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Sample records for amyloid deposition limits

  1. Whole body amyloid deposition imaging by 123I-SAP scintigraphy

    NARCIS (Netherlands)

    van Rheenen, Ronald; Glaudemans, Andor; Hazenberg, Bouke

    2011-01-01

    Amyloidosis is the name of a group of diseases characterized by extracellular deposition of amyloid fibrils. Deposition of amyloid can be localized or systemic. The 123I-SAP-scan can be used to image extent and distribution of amyloid deposition in patients with systemic AA, AL and ATTR amyloidosis.

  2. Solitary osteosclerotic plasmacytoma: association with demyelinating polyneuropathy and amyloid deposition

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    Voss, S.D.; Hall, F.M. [Dept. of Radiology, Beth Israel Deaconess Medical Center, Boston, MA (United States); Harvard Medical School, Boston, MA (United States); Murphey, M.D. [Dept. of Radiologic Pathology, Armed Forces Institute of Pathology, Washington, DC (United States); Dept. of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD (United States); Department of Radiology, University of Maryland School of Medicine, Baltimore, Maryland (United States)

    2001-09-01

    A 51-year-old man presented with a 1-year history of polyneuropathy necessitating the use of a wheelchair. Initial diagnosis was idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) and associated monoclonal gammopathy. Investigations for multiple myeloma, including bone marrow aspiration and biopsy, were negative. What was initially felt to be an incidental osteosclerotic focus noted on the radiographic bone survey was eventually shown to be a solitary osteosclereotic plasmacytoma with associated amyloid. This dramatically altered treatment. This case emphasizes the importance of including osteosclerotic plasmacytoma in the differential diagnosis of a focal sclerotic bone lesion in the clinical setting of polyneuropathy. These lesions are less likely to progress to multiple myeloma than lytic plasma cell neoplasms, and the presence of polyneuropathy often results in earlier diagnosis and treatment with enhanced prospect of cure. The finding of amyloid deposition within the osteosclerotic lesion may be of prognostic importance. (orig.)

  3. Specific localization and imaging of amyloid deposits in vivo using /sup 123/I-labeled serum amyloid P component

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    Hawkins, P.N.; Myers, M.J.; Epenetos, A.A.; Caspi, D.; Pepys, M.B.

    1988-03-01

    Highly specific, high-resolution scintigraphic images of amyloid-laden organs in mice with experimentally induced amyloid A protein (AA) amyloidosis were obtained after intravenous injection of /sup 123/I-labeled serum amyloid P component (SAP). Interestingly, a much higher proportion (up to 40%) of the injected dose of heterologous human SAP localized to amyloid and was retained there than was the case with isologous mouse SAP, indicating that human SAP binds more avidly to mouse AA fibrils than does mouse SAP. Specificity of SAP localization was established by the failure of the related proteins, human C-reactive protein and Limulus C-reactive protein, to deposit significantly in amyloid and by the absence of human SAP deposition in nonamyloidotic organs. However, only partial correlations were observed between the quantity of SAP localized and two independent estimates, histology and RIA for AA of the amount of amyloid in particular organs. It is not clear which of the three methods used reflects better the extent or clinical significance of the amyloid deposits but in vivo localization of radiolabeled SAP, detectable and quantifiable by gamma camera imaging, is apparently extremely sensitive. These findings establish the use of labeled SAP as a noninvasive in vivo diagnostic probe in experimental amyloidosis, potentially capable of revealing the natural history of the condition, and suggest that it may also be applicable generally as a specific targeting agent for diagnostic and even therapeutic purposes in clinical amyloidosis.

  4. Human serum amyloid P component is an invariant constituent of amyloid deposits and has a uniquely homogeneous glycostructure.

    OpenAIRE

    Pepys, M B; Rademacher, T W; Amatayakul-Chantler, S.; Williams, P.; Noble, G. E.; Hutchinson, W L; Hawkins, P N; Nelson, S R; Gallimore, J. R.; Herbert, J.

