fibrils formed by the peptide (CGNNQQNY) from the yeast prion protein Sup35 that is critically involved in the aggregation of the full protein. TERS results demonstrate that morphologically different amyloid fibrils are composed of a distinct set of conformations. Fibrils formed at pH 5.6 are composed of a mixture of peptide conformations (β-sheets, random coil and α-helix) while fibrils formed in pH~2 solution primarily have β-sheets. Additionally, peak positions in the amide III region of the TERS spectra suggested that peptides have parallel arrangement of β-sheets for pH~2 fibrils and antiparallel arrangement for fibrils formed at pH 5.6. We also developed a methodology for detailed analysis of the peptide secondary structure by correlating intensity changes of Raman bands in different regions of TERS spectra. Such correlation established that structural composition of peptides is highly localized with large contribution of unordered secondary structures on a fibrillar surface. PMID:27060278

  2. Oligomeric AmyloidPeptide on Sialylic Lewisx–Selectin Bonding at Cerebral Endothelial Surface

    Directory of Open Access Journals (Sweden)

    Sholpan Askarova

    2014-12-01

    Full Text Available Introduction: Alzheimer’s disease (AD is a chronic neurodegenerative disorder, which affects approximately 10% of the population aged 65 and 40% of people over the age 80. Currently, AD is on the list of diseases with no effective treatment. Thus, the study of molecular and cellular mechanisms of AD progression is of high scientific and practical importance. In fact, dysfunction of the blood-brain barrier (BBB plays an important role in the onset and progression of the disease. Increased deposition of amyloid b peptide (Aβ in cerebral vasculature and enhanced transmigration of monocytes across the BBB are frequently observed in AD brains and are some of the pathological hallmarks of the diseases. Since the transmigration of monocytes across the BBB is both a mechanical and a biochemical process, the expression of adhesion molecules and mechanical properties of endothelial cells are the critical factors that require investigation.Methods: Because of recent advances in the biological applications of atomic force microscopy (AFM, we applied AFM with cantilever tips bio-functionalized by sLex in combination with the advanced immunofluorescent microscopy (QIM to study the direct effects of Aβ42 oligomers on the selectins expression, actin polymerization, and cellular mechanical and adhesion properties in cerebral endothelial cells (mouse bEnd3 line and primary human CECs and find a possible way to attenuate these effects. Results: QIM results showed that Aβ42 increased the expressions of P-selectin on the cell surface and enhanced actin polymerization. Consistent with our QIM results, AFM data showed that Aβ42 increased the probability of cell adhesion with sLex-coated cantilever and cell stiffness. These effects were counteracted by lovstatin, a cholesterol-lowering drug.  Surprisingly, the apparent rupture force of sLex-selectin bonding was significantly lower after treatment with Aβ42, as compared with the control (i.e. no treatment

  3. Surface Plasmon Resonance Based Biosensors for Exploring the Influence of Alkaloids on Aggregation of AmyloidPeptide

    Directory of Open Access Journals (Sweden)

    Hanna Radecka

    2011-04-01

    Full Text Available The main objective of the presented study was the development of a simple analytical tool for exploring the influence of naturally occurring compounds on the aggregation of amyloidpeptide (Aβ40 in order to find potential anti-neurodegenerative drugs. The gold discs used for surface plasmon resonance (SPR measurements were modified with thioaliphatic acid. The surface functionalized with carboxylic groups was used for covalent attaching of Aβ40 probe by creation of amide bonds in the presence of EDC/NHS. The modified SPR gold discs were used for exploring the Aβ40 aggregation process in the presence of selected alkaloids: arecoline hydrobromide, pseudopelletierine hydrochloride, trigonelline hydrochloride and α-lobeline hydrochloride. The obtained results were discussed with other parameters which govern the phenomenon studied such as lipophilicity/ hydrophilicy and Aβ40-alkaloid association constants.

  4. The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae

    DEFF Research Database (Denmark)

    Hansson Petersen, Camilla A; Alikhani, Nyosha; Behbahani, Homira;

    2008-01-01

    The amyloid beta-peptide (Abeta) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Abeta and accumulation of Abeta has been detected in mitochondria. Because Abeta is not likely to be produced locally in mitochondria, we decided to...... investigate the mechanisms for mitochondrial Abeta uptake. Our results from rat mitochondria show that Abeta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane...... potential. Subfractionation studies following the import experiments revealed Abeta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Abeta to mitochondrial cristae. A similar distribution pattern of Abeta in mitochondria was shown by...

  5. Regulatory T cells delay disease progression in Alzheimer-like pathology.

    Science.gov (United States)

    Dansokho, Cira; Ait Ahmed, Dylla; Aid, Saba; Toly-Ndour, Cécile; Chaigneau, Thomas; Calle, Vanessa; Cagnard, Nicolas; Holzenberger, Martin; Piaggio, Eliane; Aucouturier, Pierre; Dorothée, Guillaume

    2016-04-01

    Recent studies highlight the implication of innate and adaptive immunity in the pathophysiology of Alzheimer's disease, and foster immunotherapy as a promising strategy for its treatment. Vaccines targeting amyloidpeptide provided encouraging results in mouse models, but severe side effects attributed to T cell responses in the first clinical trial AN1792 underlined the need for better understanding adaptive immunity in Alzheimer's disease. We previously showed that regulatory T cells critically control amyloid-β-specific CD4(+)T cell responses in both physiological and pathological settings. Here, we analysed the impact of regulatory T cells on spontaneous disease progression in a murine model of Alzheimer's disease. Early transient depletion of regulatory T cells accelerated the onset of cognitive deficits in APPPS1 mice, without altering amyloid-β deposition. Earlier cognitive impairment correlated with reduced recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, amplification of regulatory T cells through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia, and restored cognitive functions in APPPS1 mice. These data suggest that regulatory T cells play a beneficial role in the pathophysiology of Alzheimer's disease, by slowing disease progression and modulating microglial response to amyloid-β deposition. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of regulatory T cells in Alzheimer's disease. PMID:26912648

  6. Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation

    Energy Technology Data Exchange (ETDEWEB)

    Sievers, Stuart A.; Karanicolas, John; Chang, Howard W.; Zhao, Anni; Jiang, Lin; Zirafi, Onofrio; Stevens, Jason T.; Münch, Jan; Baker, David; Eisenberg, David (UCLA); (UWASH); (UL); (Kansas); (Ulm)

    2011-09-20

    Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-{beta}-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.

  7. Noopept efficiency in experimental Alzheimer disease (cognitive deficiency caused by beta-amyloid25-35 injection into Meynert basal nuclei of rats).

    Science.gov (United States)

    Ostrovskaya, R U; Belnik, A P; Storozheva, Z I

    2008-07-01

    Experiments on adult Wistar rats showed that injection of beta-amyloid25-35 (2 microg) into Meynert basal nuclei caused long-term memory deficiency which was detected 24 days after this injection by the memory trace retrieval in conditioned passive avoidance reflex (CPAR). The effects of noopept, an original nootropic and neuroprotective dipeptide, on the severity of this cognitive deficiency were studied. Preventive (for 7 days before the injury) intraperitoneal injections of noopept in a dose of 0.5 mg/kg completely prevented mnestic disorders under conditions of this model. Noopept exhibited a significant normalizing effect, if the treatment was started 15 days after the injury, when neurodegenerative changes in the basal nuclei, cortex, and hippocampus were still acutely pronounced. The mechanisms of this effect of the drug are studied, including, in addition to the choline-positive effect, its multicomponent neuroprotective effect and stimulation of production of antibodies to beta-amyloid25-35. Noopept efficiency in many models of Alzheimer disease, its high bioavailability and low toxicity suggest this dipeptide for further studies as a potential agent for the treatment of this condition (initial and moderate phases). PMID:19145356

  8. Dependence pH and proposed mechanism for aggregation of Alzheimer's disease-related amyloid-β(1-42) protein

    Science.gov (United States)

    Kobayashi, Shigeki; Tanaka, Yhuki; Kiyono, Mituhiro; Chino, Masahiro; Chikuma, Toshiyuki; Hoshi, Keiko; Ikeshima, Hideaki

    2015-08-01

    It is shown that the aggregation and oligomerization of β-amyloid protein (Aβ1-42) are strongly dependent on solution pH. Ionic forms of the side bands of Aβ1-42 were generated by adjusting the pH using different buffer solutions. As a result, it was possible to establish a relationship between the aggregation of Aβ1-42 and the pH. In addition, to gain insight into the mechanism of Aβ1-42 aggregation, aggregation models for Aβ17-42 (2-13 mer prepared at pH 7-8) were computed using a MMFF (molecular mechanics) method. When the pH was greater than the isoelectric point (IP) of Aβ17-42, the aggregation of Aβ17-42 was accelerated by intermolecular ion bridge relay binding of Asp23 with Lys28. Such binding of Asp23 with Lys28 can explain the high level of stability of Aβ fibrils and oligomers (plastic-like biopolymers found in the amyloid plaques observed in the brains of patients with Alzheimer's disease) produced as the result of Aβ aggregation. At pH 9.5, Aβ1-42 aggregation was not observed experimentally, because the side chain of Lys28 contained unprotonated amino groups (-NH2, not -NH3+). This result was also confirmed using the MMFF method.