    1994-01-01

    Human serum amyloid P component (SAP) is a normal plasma protein and the precursor of amyloid P component (AP), a universal constituent of the abnormal tissue deposits in amyloidosis, including Alzheimer disease. We show here that its single N-linked biantennary oligosaccharide does not display the microheterogeneity usually characteristic of glycoproteins. The protein and the glycan structures of AP were also invariant, their resistance to degradation suggesting a role in persistence of amyl...

  5. Frequency of pancreatic amyloid deposition in cats from south-eastern Queensland.

    Science.gov (United States)

    Lutz, T A; Ainscow, J; Rand, J S

    1994-08-01

    Stereological procedures were used to estimate the amount of amyloid deposition in the pancreatic islets of 83 cats from random sources in south-eastern Queensland. Most had only minor deposits of less than 20% of islet volume (median 9%), but deposits equal to more than 50% of the islet volume were found in 10% of the cats. Amyloid deposition in pancreatic islets was correlated with the age of the cat. Although similar observations have been made previously in cats from the USA, the frequency of amyloid deposition was higher in this population of cats from south-eastern Queensland.

  6. Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein.

    NARCIS (Netherlands)

    Miao, J.; Xu, F.; Davis, J.; Otte-Holler, I.; Verbeek, M.M.; Nostrand, W.E. van

    2005-01-01

    Cerebral vascular amyloid beta-protein (Abeta) deposition, also known as cerebral amyloid angiopathy, is a common pathological feature of Alzheimer's disease. Additionally, several familial forms of cerebral amyloid angiopathy exist including the Dutch (E22Q) and Iowa (D23N) mutations of Abeta. Incr

  7. Limited Deposit Insurance Coverage and Bank Competition

    OpenAIRE

    Shy, Oz; Stenbacka, Rune; Yankov, Vladimir

    2014-01-01

    Deposit insurance designs in many countries place a limit on the coverage of deposits in each bank. However, no limits are placed on the number of accounts held with different banks. Therefore, under limited deposit insurance, some consumers open accounts with different banks to achieve higher or full deposit insurance coverage. We compare three regimes of deposit insurance: No deposit insurance, unlimited deposit insurance, and limited deposit insurance. We show that limited deposit insuranc...

  8. Amyloid Deposition Is Linked to Aberrant Entorhinal Activity among Cognitively Normal Older Adults

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    Mormino, Elizabeth C.; Wigman, Sarah E.; Ward, Andrew M.; Vannini, Patrizia; McLaren, Donald G.; Becker, J. Alex; Schultz, Aaron P.; Hedden, Trey; Johnson, Keith A.; Sperling, Reisa A.

    2014-01-01

    Normal aging is often difficult to distinguish from the earliest stages of Alzheimer's disease. Years before clinical memory deficits manifest, amyloiddeposits in the cortex in many older individuals. Neuroimaging studies indicate that a set of densely connected neocortical regions, referred to as the default network, is especially vulnerable to amyloiddeposition. Yet, the impact of amyloid-β on age-related changes within the medial temporal lobe (MTL) memory system is less clear. Here we demonstrate that cognitively normal older humans, compared with young adults, show reduced ability to modulate hippocampal activations and entorhinal deactivations during an episodic memory task. Among older adults, amyloiddeposition was associated with failure to modulate activity in entorhinal cortex, but not hippocampus. Furthermore, we show that entorhinal regions demonstrating amyloid-β-related dysfunction are directly connected to the neocortical regions of the default network. Together these findings link neocortical amyloiddeposition to neuronal dysfunction specifically in entorhinal cortex, while aging is associated with more widespread functional changes across the MTL. PMID:24719099

  9. Association between Cerebral Amyloid Deposition and Clinical Factors Including Cognitive Function in Geriatric Depression: Pilot Study Using Amyloid Positron Emission Tomography

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    Kim, Hye-Geum; Kong, Eun-Jung; Cheon, Eun-Jin; Kim, Hae-Won; Koo, Bon-Hoon