  9. β-Amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues

    International Nuclear Information System (INIS)

    Progressive cerebral deposition of extracellular filaments composed of the β-amyloid protein (βAP) is a constant feature of Alzheimer disease (AD). Since the gene on chromosome 21 encoding the βAP precursor (βAPP) is not known to be altered in AD, transcriptional or posttranslational changes may underlie accelerated βAP deposition. Using two antibodies to the predicted carboxyl terminus of βAPP, the authors have identified the native βAPP in brain and nonneural human tissues as a 110- to 135-kDa protein complex that is insoluble in buffer and found in various membrane-rich subcellular fractions. These proteins are relatively uniformly distributed in adult brain, abundant in fetal brain, and detected in nonneural tissues that contain βAPP mRNA. Similarly sized proteins occur in rat, cow, and monkey brain and in cultured human HL-60 and HeLa cells; the precise patterns in the 110- to 135-kDa range are heterogeneous among various tissues and cell lines. They conclude that the highly conserved βAPP molecule occurs in mammalian tissues as a heterogeneous group of membrane-associated proteins of ∼ 120 kDa. Detection of the nonamyloidogenic carboxyl terminus within plaques suggests that proteolytic processing of the βAPP into insoluble filaments occurs locally in cortical regions that develop β-amyloid deposits with age

  10. Selenomethionine reduces the deposition of beta-amyloid plaques by modulating β-secretase and enhancing selenoenzymatic activity in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Zhang, Zhong-Hao; Chen, Chen; Wu, Qiu-Yan; Zheng, Rui; Liu, Qiong; Ni, Jia-Zuan; Hoffmann, Peter R; Song, Guo-Li

    2016-08-01

    Alzheimer's disease (AD) is characterized by the production of large amounts of beta-amyloid (Aβ) and the accumulation of extracellular senile plaques, which have been considered to be potential targets in the treatment of AD. Selenium (Se) is a nutritionally essential trace element with known antioxidant potential and Se status has been shown to decrease with age and has a close relationship with cognitive competence in AD. Selenomethionine (Se-Met), a major reserve form of Se in organisms, has been shown in our previous study to ameliorate the decline in cognitive function, increase oxidation resistance, and reduce tau hyperphosphorylation in a triple transgenic mouse model of AD. However, it has not been reported whether Se-Met has any effects on Aβ pathology in AD mice. To study the effect of Se-Met on Aβ pathology and the function of selenoproteins/selenoenzymes in 3× Tg-AD mice, 3× Tg-AD mice at 8 months of age were treated with Se-Met for 3 months. Se-Met led to significantly reduced production and deposition of Aβ, down-regulation of β-secretase levels and enhanced activity of selenoenzymes as well as increased levels of Se in the hippocampus and cortex. Se-Met reduces amyloidogenic processing of amyloid precursor protein while modulating β-secretase and selenoenzymatic activity in AD mice. These results indicate that Se-Met might exert its therapeutic effect through multiple pathways in AD. PMID:27465436

  11. An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling.

    Science.gov (United States)

    Hashimoto, Yuichi; Toyama, Yuka; Kusakari, Shinya; Nawa, Mikiro; Matsuoka, Masaaki

    2016-06-01

    A missense mutation (T835M) in the uncoordinated-5C (UNC5C) netrin receptor gene increases the risk of late-onset Alzheimer disease (AD) and also the vulnerability of neurons harboring the mutation to various insults. The molecular mechanisms underlying T835M-UNC5C-induced death remain to be elucidated. In this study, we show that overexpression of wild-type UNC5C causes low-grade death, which is intensified by an AD-linked mutation T835M. An AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1, inhibit this death. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of death-associated protein kinase 1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid β precursor protein (APP). Notably, netrin1 also binds to APP and partially inhibits the death-signaling cascade, induced by APP. These results may provide new insight into the amyloid β-independent pathomechanism of AD. PMID:27068745

  12. Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer's disease with combined amyloid-β and cerebrovascular pathology.

    Directory of Open Access Journals (Sweden)

    Panayiota Papadopoulos

    Full Text Available Animal models of Alzheimer's disease (AD are invaluable in dissecting the pathogenic mechanisms and assessing the efficacy of potential new therapies. Here, we used the peroxisome proliferator-activated receptor gamma agonist pioglitazone in an attempt to rescue the pathogenic phenotype in adult (12 months and aged (>18 months bitransgenic A/T mice that overexpress a mutated human amyloid precursor protein (APPSwe,Ind and a constitutively active form of transforming growth factor-β1 (TGF-β1. A/T mice recapitulate the AD-related cognitive deficits, amyloid beta (Aβ and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone normalized neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort notwithstanding a progressing Aβ pathology. While pioglitazone preserved the constitutive nitric oxide synthesis in the vessel wall, it unexpectedly failed to restore cerebrovascular reactivity in A/T mice and even exacerbated the dilatory deficits. These data demonstrate pioglitazone's efficacy on selective AD hallmarks in a complex AD mouse model of comorbid amyloidosis and cerebrovascular pathology. They further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metabolism in AD patients devoid of cerebrovascular pathology.

  13. Stoichiometric inhibition of amyloid beta-protein aggregation with peptides containing alternating alpha,alpha-disubstituted amino acids.

    Science.gov (United States)

    Etienne, Marcus A; Aucoin, Jed P; Fu, Yanwen; McCarley, Robin L; Hammer, Robert P

    2006-03-22

    We have prepared two peptides based on the hydrophobic core (Lys-Leu-Val-Phe-Phe) of amyloid beta-protein (Abeta) that contain alpha,alpha-disubstituted amino acids at alternating positions, but differ in the positioning of the oligolysine chain (AMY-1, C-terminus; AMY-2, N-terminus). We have studied the effects of AMY-1 and AMY-2 on the aggregation of Abeta and find that, at stoichiometric concentrations, both peptides completely stop Abeta fibril growth. Equimolar mixtures of AMY-1 and Abeta form only globular aggregates as imaged by scanning force microscopy and transmission electron microscopy. These samples show no signs of protofibrillar or fibrillar material even after prolonged periods of time (4.5 months). Also, 10 mol % of AMY-1 prevents Abeta self-assembly for long periods of time; aged samples (4.5 months) show only a few protofibrillar or fibrillar aggregates. Circular dichroism spectroscopy of equimolar mixtures of AMY-1 and Abeta show that the secondary structure of the mixture changes over time and progresses to a predominantly beta-sheet structure, which is consistent with the design of these inhibitors preferring a sheet-like conformation. Changing the position of the charged tail on the peptide, AMY-2 interacts with Abeta differently in that equimolar mixtures form large ( approximately 1 mum) globular aggregates which do not progress to fibrils, but precipitate out of solution. The differences in the aggregation mediated by the two peptides is discussed in terms of a model where the inhibitors act as cosurfactants that interfere with the native ability of Abeta to self-assemble by disrupting hydrophobic interactions either at the C-terminus or N-terminus of Abeta. PMID:16536517

  14. X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-β conformation

    International Nuclear Information System (INIS)

    Information about the structure of the paired helical filaments (PHF) that accumulate within human neurons and the amyloid fibers that accumulate in the extracellular spaces between neurons in Alzheimer disease has so far depended on electron microscopy of thin-sectioned or negatively stained material. To determine the protein conformation of these abnormal fibers, the authors have obtained x-ray diffraction patterns from unfixed human brain fractions highly enriched in PHF and from purified amyloid cores isolated from senile plaques. The predominant x-ray scatter evident from both types of samples, either wet or dry, is a sharp reflection at 4.76-A spacing and a diffuse one at about 10.6-A spacing. These features are characteristic of a β-pleated sheet type of protein conformation. In doubly oriented dried pellets of PHF fractions, the two reflections are accentuated at right angles to each other and the arc at 4.76-A spacing is in the fiber direction indicating a cross-β conformation. From the integral widths of the reflections they estimate the cross-β crystallite to be about 80 A long in the fiber direction and about 40 A thick. These dimensions correspond to approximately four pleated sheets, each of which consists of approximately 16 hydrogen-bonded polypeptide chains running normal to the fiber direction. The cross-β conformation of PHF and amyloid fibers that they have found from x-ray diffraction in is contrast to the predominant α-helical coiled-coil conformation of the neurofilaments with which they share epitopes and from which they have been postulated to derive

  15. Screening for a human single chain Fv antibody against epitope on amyloid-beta 1-40 from a human phage display library

    Institute of Scientific and Technical Information of China (English)

    ZHAO Zhen-fu; GAO Guo-quan; LIU Shu; ZOU Jun-tao; XIE Yao; YUAN Qun-fang; WANG Hua-qiao; YAO Zhi-bin

    2007-01-01

    @@ Amyloid-beta peptides (Aβ) are believed to be responsible for the mental decline in patients with Alzheimer's disease (AD). In 1999, Schenk et al1 reported that immunization with Aβ attenuated AD-like pathology in the PDAPP mouse, and developed a new vaccination approach to AD.

  16. Repeated intraperitoneal injections of liposomes containing phosphatidic acid and cardiolipin reduce amyloid-β levels in APP/PS1 transgenic mice

    DEFF Research Database (Denmark)

    Ordóñez-Gutiérrez, Lara; Re, Francesca; Bereczki, Erika;

    2015-01-01

    UNLABELLED: The accumulation of extracellular amyloid-beta (Aβ) peptide and intracellular neurofibrillary tangles in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). It is thought that an equilibrium exists between Aβ in the brain and in the peripheral blood and th...

  17. Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease.

    Science.gov (United States)

    Salameh, Therese S; Rhea, Elizabeth M; Banks, William A; Hanson, Angela J

    2016-09-01

    An increased risk for Alzheimer's disease is associated with dyslipidemia and insulin resistance. A separate literature shows the genetic risk for developing Alzheimer's disease is strongly correlated to the presence of the E4 isoform of the apolipoprotein E carrier protein. Understanding how apolipoprotein E carrier protein, lipids, amyloid β peptides, glucose, central nervous system insulin, and peripheral insulin interact with one another in Alzheimer's disease is an area of increasing interest. Here, we will review the evidence relating apolipoprotein E carrier protein, lipids, and insulin action to Alzheimer's disease and Aβ peptides and then propose mechanisms as to how these factors might interact with one another to impair cognition and promote Alzheimer's disease. PMID:27470930

  18. Alzheimer's Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein.

    LENUS (Irish Health Repository)

    Barry, Andrew E

    2011-05-18

    Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer\\'s disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.

  19. Vascular aspects of Alzheimer's disease: role of oxidative stress on vascular miocytes B-amyloid production and B-amyloid-induced toxicity in endothelial cells

    OpenAIRE

    Coma Camprod??n, Mireia

    2007-01-01

    En aquest treball de tesis doctoral s'estudia el paper de l'estrès oxidatiu tant a la etiologia com a la patofisiologia del dany vascular associat a la malaltia d'Alzheimer. Es demostra la capacitat de les cèl·lules musculars llises vasculars de produir pèptid β-amiloide (Aβ). L'estrès oxidatiu associat a edats avançades, estimula el processament amiloidogènic de l' APP a cèl·lules musculars llises vasculars portant a un augment de producció d' Aβ1-40 i Aβ1-42 contribuint ...

  20. The Peptide Vaccine Combined with Prior Immunization of a Conventional Diphtheria-Tetanus Toxoid Vaccine Induced Amyloid β Binding Antibodies on Cynomolgus Monkeys and Guinea Pigs

    Directory of Open Access Journals (Sweden)

    Akira Yano

    2015-01-01

    Full Text Available The reduction of brain amyloid beta (Aβ peptides by anti-Aβ antibodies is one of the possible therapies for Alzheimer’s disease. We previously reported that the Aβ peptide vaccine including the T-cell epitope of diphtheria-tetanus combined toxoid (DT induced anti-Aβ antibodies, and the prior immunization with conventional DT vaccine enhanced the immunogenicity of the peptide. Cynomolgus monkeys were given the peptide vaccine subcutaneously in combination with the prior DT vaccination. Vaccination with a similar regimen was also performed on guinea pigs. The peptide vaccine induced anti-Aβ antibodies in cynomolgus monkeys and guinea pigs without chemical adjuvants, and excessive immune responses were not observed. Those antibodies could preferentially recognize Aβ40, and Aβ42 compared to Aβ fibrils. The levels of serum anti-Aβ antibodies and plasma Aβ peptides increased in both animals and decreased the brain Aβ40 level of guinea pigs. The peptide vaccine could induce a similar binding profile of anti-Aβ antibodies in cynomolgus monkeys and guinea pigs. The peptide vaccination could be expected to reduce the brain Aβ peptides and their toxic effects via clearance of Aβ peptides by generated antibodies.

  1. Progress in the development of therapeutic antibodies targeting prion proteins and β-amyloid peptides

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Prion diseases and Alzheimer’s disease (AD) are characterized by protein misfolding, and can lead to dementia. However, prion diseases are infectious and transmissible, while AD is not. The similarities and differences between these diseases have led researchers to perform comparative studies. In the last 2 decades, progress has been made in immunotherapy using anti-prion protein and anti-β-amyloid antibodies. In this study, we review new ideas and strategies for therapeutic antibodies targeting prion diseases and AD through conformation dependence.

  2. APP processing in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Zhang Yun-wu

    2011-01-01

    Full Text Available Abstract An important pathological feature of Alzheimer's disease (AD is the presence of extracellular senile plaques in the brain. Senile plaques are composed of aggregations of small peptides called β-amyloid (Aβ. Multiple lines of evidence demonstrate that overproduction/aggregation of Aβ in the brain is a primary cause of AD and inhibition of Aβ generation has become a hot topic in AD research. Aβ is generated from β-amyloid precursor protein (APP through sequential cleavages first by β-secretase and then by γ-secretase complex. Alternatively, APP can be cleaved by α-secretase within the Aβ domain to release soluble APPα and preclude Aβ generation. Cleavage of APP by caspases may also contribute to AD pathologies. Therefore, understanding the metabolism/processing of APP is crucial for AD therapeutics. Here we review current knowledge of APP processing regulation as well as the patho/physiological functions of APP and its metabolites.

  3. Pomegranate Polyphenols and Extract Inhibit Nuclear Factor of Activated T-Cell Activity and Microglial Activation In Vitro and in a Transgenic Mouse Model of Alzheimer Disease123

    OpenAIRE

    Rojanathammanee, Lalida; Puig, Kendra L.; Combs, Colin K.

    2013-01-01

    Alzheimer disease (AD) brain is characterized by extracellular plaques of amyloid β (Aβ) peptide with reactive microglia. This study aimed to determine whether a dietary intervention could attenuate microgliosis. Memory was assessed in 12-mo-old male amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice via Barnes maze testing followed by division into either a control-fed group provided free access to normal chow and water or a treatment group provided free access to normal chow a...

  4. Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease

    OpenAIRE

    Yahata, Naoki; Asai, Masashi; Kitaoka, Shiho; Takahashi, Kazutoshi; Asaka, Isao; Hioki, Hiroyuki; KANEKO, TAKESHI; Maruyama, Kei; Saido, Takaomi C.; Nakahata, Tatsutoshi; Asada, Takashi; Yamanaka, Shinya; Iwata, Nobuhisa; Inoue, Haruhisa

    2011-01-01

    Background Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug dis...

  5. Sleep and Alzheimer disease pathology—a bidirectional relationship

    OpenAIRE

    Ju, Yo-El S.; Lucey, Brendan P.; Holtzman, David M.

    2013-01-01

    Factors other than age and genetics may increase the risk of developing Alzheimer disease (AD). Accumulation of the amyloid-β (Aβ) peptide in the brain seems to initiate a cascade of key events in the pathogenesis of AD. Moreover, evidence is emerging that the sleep–wake cycle directly influences levels of Aβ in the brain. In experimental models, sleep deprivation increases the concentration of soluble Aβ and results in chronic accumulation of Aβ, whereas sleep extension has the opposite effe...

  6. Why nutraceuticals do not prevent or treat Alzheimer's disease

    OpenAIRE

    Naughton Declan P; Fisher Anna EO

    2005-01-01

    Abstract A great deal of research has pointed to deleterious roles of metal ions in the development of Alzheimer's disease. These include: i) the precipitation and aggregation of amyloid β (Aβ) peptides to form senile plaques and neurofibrillary tangles, and/or ii) the augmentation of oxidative stress by metal ion mediated production and activation of hydrogen peroxide. The growing trend in nutraceutical intake is in part a result of the belief that they postpone the development of dementias ...

  7. Proliferation in the Alzheimer hippocampus is due to microglia, not astroglia, and occurs at sites of amyloid deposition

    NARCIS (Netherlands)

    M.W. Marlatt; J. Bauer; E. Aronica; E.S. van Haastert; J.J.M. Hoozemans; M. Joels; P.J. Lucassen

    2014-01-01

    Microglia and astrocytes contribute to Alzheimer’s disease (AD) etiology and may mediate early neuroinflammatory responses. Despite their possible role in disease progression and despite the fact that they can respond to amyloid deposition in model systems, little is known about whether astro- or mi

  8. 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...

  9. αB-Crystallin inhibits the cell toxicity associated with amyloid fibril formation by κ-casein and the amyloidpeptide

    OpenAIRE

    Dehle, Francis C.; Ecroyd, Heath; Musgrave, Ian F.; Carver, John A.

    2010-01-01

    Amyloid fibril formation is associated with diseases such as Alzheimer’s, Parkinson’s, and prion diseases. Inhibition of amyloid fibril formation by molecular chaperone proteins, such as the small heat-shock protein αB-crystallin, may play a protective role in preventing the toxicity associated with this form of protein misfolding. Reduced and carboxymethylated κ-casein (RCMκ-CN), a protein derived from milk, readily and reproducibly forms fibrils at physiological temperature and pH. We inves...

  10. Small-Animal PET Imaging of Amyloid-Beta Plaques with [11C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease

    OpenAIRE

    Manook, André; Yousefi, Behrooz H.; Willuweit, Antje; Platzer, Stefan; Reder, Sybille; Voss, Andreas; Huisman, Marc; Settles, Markus; Neff, Frauke; Velden, Joachim; Schoor, Michael; von der Kammer, Heinz; Wester, Hans-Jürgen; Schwaiger, Markus; Henriksen, Gjermund

    2012-01-01

    In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain...

  11. Glycation in Parkinson's disease and Alzheimer's disease.

    Science.gov (United States)

    Vicente Miranda, Hugo; El-Agnaf, Omar M A; Outeiro, Tiago Fleming

    2016-06-01

    Glycation is a spontaneous age-dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, α-synuclein can be glycated, at least under experimental conditions. In Alzheimer's disease, glycation of amyloid β peptide exacerbates its toxicity and contributes to neurodegeneration. Recent studies establish diabetes mellitus as a risk factor for several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, the mechanisms underlying this connection remain unclear. We hypothesize that hyperglycemia might play an important role in the development of these disorders, possibly by also inducing protein glycation and thereby dysfunction, aggregation, and deposition. Here, we explore protein glycation as a common player in Parkinson's and Alzheimer's diseases and propose it may constitute a novel target for the development of strategies for neuroprotective therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society. PMID:26946341

  12. The S100B/RAGE Axis in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Estelle Leclerc

    2010-01-01

    Full Text Available Increasing evidence suggests that the small EF-hand calcium-binding protein S100B plays an important role in Alzheimer's disease. Among other evidences are the increased levels of both S100B and its receptor, the Receptor for Advanced Glycation Endproducts (RAGEs in the AD diseased brain. The regulation of RAGE signaling by S100B is complex and probably involves other ligands including the amyloid beta peptide (A, the Advanced Glycation Endproducts (AGEs, or transtheyretin. In this paper we discuss the current literature regarding the role of S100B/RAGE activation in Alzheimer's disease.