    2016-01-01

    The purpose of this study was to explore the relationship between cerebral amyloid deposition and overall clinical factors including cognitive functions in geriatric depression by using 18F-florbetaben positron emission tomography. Thirteen subjects aged over 60 years who had a history of major depressive disorder and also had subjective memory complaint were included. Of all subjects, 3 subjects judged as amyloid positive, and the others judged as amyloid negative. Their memory, visuospatial functions and attention abilities were negatively correlated with amyloid deposition in specific brain regions, but their language and recognition abilities were not correlated with any region. The amyloid deposition of the whole brain region was significantly negatively correlated with immediate memory. PMID:27776391

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

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    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

  11. Inhibition of Insulin-Degrading Enzyme Does Not Increase Islet Amyloid Deposition in Vitro.

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    Hogan, Meghan F; Meier, Daniel T; Zraika, Sakeneh; Templin, Andrew T; Mellati, Mahnaz; Hull, Rebecca L; Leissring, Malcolm A; Kahn, Steven E

    2016-09-01

    Islet amyloid deposition in human type 2 diabetes results in β-cell loss. These amyloid deposits contain the unique amyloidogenic peptide human islet amyloid polypeptide (hIAPP), which is also a known substrate of the protease insulin-degrading enzyme (IDE). Whereas IDE inhibition has recently been demonstrated to improve glucose metabolism in mice, inhibiting it has also been shown to increase cell death when synthetic hIAPP is applied exogenously to a β-cell line. Thus, we wanted to determine whether a similar deleterious effect is observed when hIAPP is endogenously produced and secreted from islets. To address this issue, we cultured hIAPP transgenic mouse islets that have the propensity to form amyloid for 48 and 144 hours in 16.7 mM glucose in the presence and absence of the IDE inhibitor 1. At neither time interval did IDE inhibition increase amyloid formation or β-cell loss. Thus, the inhibition of IDE may represent an approach to improve glucose metabolism in human type 2 diabetes, without inducing amyloid deposition and its deleterious effects.

  12. Dynamic changes of beta-amyloid protein deposition in hippocampus of female ovariectomized rats

    Institute of Scientific and Technical Information of China (English)

    Huiqing Xie; Jianda Zhou; Shaodan Sun; Xuhong Li; Liming Deng; Fengmei Li

    2008-01-01

    BACKGROUND: To evaluate and summarize the effects of cerebral perfusion and vascular reserve on the treatment of SICAS. Recently, research on β-amyloid protein has focused on the regulatory effects of es-trogen or phytoestrogen on its deposition. However, there have been only a few reports on dynamic changes of β-amyloid protein deposition in hippocampus of ovariectomized rats.OBJECTIVE: To measureβ-amyloid protein deposition in the hippocampal formation of ovariectomized rats by using immunohistochemistry; to observe time-dependent dynamic changes. DESIGN: Randomized controlled animal study.SETTING: Third Xiangya Hospital of Central South University.MATERIALS: The experiment was carried out in the Central Laboratory of the Third Xiangya Hospital of Central South University from November 2005 to December 2006. Fifty healthy female Sprague Dawley (SD) rats, weighing (293 ± 10) g, were provided by the Animal Laboratory of Xiangya Medical College, Central South University. All rats had neither a childbearing history nor hepatic or renal disease, or skeletal deformity. Β-amyloid protein immunohistochemical kit was provided by Wuhan Boster Company. The ex-periment was in accordance with animal ethics standards.METHODS: All rats were randomly divided into five groups, including normal control group (n = 10), sham operation group (n = 10), and ovariectomized group (n = 30). After anesthesia in the ovariectomized group, the bilateral ovaries were separated and resected. The same volume of fat was resected in the sham operation group. Rats from the normal control group, however, did not receive any surgical treatments. Rats in the normal control group and sham operation group were sacrificed by anesthesia 7 weeks after surgery. Every ten rats from the ovariectomized group was respectively sacrificed at 7, 15, and 30 weeks after surgery. Immunohistochemistry was used to detectβ-amyloid protein deposition in hippocampal sections. Cell counting and gray value