  13. The aggregation kinetics of Alzheimer’s β-amyloid peptide is controlled by stochastic nucleation

    OpenAIRE

    Hortschansky, Peter; Schroeckh, Volker; Christopeit, Tony; Zandomeneghi, Giorgia; Fändrich, Marcus

    2005-01-01

    We report here a recombinant expression system that allows production of large quantities of Alzheimer’s Aβ(1–40) peptide. The material is competent to dissolve in water solutions with “random-coil properties,” although its conformation and factual oligomerization state are determined by the physico-chemical solution conditions. When dissolved in 50 mM sodium phosphate buffer (pH 7.4) at 37°C, the peptide is able to undergo a nucleated polymerization reaction. The aggregation profile is chara...

  14. Hypocretin and brain β-amyloid peptide interactions in cognitive disorders and narcolepsy

    Directory of Open Access Journals (Sweden)

    Yves A Dauvilliers

    2014-06-01

    Full Text Available Objective: To examine relationships between cerebrospinal fluid (CSF Alzheimer’ disease (AD biomarkers and hypocretin-1 levels in patients with cognitive abnormalities and hypocretin-deficient narcolepsy-cataplexy (NC, estimate diagnostic accuracy, and determine correlations with sleep disturbances. Background: Sleep disturbances are frequent in AD. Interactions between brain β-amyloid (Aβ aggregation and a wake-related neurotransmitter hypocretin have been reported in a mouse model of AD. Methods: Ninety-one cognitive patients (37 AD, 16 mild cognitive impairment – MCI that converts to AD, 38 other dementias and 15 elderly patients with NC were recruited. Patients were diagnosed blind to CSF results. CSF A42, total tau, ptau181, and hypocretin-1 were measured. Sleep disturbances were assessed with questionnaires in 32 cognitive patients. Results: Lower CSF Aβ42 but higher tau and P-tau levels were found in AD and MCI compared to other dementias. CSF hypocretin-1 levels were higher in patients with MCI due to AD compared to other dementias, with a similar tendency for patients with advanced AD. CSF hypocretin-1 was significantly and independently associated with AD/MCI due to AD, with an OR of 2.70 after full adjustment, exceeding that for Aβ42. Aβ42 correlated positively with hypocretin-1 levels in advanced stage AD. No association was found between sleep disturbances and CSF biomarkers. No patients with NC achieved pathological cutoffs for Aβ42, with respectively one and four patients with NC above tau and P-tau cutoffs and no correlations between hypocretin-1 and other biomarkers. Conclusions: Our results suggest a pathophysiological relationship between Aβ42 and hypocretin-1 in the AD process, with higher CSF hypocretin-1 levels in early disease stages. Further longitudinal studies are needed to validate these biomarker interactions and to determine the cause-effect relationship and the role of wake/sleep behavior in amyloid

  15. Curcumin Ameliorates the Reduction Effect of PGE2 on Fibrillar β-Amyloid Peptide (1-42)-Induced Microglial Phagocytosis through the Inhibition of EP2-PKA Signaling in N9 Microglial Cells.

    Science.gov (United States)

    He, Gen-Lin; Luo, Zhen; Yang, Ju; Shen, Ting-Ting; Chen, Yi; Yang, Xue-Sen

    2016-01-01

    Inflammatory activation of microglia and β amyloid (Aβ) deposition are considered to work both independently and synergistically to contribute to the increased risk of Alzheimer's disease (AD). Recent studies indicate that long-term use of phenolic compounds provides protection against AD, primarily due to their anti-inflammatory actions. We previously suggested that phenolic compound curcumin ameliorated phagocytosis possibly through its anti-inflammatory effects rather than direct regulation of phagocytic function in electromagnetic field-exposed N9 microglial cells (N9 cells). Here, we explored the prostaglandin-E2 (PGE2)-related signaling pathway that involved in curcumin-mediated phagocytosis in fibrillar β-amyloid peptide (1-42) (fAβ42)-stimulated N9 cells. Treatment with fAβ42 increased phagocytosis of fluorescent-labeled latex beads in N9 cells. This increase was attenuated in a dose-dependent manner by endogenous and exogenous PGE2, as well as a selective EP2 or protein kinase A (PKA) agonist, but not by an EP4 agonist. We also found that an antagonist of EP2, but not EP4, abolished the reduction effect of PGE2 on fAβ42-induced microglial phagocytosis. Additionally, the increased expression of endogenous PGE2, EP2, and cyclic adenosine monophosphate (AMP), and activation of vasodilator-stimulated phosphoprotein, cyclic AMP responsive element-binding protein, and PKA were depressed by curcumin administration. This reduction led to the amelioration of the phagocytic abilities of PGE2-stimulated N9 cells. Taken together, these data suggested that curcumin restored the attenuating effect of PGE2 on fAβ42-induced microglial phagocytosis via a signaling mechanism involving EP2 and PKA. Moreover, due to its immune modulatory effects, curcumin may be a promising pharmacological candidate for neurodegenerative diseases. PMID:26824354

  16. Curcumin Ameliorates the Reduction Effect of PGE2 on Fibrillar β-Amyloid Peptide (1-42-Induced Microglial Phagocytosis through the Inhibition of EP2-PKA Signaling in N9 Microglial Cells.

    Directory of Open Access Journals (Sweden)

    Gen-Lin He

    Full Text Available Inflammatory activation of microglia and β amyloid (Aβ deposition are considered to work both independently and synergistically to contribute to the increased risk of Alzheimer's disease (AD. Recent studies indicate that long-term use of phenolic compounds provides protection against AD, primarily due to their anti-inflammatory actions. We previously suggested that phenolic compound curcumin ameliorated phagocytosis possibly through its anti-inflammatory effects rather than direct regulation of phagocytic function in electromagnetic field-exposed N9 microglial cells (N9 cells. Here, we explored the prostaglandin-E2 (PGE2-related signaling pathway that involved in curcumin-mediated phagocytosis in fibrillar β-amyloid peptide (1-42 (fAβ42-stimulated N9 cells. Treatment with fAβ42 increased phagocytosis of fluorescent-labeled latex beads in N9 cells. This increase was attenuated in a dose-dependent manner by endogenous and exogenous PGE2, as well as a selective EP2 or protein kinase A (PKA agonist, but not by an EP4 agonist. We also found that an antagonist of EP2, but not EP4, abolished the reduction effect of PGE2 on fAβ42-induced microglial phagocytosis. Additionally, the increased expression of endogenous PGE2, EP2, and cyclic adenosine monophosphate (AMP, and activation of vasodilator-stimulated phosphoprotein, cyclic AMP responsive element-binding protein, and PKA were depressed by curcumin administration. This reduction led to the amelioration of the phagocytic abilities of PGE2-stimulated N9 cells. Taken together, these data suggested that curcumin restored the attenuating effect of PGE2 on fAβ42-induced microglial phagocytosis via a signaling mechanism involving EP2 and PKA. Moreover, due to its immune modulatory effects, curcumin may be a promising pharmacological candidate for neurodegenerative diseases.

  17. The PSEN1 I143T mutation in a Swedish family with Alzheimer disease: Clinical report and quantification of Aβ in different brain regions

    OpenAIRE

    Graff, Caroline; Keller, Lina; Welander, Hedvig; Chiang, Huei-Hsin; Tjernberg, Lars O.; Nennesmo, Inger; Wallin, Åsa K

    2010-01-01

    Abstract Early onset dominantly-inherited forms of Alzheimer disease are rare, but studies of such cases have revealed important information about the disease mechanisms. Importantly, mutations in APP, PSEN1 and PSEN2, alter the APP processing and lead to an increased amyloid ?-peptide (A?) 42/40 ratio. This, together with other studies on the pathogenic mechanisms, show that A?42 is a major player in the etiology of Alzheimer disease. Here we present a clinical and neuropathologic...

  18. The biochemical aftermath of anti-amyloid immunotherapy

    Directory of Open Access Journals (Sweden)

    Nicoll James AR

    2010-10-01

    Full Text Available Abstract Background Active and passive immunotherapy in both amyloid-beta precursor protein (APP transgenic mice and Alzheimer's Disease (AD patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were actively immunized with the Aβ peptide 1-42 (AN-1792 and subjected to detailed postmortem biochemical analyses. These patients were compared to 6 non-immunized AD cases and 5 non-demented control (NDC cases. Results All patients were assessed for the presence of AD pathology including amyloid plaques, neurofibrillary tangles and vascular amyloidosis. This effort revealed that two immunotherapy recipients had dementia as a consequence of diseases other than AD. Direct neuropathological examination consistently demonstrated small to extensive areas in which amyloid plaques apparently were disrupted. Characterization of Aβ species remnants by ELISA suggested that total Aβ levels may have been reduced, although because the amounts of Aβ peptides among treated individuals were extremely variable, those data must be regarded as tentative. Chromatographic analysis and Western blots revealed abundant dimeric Aβ peptides. SELDI-TOF mass spectrometry demonstrated a substantive number of Aβ-related peptides, some of them with elongated C-terminal sequences. Pro-inflammatory TNF-α levels were significantly increased in the gray matter of immunized AD cases compared to the NDC and non-immunized AD groups. Conclusions Immunotherapy responses were characterized by extreme variability. Considering the broad range of biological variation that characterizes aging and complicates the recognition of reliable AD biomarkers, such disparities will make the interpretation of outcomes derived from epidemiologic and therapeutic investigations challenging. Although in some cases the apparent removal of amyloid plaques

  19. Proliferation in the Alzheimer Hippocampus Is due to Microglia, Not Astroglia, and Occurs at Sites of Amyloid Deposition

    OpenAIRE

    Marlatt, Michael W.; Jan Bauer; Eleonora Aronica; van Haastert, Elise S.; Hoozemans, Jeroen J.M.; Marian Joels; Lucassen, Paul J.

    2014-01-01

    Microglia and astrocytes contribute to Alzheimer’s disease (AD) etiology and may mediate early neuroinflammatory responses. Despite their possible role in disease progression and despite the fact that they can respond to amyloid deposition in model systems, little is known about whether astro- or microglia can undergo proliferation in AD and whether this is related to the clinical symptoms or to local neuropathological changes. Previously, proliferation was found to be increased in glia-rich ...

  20. Proliferation in the Alzheimer Hippocampus Is due to Microglia, Not Astroglia, and Occurs at Sites of Amyloid Deposition

    Directory of Open Access Journals (Sweden)

    Michael W. Marlatt

    2014-01-01

    Full Text Available Microglia and astrocytes contribute to Alzheimer’s disease (AD etiology and may mediate early neuroinflammatory responses. Despite their possible role in disease progression and despite the fact that they can respond to amyloid deposition in model systems, little is known about whether astro- or microglia can undergo proliferation in AD and whether this is related to the clinical symptoms or to local neuropathological changes. Previously, proliferation was found to be increased in glia-rich regions of the presenile hippocampus. Since their phenotype was unknown, we here used two novel triple-immunohistochemical protocols to study proliferation in astro- or microglia in relation to amyloid pathology. We selected different age-matched cohorts to study whether proliferative changes relate to clinical severity or to neuropathological changes. Proliferating cells were found across the hippocampus but never in mature neurons or astrocytes. Almost all proliferating cells were colabeled with Iba1+, indicating that particularly microglia contribute to proliferation in AD. Proliferating Iba1+ cells was specifically seen within the borders of amyloid plaques, indicative of an active involvement in, or response to, plaque accumulation. Thus, consistent with animal studies, proliferation in the AD hippocampus is due to microglia, occurs in close proximity of plaque pathology, and may contribute to the neuroinflammation common in AD.

  1. Synaptic silencing and plasma membrane dyshomeostasis induced by amyloidpeptide are prevented by Aristotelia chilensis enriched extract.

    Science.gov (United States)

    Fuentealba, Jorge; Dibarrart, Andrea; Saez-Orellana, Francisco; Fuentes-Fuentes, María Cecilia; Oyanedel, Carlos N; Guzmán, José; Perez, Claudia; Becerra, José; Aguayo, Luis G

    2012-01-01

    Alzheimer's disease (AD) is characterized by the presence of different types of extracellular and neurotoxic aggregates of amyloid-β (Aβ). Recently, bioactive compounds extracted from natural sources showing neuroprotective properties have become of interest in brain neurodegeneration. We have purified, characterized, and evaluated the protective potential of one extract enriched in polyphenols obtained from Aristotelia chilensis (MQ), a Chilean berry fruit, in neuronal models of AD induced by soluble oligomers of Aβ1-40. For example, using primary hippocampal cultures from rats (E18), we observed neuroprotection when the neurons were co-incubated with Aβ (0.5 μM) plus MQ for 24 h (Aβ = 23 ± 2%; Aβ + MQ = 3 ± 1%; n = 3). In parallel, co-incubation of Aβ with MQ recovered the frequency of Ca2+ transient oscillations when compared to neurons treated with Aβ alone (Aβ = 72 ± 3%; Aβ + MQ = 86 ± 2%; n = 5), correlating with the changes observed in spontaneous synaptic activity. Additionally, MAP-2 immunostaining showed a preservation of the dendritic tree, suggesting that the toxic effect of Aβ is prevented in the presence of MQ. A new complex mechanism is proposed by which MQ induces neuroprotective effects including antioxidant properties, modulation of cell survival pathways, and/or direct interaction with the Aβ aggregates. Our results suggest that MQ induces changes in the aggregation kinetics of Aβ producing variations in the nucleation phase (Aβ: k1 = 2.7 ± 0.4 × 10-3 s-1 MQ: k1 = 8.3 ± 0.6 × 10-3 s-1) and altering Thioflavin T insertion in β-sheets. In conclusion, MQ induces a potent neuroprotection by direct interaction with the Aβ aggregates, generating far less toxic species and in this way protecting the neuronal network. PMID:22728896

  2. The Effects of Endogenous Non-Peptide Molecule Isatin and Hydrogen Peroxide on Proteomic Profiling of Rat Brain Amyloid-β Binding Proteins: Relevance to Alzheimer’s Disease?

    Directory of Open Access Journals (Sweden)

    Alexei E. Medvedev

    2014-12-01

    Full Text Available The amyloidpeptide is considered as a key player in the development and progression of Alzheimer’s disease (AD. Although good evidence exists that amyloid-β accumulates inside cells, intracellular brain amyloid-binding proteins remain poorly characterized. Proteomic profiling of rat brain homogenates, performed in this study, resulted in identification of 89 individual intracellular amyloid-binding proteins, and approximately 25% of them were proteins that we had previously identified as specifically binding to isatin, an endogenous neuroprotector molecule. A significant proportion of the amyloid-binding proteins (more than 30% are differentially expressed or altered/oxidatively modified in AD patients. Incubation of brain homogenates with 70 µM hydrogen peroxide significantly influenced the profile of amyloid-β binding proteins and 0.1 mM isatin decreased the number of identified amyloid-β binding proteins both in control and hydrogen peroxide treated brain homogenates. The effects of hydrogen peroxide and isatin have been confirmed in optical biosensor experiments with purified glyceraldehyde-3-phosphate dehydrogenase, one of the known crucial amyloid-β binding proteins (also identified in this study. Data obtained suggest that isatin protects crucial intracellular protein targets against amyloid binding, and possibly favors intracellular degradation of this protein via preventing formation of amyloid-β oligomers described in the literature for some isatin derivatives.

  3. Amyloidpeptides and tau protein as biomarkers in cerebrospinal and interstitial fluid following traumatic brain injury: A review of experimental and clinical studies

    Directory of Open Access Journals (Sweden)

    Parmenion P. Tsitsopoulos

    2013-06-01

    Full Text Available Traumatic brain injury (TBI survivors frequently suffer from life-long deficits in cognitive functions and a reduced quality of life. Axonal injury, observed in most severe TBI patients, results in accumulation of amyloid precursor protein (APP. Post-injury enzymatic cleavage of APP can generate amyloid-β (Aβ peptides, a hallmark finding in Alzheimer’s disease (AD. At autopsy, brains of AD and a subset of TBI victims display some similarities including accumulation of Aβ peptides and neurofibrillary tangles of hyperphosphorylated tau proteins. Most epidemiological evidence suggests a link between TBI and AD, implying that TBI has neurodegenerative sequelae. Aβ peptides and tau may be used as biomarkers in interstitial fluid (ISF using cerebral microdialysis and/or cerebrospinal fluid (CSF following clinical TBI. In the present review, the available clinical and experimental literature on Aβ peptides and tau as potential biomarkers following TBI is comprehensively analyzed. Elevated CSF and ISF tau protein levels have been observed following severe TBI and suggested to correlate with clinical outcome. Although Aβ peptides are produced by normal neuronal metabolism, high levels of long and/or fibrillary Aβ peptides may be neurotoxic. Increased CSF and/or ISF Aβ levels post-injury may be related to neuronal activity and/or the presence of axonal injury. The heterogeneity of animal models, clinical cohorts, analytical techniques and the complexity of TBI in available studies make the clinical value of tau and Aβ as biomarkers uncertain at present. Additionally, the link between early post-injury changes in tau and Aβ peptides and the future risk of developing AD remains unclear. Future studies using e.g. rapid biomarker sampling combined with enhanced analytical techniques and/or novel pharmacological tools could provide additional information on the importance of Aβ peptides and tau protein in both the acute pathophysiology and long

  4. Improved discrimination of autopsy-confirmed Alzheimer's disease (AD) from non-AD dementias using CSF P-tau181P

    NARCIS (Netherlands)

    Koopman, Karen; Le Bastard, Nathalie; Martin, Jean Jacques; Nagels, Guy; De Deyn, Peter P.; Engelborghs, Sebastiaan

    2009-01-01

    To establish diagnostic accuracy (acc) and optimal cut-off levels of CSF tau phosphorylated at threonine 181 (P-tau(181P)) for discriminating Alzheimer's disease (AD) from non-AD dementias in autopsy-confirmed dementia patients, CSF levels of beta-amyloid peptide (A beta(1-42)). total tau protein (T

  5. Bioinspired peptide nanotubes: Deposition technology and physical properties

    International Nuclear Information System (INIS)

    Proteins and peptides have the intrinsic ability to self-assemble into elongated solid nanofibrils, which give rise to amyloid progressive neurodegenerative diseases (Alzheimer's, Parkinson, etc.). It has been found that of the core recognition motif of Aβ peptide is the diphenylalanine element. The diphenylalanine peptide can self-assemble into well-ordered peptide nanotubes (PNT). In this paper we report on our newly developed process-vapor deposition of PNT and 'bottom-up' nanotechnological techniques of PNT patterning. Study of several physical properties of PNT such as optical and electrochemical are presented. The results may lead to the development of a new generation of PNT-based bioinspired functional nanodevices.

  6. Diagnostic accuracy of {sup 18}F amyloid PET tracers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis

    Energy Technology Data Exchange (ETDEWEB)

    Morris, Elizabeth; Chalkidou, Anastasia [St Thomas' Hospital, King' s Technology Evaluation Centre, King' s College London, London (United Kingdom); St Thomas' Hospital, Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King' s College London, London (United Kingdom); Hammers, Alexander [St Thomas' Hospital, Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King' s College London, London (United Kingdom); Peacock, Janet; Summers, Jennifer [St Thomas' Hospital, King' s Technology Evaluation Centre, King' s College London, London (United Kingdom); King' s College London, Division of Health and Social Care Research, London (United Kingdom); King' s College London, NIHR Biomedical Research Centre at Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom); Keevil, Stephen [St Thomas' Hospital, King' s Technology Evaluation Centre, King' s College London, London (United Kingdom); St Thomas' Hospital, Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King' s College London, London (United Kingdom); St Thomas' Hospital, Department of Medical Physics, Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom)

    2016-02-15

    Imaging or tissue biomarker evidence has been introduced into the core diagnostic pathway for Alzheimer's disease (AD). PET using {sup 18}F-labelled beta-amyloid PET tracers has shown promise for the early diagnosis of AD. However, most studies included only small numbers of participants and no consensus has been reached as to which radiotracer has the highest diagnostic accuracy. First, we performed a systematic review of the literature published between 1990 and 2014 for studies exploring the diagnostic accuracy of florbetaben, florbetapir and flutemetamol in AD. The included studies were analysed using the QUADAS assessment of methodological quality. A meta-analysis of the sensitivity and specificity reported within each study was performed. Pooled values were calculated for each radiotracer and for visual or quantitative analysis by population included. The systematic review identified nine studies eligible for inclusion. There were limited variations in the methods between studies reporting the same radiotracer. The meta-analysis results showed that pooled sensitivity and specificity values were in general high for all tracers. This was confirmed by calculating likelihood ratios. A patient with a positive ratio is much more likely to have AD than a patient with a negative ratio, and vice versa. However, specificity was higher when only patients with AD were compared with healthy controls. This systematic review and meta-analysis found no marked differences in the diagnostic accuracy of the three beta-amyloid radiotracers. All tracers perform better when used to discriminate between patients with AD and healthy controls. The sensitivity and specificity for quantitative and visual analysis are comparable to those of other imaging or biomarker techniques used to diagnose AD. Further research is required to identify the combination of tests that provides the highest sensitivity and specificity, and to identify the most suitable position for the tracer in the

  7. Comparison of the binding characteristics of [{sup 18}F]THK-523 and other amyloid imaging tracers to Alzheimer's disease pathology

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  8. Diagnostic accuracy of 18F amyloid PET tracers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis

    International Nuclear Information System (INIS)

    Imaging or tissue biomarker evidence has been introduced into the core diagnostic pathway for Alzheimer's disease (AD). PET using 18F-labelled beta-amyloid PET tracers has shown promise for the early diagnosis of AD. However, most studies included only small numbers of participants and no consensus has been reached as to which radiotracer has the highest diagnostic accuracy. First, we performed a systematic review of the literature published between 1990 and 2014 for studies exploring the diagnostic accuracy of florbetaben, florbetapir and flutemetamol in AD. The included studies were analysed using the QUADAS assessment of methodological quality. A meta-analysis of the sensitivity and specificity reported within each study was performed. Pooled values were calculated for each radiotracer and for visual or quantitative analysis by population included. The systematic review identified nine studies eligible for inclusion. There were limited variations in the methods between studies reporting the same radiotracer. The meta-analysis results showed that pooled sensitivity and specificity values were in general high for all tracers. This was confirmed by calculating likelihood ratios. A patient with a positive ratio is much more likely to have AD than a patient with a negative ratio, and vice versa. However, specificity was higher when only patients with AD were compared with healthy controls. This systematic review and meta-analysis found no marked differences in the diagnostic accuracy of the three beta-amyloid radiotracers. All tracers perform better when used to discriminate between patients with AD and healthy controls. The sensitivity and specificity for quantitative and visual analysis are comparable to those of other imaging or biomarker techniques used to diagnose AD. Further research is required to identify the combination of tests that provides the highest sensitivity and specificity, and to identify the most suitable position for the tracer in the

  9. Evaluation of software tools for automated identification of neuroanatomical structures in quantitative β-amyloid PET imaging to diagnose Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Tuszynski, Tobias; Luthardt, Julia; Butzke, Daniel; Tiepolt, Solveig; Seese, Anita; Barthel, Henryk [Leipzig University Medical Centre, Department of Nuclear Medicine, Leipzig (Germany); Rullmann, Michael; Hesse, Swen; Sabri, Osama [Leipzig University Medical Centre, Department of Nuclear Medicine, Leipzig (Germany); Leipzig University Medical Centre, Integrated Treatment and Research Centre (IFB) Adiposity Diseases, Leipzig (Germany); Gertz, Hermann-Josef [Leipzig University Medical Centre, Department of Psychiatry, Leipzig (Germany); Lobsien, Donald [Leipzig University Medical Centre, Department of Neuroradiology, Leipzig (Germany)

    2016-06-15

    For regional quantification of nuclear brain imaging data, defining volumes of interest (VOIs) by hand is still the gold standard. As this procedure is time-consuming and operator-dependent, a variety of software tools for automated identification of neuroanatomical structures were developed. As the quality and performance of those tools are poorly investigated so far in analyzing amyloid PET data, we compared in this project four algorithms for automated VOI definition (HERMES Brass, two PMOD approaches, and FreeSurfer) against the conventional method. We systematically analyzed florbetaben brain PET and MRI data of ten patients with probable Alzheimer's dementia (AD) and ten age-matched healthy controls (HCs) collected in a previous clinical study. VOIs were manually defined on the data as well as through the four automated workflows. Standardized uptake value ratios (SUVRs) with the cerebellar cortex as a reference region were obtained for each VOI. SUVR comparisons between ADs and HCs were carried out using Mann-Whitney-U tests, and effect sizes (Cohen's d) were calculated. SUVRs of automatically generated VOIs were correlated with SUVRs of conventionally derived VOIs (Pearson's tests). The composite neocortex SUVRs obtained by manually defined VOIs were significantly higher for ADs vs. HCs (p=0.010, d=1.53). This was also the case for the four tested automated approaches which achieved effect sizes of d=1.38 to d=1.62. SUVRs of automatically generated VOIs correlated significantly with those of the hand-drawn VOIs in a number of brain regions, with regional differences in the degree of these correlations. Best overall correlation was observed in the lateral temporal VOI for all tested software tools (r=0.82 to r=0.95, p<0.001). Automated VOI definition by the software tools tested has a great potential to substitute for the current standard procedure to manually define VOIs in β-amyloid PET data analysis. (orig.)

  10. Metal-amyloidpeptide interactions: a preliminary investigation of molecular mechanisms for Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Although humans have spent exactly 100 years combating Alzheimer’s disease (AD), the molecular mechanisms of AD remain unclear. Owing to the rapid growth of the oldest age groups of the popula-tion and the continuous increase of the incidence of AD, it has become one of the crucial problems to modern sciences. It would be impossible to prevent or reverse AD at the root without elucidating its molecular mechanisms. From the point of view of metal-amyloidpeptide (Aβ) interactions, we review the molecular mechanisms of AD, mainly including Cu2+ and Zn2+ inducing the aggregation of Aβ, cata-lysing the production of active oxygen species from Aβ, as well as interacting with the ion-channel-like structures of Aβ. Moreover, the development of therapeutic drugs on the basis of metal-Aβ interactions is also briefly introduced. With the increasingly rapid progress of the molecular mechanisms of AD, we are now entering a new dawn that promises the delivery of revolutionary developments for the control of dementias.

  11. Blood amyloid beta levels in healthy, mild cognitive impairment and Alzheimer's disease individuals: replication of diastolic blood pressure correlations and analysis of critical covariates.

    Directory of Open Access Journals (Sweden)

    Agustín Ruiz

    Full Text Available Plasma amyloid beta (Aβ levels are being investigated as potential biomarkers for Alzheimer's disease. In AB128 cross-sectional study, a number of medical relevant correlates of blood Aβ40 or Aβ42 were analyzed in 140 subjects (51 Alzheimer's disease patients, 53 healthy controls and 36 individuals diagnosed with mild cognitive impairment. We determined the association between multiple variables with Aβ40 and Aβ42 levels measured in three different blood compartments called i Aβ directly accessible (DA in the plasma, ii Aβ recovered from the plasma matrix (RP after diluting the plasma sample in a formulated buffer, and iii associated with the remaining cellular pellet (CP. We confirmed that diastolic blood pressure (DBP is consistently correlated with blood DA Aβ40 levels (r=-0.19, P=0.032. These results were consistent in the three phenotypic groups studied. Importantly, the observation resisted covariation with age, gender or creatinine levels. Observed effect size and direction of Aβ40 levels/DBP correlation are in accordance with previous reports. Of note, DA Aβ40 and the RP Aβ40 were also strongly associated with creatinine levels (r=0.599, P<<0.001 and to a lesser extent to urea, age, hematocrit, uric acid and homocysteine (p<0.001. DBP and the rest of statistical significant correlates identified should be considered as potential confounder factors in studies investigating blood Aβ levels as potential AD biomarker. Remarkably, the factors affecting Aβ levels in plasma (DA, RP and blood cell compartments (CP seem completely different.

  12. Influence of scan duration on the accuracy of β-amyloid PET with florbetaben in patients with Alzheimer's disease and healthy volunteers

    International Nuclear Information System (INIS)

    Florbetaben is a β-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 β-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 (kappa20min = 0.94, kappa10min = 0.94, kappa5min = 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 β-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 and HVs. Thus, a reduction in scan duration seems conceivable for the future

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    Science.gov (United States)

    Zhang-Haagen, Bo; Biehl, Ralf; Nagel-Steger, Luitgard; Radulescu, Aurel; Richter, Dieter; Willbold, Dieter

    2016-01-01

    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. PMID:26919121

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Link between Aluminum and the Pathogenesis of Alzheimer's Disease: The Integration of the Aluminum and Amyloid Cascade Hypotheses

    OpenAIRE

    Masahiro Kawahara; Midori Kato-Negishi

    2011-01-01

    Whilst being environmentally abundant, aluminum is not essential for life. On the contrary, aluminum is a widely recognized neurotoxin that inhibits more than 200 biologically important functions and causes various adverse effects in plants, animals, and humans. The relationship between aluminum exposure and neurodegenerative diseases, including dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii Peninsula and Guam, and Alzheimer's disease (AD) has been...

  17. High tryptophan diet reduces CA1 intraneuronal ss-amyloid in the triple transgenic mouse model of Alzheimer's disease.

    Czech Academy of Sciences Publication Activity Database

    Noristani, H. N.; Verkhratsky, A.; Rodríguez Arellano, Jose Julio

    2012-01-01

    Roč. 11, č. 5 (2012), s. 810-822. ISSN 1474-9718 R&D Projects: GA ČR GA309/09/1696; GA ČR GA305/08/1384; GA ČR(CZ) GAP304/11/0184 Institutional research plan: CEZ:AV0Z50390703 Institutional support: RVO:68378041 Keywords : Alzheimer's disease * hippocampus * L-tryptophan diet Subject RIV: FH - Neurology Impact factor: 5.705, year: 2012

  18. 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.)

  19. Aliphatic peptides show similar self-assembly to amyloid core sequences, challenging the importance of aromatic interactions in amyloidosis

    OpenAIRE

    Lakshmanan, Anupama; Cheong, Daniel W.; Accardo, Angelo; Di Fabrizio, Enzo; Riekel, Christian; Hauser, Charlotte A. E.

    2012-01-01

    The self-assembly of abnormally folded proteins into amyloid fibrils is a hallmark of many debilitating diseases, from Alzheimer’s and Parkinson diseases to prion-related disorders and diabetes type II. However, the fundamental mechanism of amyloid aggregation remains poorly understood. Core sequences of four to seven amino acids within natural amyloid proteins that form toxic fibrils have been used to study amyloidogenesis. We recently reported a class of systematically designed ultrasmall p...

  20. Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models.

    Science.gov (United States)

    Kostylev, Mikhail A; Kaufman, Adam C; Nygaard, Haakon B; Patel, Pujan; Haas, Laura T; Gunther, Erik C; Vortmeyer, Alexander; Strittmatter, Stephen M

    2015-07-10

    Alzheimer disease (AD) is characterized by amyloid-β accumulation, with soluble oligomers (Aβo) being the most synaptotoxic. However, the multivalent and unstable nature of Aβo limits molecular characterization and hinders research reproducibility. Here, we characterized multiple Aβo forms throughout the life span of various AD mice and in post-mortem human brain. Aβo exists in several populations, where prion protein (PrP(C))-interacting Aβo is a high molecular weight Aβ assembly present in multiple mice and humans with AD. Levels of PrP(C)-interacting Aβo match closely with mouse memory and are equal or superior to other Aβ measures in predicting behavioral impairment. However, Aβo metrics vary considerably between mouse strains. Deleting PrP(C) expression in mice with relatively low PrP(C)-interacting Aβo (Tg2576) results in partial rescue of cognitive performance as opposed to complete recovery in animals with a high percentage of PrP(C)-interacting Aβo (APP/PSEN1). These findings highlight the relative contributions and interplay of Aβo forms in AD. PMID:26018073

  1. Curcumin Attenuates Beta-Amyloid-Induced Neuroinflammation via Activation of Peroxisome Proliferator-Activated Receptor-Gamma Function in a Rat Model of Alzheimer's Disease.

    Science.gov (United States)

    Liu, Zun-Jing; Li, Zhong-Hao; Liu, Lei; Tang, Wen-Xiong; Wang, Yu; Dong, Ming-Rui; Xiao, Cheng

    2016-01-01

    Neuroinflammation is known to have a pivotal role in the pathogenesis of Alzheimer's disease (AD), and curcumin has been reported to have therapeutical effects on AD because of its anti-inflammatory effects. Curcumin is not only a potent PPARγ agonist, but also has neuroprotective effects on cerebral ischemic injury. However, whether PPARγ activated by curcumin is responsible for the anti-neuroinflammation and neuroprotection on AD remains unclear, and needs to be further investigated. Here, using both APP/PS1 transgenic mice and beta-amyloid-induced neuroinflammation in mixed neuronal/glial cultures, we showed that curcumin significantly alleviated spatial memory deficits in APP/PS1 mice and promoted cholinergic neuronal function in vivo and in vitro. Curcumin also reduced the activation of microglia and astrocytes, as well as cytokine production and inhibited nuclear factor kappa B (NF-κB) signaling pathway, suggesting the beneficial effects of curcumin on AD are attributable to the suppression of neuroinflammation. Attenuation of these beneficial effects occurred when co-administrated with PPARγ antagonist GW9662 or silence of PPARγ gene expression, indicating that PPARγ might be involved in anti-inflammatory effects. Circular dichroism and co-immunoprecipitation analysis showed that curcumin directly bound to PPARγ and increased the transcriptional activity and protein levels of PPARγ. Taking together, these data suggested that PPARγ might be a potential target of curcumin, acting to alleviate neuroinflammation and improve neuronal function in AD. PMID:27594837

  2. Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite, and synaptic pathology in the APP/PS1 transgenic model of Alzheimer's disease.

    Science.gov (United States)

    Fernandez-Martos, Carmen M; King, Anna E; Atkinson, Rachel A K; Woodhouse, Adele; Vickers, James C

    2015-10-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with the loss of cognitive function. Neurofilament (NF) triplet proteins, the major structural (intermediate filament) proteins of neurons, are expressed in a subset of pyramidal cells that show a high degree of vulnerability to degeneration in AD. Alterations in the NF triplet proteins in amyloid-beta (Aβ) plaque-associated dystrophic neurites (DNs) represent the first cytoskeletal aberration to occur in the neocortex in the earliest stages of AD. We generated transgenic APP/PS1 (APPswe/PSEN1dE9) mice on the neurofilament light knockout (NFL KO) background to explore the role of NFL deletion in the context of DN formation, synaptic changes, and other neuropathologic features. Our analysis demonstrated that NFL deficiency significantly increased neocortical DN pathology, Aβ deposition, synapse vulnerability, and microgliosis in APP/PS1 mice. Thus, NFs may have a role in protecting neurites from dystrophy and in regulating cellular pathways related to the generation of Aβ plaques. PMID:26344875

  3. Alpha-tocopherol quinine ameliorates spatial memory deficits by reducing beta-amyloid oligomers, neuroinflammation and oxidative stress in transgenic mice with Alzheimer's disease.

    Science.gov (United States)

    Wang, Shao-Wei; Yang, Shi-Gao; Liu, Wen; Zhang, Yang-Xin; Xu, Peng-Xin; Wang, Teng; Ling, Tie-Jun; Liu, Rui-Tian

    2016-01-01

    The pathologies of Alzheimer's disease (AD) is associated with soluble beta-amyloid (Aβ) oligomers, neuroinflammation and oxidative stress. Decreasing the levels of Aβ oligomer, glial activation and oxidative stress are potential therapeutic approaches for AD treatment. We previously found alpha-tocopherol quinine (α-TQ) inhibited Aβ aggregation and cytotoxicity, decreased the release of inflammatory cytokines and reactive oxygen species (ROS) in vitro. However, whether α-TQ ameliorates memory deficits and other neuropathologies in mice or patients with AD remains unknown. In this study, we reported that orally administered α-TQ ameliorated memory impairment in APPswe/PS1dE9 transgenic mice, decreased oxidative stress and the levels of Aβ oligomer in the brains of mice, prevented the production of inducible nitric oxide synthase and inflammatory mediators, such as interleukin-6 and interleukin-1β, and inhibited microglial activation by inhibiting NF-κB signaling pathway. These findings suggest that α-TQ has potential therapeutic value for AD treatment. PMID:26358659

  4. Outstanding Phenotypic Differences in the Profile of Amyloid-β between Tg2576 and APPswe/PS1dE9 Transgenic Mouse Models of Alzheimer's Disease.

    Science.gov (United States)

    Allué, José Antonio; Sarasa, Leticia; Izco, María; Pérez-Grijalba, Virginia; Fandos, Noelia; Pascual-Lucas, María; Ogueta, Samuel; Pesini, Pedro; Sarasa, Manuel

    2016-05-30

    APPswe/PS1dE9 and Tg2576 are very common transgenic mouse models of Alzheimer's disease (AD), used in many laboratories as tools to research the mechanistic process leading to the disease. In order to augment our knowledge about the amyloid-β (Aβ) isoforms present in both transgenic mouse models, we have developed two chromatographic methods, one acidic and the other basic, for the characterization of the Aβ species produced in the brains of the two transgenic mouse models. After immunoprecipitation and micro-liquid chromatography-electrospray ionization mass spectrometry/mass spectrometry, 10 species of Aβ, surprisingly all of human origin, were detected in the brain of Tg2576 mouse, whereas 39 species, of both murine and human origin, were detected in the brain of the APP/PS1 mouse. To the best of our knowledge, this is the first study showing the identification of such a high number of Aβ species in the brain of the APP/PS1 transgenic mouse, whereas, in contrast, a much lower number of Aβ species were identified in the Tg2576 mouse. Therefore, this study brings to light a relevant phenotypic difference between these two popular mice models of AD. PMID:27258422

  5. Intranasal Delivery of NEMO-Binding Domain Peptide Prevents Memory Loss in a Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Rangasamy, Suresh B; Corbett, Grant T; Roy, Avik; Modi, Khushbu K; Bennett, David A; Mufson, Elliott J; Ghosh, Sankar; Pahan, Kalipada

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia. Despite intense investigations, no effective therapy is available to halt its progression. We found that NF-κB was activated within the hippocampus and cortex of AD subjects and that activated forms of NF-κB negatively correlated with cognitive function monitored by Mini-Mental State Examination and global cognitive z score. Accordingly, NF-κB activation was also observed in the hippocampus of a transgenic (5XFAD) mouse model of AD. It has been shown that peptides corresponding to the NF-κB essential modifier (NEMO)-binding domain (NBD) of IκB kinase α (IKKα) or IκB kinase β (IKKβ) specifically inhibit the induction of NF-κB activation without inhibiting the basal NF-κB activity. Interestingly, after intranasal administration, wild-type NBD peptide entered into the hippocampus, reduced hippocampal activation of NF-κB, suppressed hippocampal microglial activation, lowered the burden of Aβ in the hippocampus, attenuated apoptosis of hippocampal neurons, protected plasticity-related molecules, and improved memory and learning in 5XFAD mice. Mutated NBD peptide had no such protective effect, indicating the specificity of our finding. These results suggest that selective targeting of NF-κB activation by intranasal administration of NBD peptide may be of therapeutic benefit for AD patients. PMID:26401561

  6. New developments in animal models of Alzheimer's disease.

    Science.gov (United States)

    Janus, C; Phinney, A L; Chishti, M A; Westaway, D

    2001-09-01

    Alzheimer's disease (AD) is characterized by deterioration in mental function leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid-beta peptide (A beta), whereas NFTs are assemblies of hyperphosphorylated forms of the microtubule-associated protein tau. Electron microscopy of NFTs reveals structures known as paired helical filaments (PHFs). In familial AD (FAD), mutations in three distinct genes drive A beta synthesis by favoring endoproteolytic secretase cleavages that liberate A beta from the Alzheimer beta-amyloid precursor protein (APP). This suggests that excess A beta initiates a pathogenic cascade in humans that culminates in all the pathologic and cellular hallmarks of AD. Building upon the knowledge of FAD mutations, incremental technical advances have now allowed reproduceable creation of APP transgenic mice that exhibit AD-like amyloid pathology and A beta burdens. These transgenic mouse lines also exhibit deficits in spatial reference and working memory, with immunization against A beta abrogating both AD-associated phenotypes. Besides establishing a proof of principle for A beta-directed therapies, these findings suggest a potential to identify individual elements in the pathogenic pathway that lead to cognitive dysfunction. Furthermore, transgenic APP mice with potent amyloid deposition will likely form a beach-head to capture the final elements of AD neuropathology--cell loss and NFTs composed of PHFs--that are missing from current transgenic models. PMID:11898556

  7. A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Qi Chen

    Full Text Available Currently, the major drug discovery paradigm for neurodegenerative diseases is based upon high affinity ligands for single disease-specific targets. For Alzheimer's disease (AD, the focus is the amyloid beta peptide (Aß that mediates familial Alzheimer's disease pathology. However, given that age is the greatest risk factor for AD, we explored an alternative drug discovery scheme that is based upon efficacy in multiple cell culture models of age-associated pathologies rather than exclusively amyloid metabolism. Using this approach, we identified an exceptionally potent, orally active, neurotrophic molecule that facilitates memory in normal rodents, and prevents the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.

  8. Critical role for sphingosine kinase-1 in regulating survival of neuroblastoma cells exposed to amyloid-beta peptide.

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    Gomez-Brouchet, Anne; Pchejetski, Dimitri; Brizuela, Leyre; Garcia, Virginie; Altié, Marie-Françoise; Maddelein, Marie-Lise; Delisle, Marie-Bernadette; Cuvillier, Olivier

    2007-08-01

    We examined the role of sphingosine kinase-1 (SphK1), a critical regulator of the ceramide/sphingosine 1-phosphate (S1P) biostat, in the regulation of death and survival of SH-SY5Y neuroblastoma cells in response to amyloid beta (Abeta) peptide (25-35). Upon incubation with Abeta, SH-SY5Y cells displayed a marked down-regulation of SphK1 activity coupled with an increase in the ceramide/S1P ratio followed by cell death. This mechanism was redox-sensitive; N-acetylcysteine totally abrogated the down-regulation of SphK1 activity and strongly inhibited Abeta-induced cell death. SphK1 overexpression impaired the cytotoxicity of Abeta, whereas SphK1 silencing by RNA interference mimicked Abeta-induced cell death, thereby establishing a critical role for SphK1. We further demonstrated that SphK1 could mediate the well established cytoprotective action of insulin-like growth factor (IGF-I) against Abeta toxicity. A dominant-negative form of SphK1 or its pharmacological inhibition not only abrogated IGF-I-triggered stimulation of SphK1 but also hampered IGF-I protective effect. Similarly to IGF-I, the neuroprotective action of TGF-beta1 was also dependent on SphK1 activity; activation of SphK1 as well as cell survival were impeded by a dominant-negative form of SphK1. Taken together, these results provide the first illustration of SphK1 role as a critical regulator of death and survival of Abeta-treated cells. PMID:17522181

  9. Plasma based markers of [11C] PiB-PET brain amyloid burden.

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    Steven John Kiddle

    Full Text Available Changes in brain amyloid burden have been shown to relate to Alzheimer's disease pathology, and are believed to precede the development of cognitive decline. There is thus a need for inexpensive and non-invasive screening methods that are able to accurately estimate brain amyloid burden as a marker of Alzheimer's disease. One potential method would involve using demographic information and measurements on plasma samples to establish biomarkers of brain amyloid burden; in this study data from the Alzheimer's Disease Neuroimaging Initiative was used to explore this possibility. Sixteen of the analytes on the Rules Based Medicine Human Discovery Multi-Analyte Profile 1.0 panel were found to associate with [(11C]-PiB PET measurements. Some of these markers of brain amyloid burden were also found to associate with other AD related phenotypes. Thirteen of these markers of brain amyloid burden--c-peptide, fibrinogen, alpha-1-antitrypsin, pancreatic polypeptide, complement C3, vitronectin, cortisol, AXL receptor kinase, interleukin-3, interleukin-13, matrix metalloproteinase-9 total, apolipoprotein E and immunoglobulin E--were used along with co-variates in multiple linear regression, and were shown by cross-validation to explain >30% of the variance of brain amyloid burden. When a threshold was used to classify subjects as PiB positive, the regression model was found to predict actual PiB positive individuals with a sensitivity of 0.918 and a specificity of 0.545. The number of APOE [Symbol: see text] 4 alleles and plasma apolipoprotein E level were found to contribute most to this model, and the relationship between these variables and brain amyloid burden was explored.

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

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    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

  11. Emerging concepts of how β-amyloid proteins and pro-inflammatory cytokines might collaborate to produce an 'Alzheimer brain' (Review).

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    Dal Pra, Ilaria; Chiarini, Anna; Pacchiana, Raffaella; Chakravarthy, Balu; Whitfield, James F; Armato, Ubaldo

    2008-01-01

    Three steps lead to the development of full-blown sporadic or late-onset Alzheimer's disease or dementia (AD). In the young brain, amyloid β-(1-42) (Aβ 42) is a normal aggregation-prone protein product of neuronal activity that is kept at a safe low level by proteolysis in neurons and glial cells, and by expulsion across the blood-brain barrier. But clearance declines with advancing age. Step 1: Because of the normal decline with age of the Aβ 42-clearing mechanisms, toxic amyloid-derived diffusible ligands (ADDLs) made of dodecamers of the aggregation-prone Aβ 42 start accumulating. These Aβ 42 dodecamers selectively target the initially huge numbers of excitatory synapses of neurons and cause them to start slowly dropping, which increasingly impairs plasticity and sooner or later starts noticeably affecting memory formation. At a certain point, this increasing loss of synapses induces the neurons to redirect their still-expressed cell cycle proteins from post-mitotic jobs, such as maintaining synapses, to starting a cell cycle and partially or completely replicating DNA without entering mitosis. The resulting aneuploid or tetraploid neurons survive for as long as 6-12 months as quasi-functional 'undead zombies', with developing tangles of hyperphosphorylated τ protein disrupting the vital anterograde axonal transport of mitochondria and other synapse-vital components. Step 2: The hallmark AD plaques appear as Aβ 42 clearance continues to decline and the formation of Aβ 42 non-diffusible fibrils begins in the aging brain. Step 3: A terminal cytokine-driven maëlstrom begins in the aging brain when microglia, the brain's professional macrophages, are activated in and around the plaques. They produce pro-inflammatory cytokines, such as IFN-γ, IL-1β and TNF-α. One of these, IFN-γ, causes the astrocytes enwrapping the neuronal synapses to express their β-secretase (BACE1) genes and produce and release Aβ 42, which can kill the closely apposed neurons by

  12. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study

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    Rodriguez-Vieitez, Elena; Ni, Ruiqing; Voytenko, Larysa; Marutle, Amelia [Karolinska Institutet, Division of Translational Alzheimer Neurobiology, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Centre for Psychiatric Research, Department of Clinical Neuroscience, Stockholm (Sweden); Nanyang Technological University, NTU - Imperial College, Lee Kong Chian School of Medicine, Singapore (Singapore); Toth, Miklos; Haeggkvist, Jenny [Karolinska Institutet, Centre for Psychiatric Research, Department of Clinical Neuroscience, Stockholm (Sweden); Nordberg, Agneta [Karolinska Institutet, Division of Translational Alzheimer Neurobiology, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden)

    2015-04-17