  13. Visual Hallucinations and Amyloid Deposition in Parkinson's Disease Dementia: A Case Report.

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    Um, Yoo Hyun; Kim, Tae-Won; Jeong, Jong-Hyun; Seo, Ho-Jun; Han, Jin-Hee; Hong, Seung-Chul; Jung, Won-Sang; Choi, Woo Hee; Lee, Chang-Uk; Lim, Hyun Kook

    2016-05-01

    Parkinson's disease dementia (PDD) is notorious for its debilitating clinical course and high mortality rates. Consequently, various attempts to investigate predictors of cognitive decline in Parkinson's disease (PD) have been made. Here we report a case of a 75-year-old female patient with PD who visited the clinic with complaints of recurrent visual hallucinations and cognitive decline, whose symptoms were ameliorated by the titration of rivastigmine. Imaging results showed pronounced diffuse cortical amyloid deposition evidenced by 18F-florbetaben amyloid positron emission tomography (PET) imaging. This observation suggests that pronounced amyloid deposition and visual hallucinations in PD patients could be clinically significant predictors of cognitive decline in PD patients. Future research should concentrate on accumulating more evidence for possible predictors of cognitive decline and their association with PD pathology that can enable an early intervention and standardized treatment in PDD patients. PMID:27247605

  14. Tissue distribution of amyloid deposits in Abyssinian cats with familial amyloidosis.

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    DiBartola, S P; Tarr, M J; Benson, M D

    1986-07-01

    The tissue distribution of amyloid deposits was studied in 15 related Abyssinian cats with familial amyloidosis. There was interstitial medullary amyloidosis in the kidneys of all 15 cats but only 11 had detectable glomerular involvement. The thyroid glands, stomach and colon were affected in all cats examined. Most of the cats also had amyloid deposits in the small intestine, spleen, heart, adrenals, pancreas, liver, lymph nodes and bladder. In 50 per cent or fewer of the cats examined, there was involvement of the parathyroids, lung and gonads. The central nervous system was not involved in any of the 3 cats evaluated. In 8 of the cats, no concurrent inflammatory disease could be detected. The tissue distribution of amyloid deposits resembled that found in other breeds of domestic cats with systemic amyloidosis. Despite the wide tissue distribution of amyloid deposits, clinical signs were related to renal amyloidosis. Familial amyloidosis in the Abyssinian cat may represent a valuable spontaneous animal model for the study of Familial Mediterranean Fever in man and the pathogenesis of reactive amyloidosis in general. PMID:3734172

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

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    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.

  16. Expression of complement system components during aging and amyloid deposition in APP transgenic mice

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    Wiederhold Karl-Heinz

    2009-11-01

    Full Text Available Abstract Background A causal role of the complement system in Alzheimer's disease pathogenesis has been postulated based on the identification of different activated components up to the membrane attack complex at amyloid plaques in brain. However, histological studies of amyloid plaque bearing APP transgenic mice provided only evidence for an activation of the early parts of the complement cascade. To better understand the contribution of normal aging and amyloid deposition to the increase in complement activation we performed a detailed characterization of the expression of the major mouse complement components. Methods APP23 mice expressing human APP751 with the Swedish double mutation as well as C57BL/6 mice were used at different ages. mRNA was quantified by Realtime PCR and the age- as well as amyloid induced changes determined. The protein levels of complement C1q and C3 were analysed by Western blotting. Histology was done to test for amyloid plaque association and activation of the complement cascade. Results High mRNA levels were detected for C1q and some inhibitory complement components. The expression of most activating components starting at C3 was low. Expression of C1q, C3, C4, C5 and factor B mRNA increased with age in control C57BL/6 mice. C1q and C3 mRNA showed a substantial additional elevation during amyloid formation in APP23 mice. This increase was confirmed on the protein level using Western blotting, whereas immunohistology indicated a recruitment of complement to amyloid plaques up to the C3 convertase. Conclusion Early but not late components of the mouse complement system show an age-dependent increase in expression. The response to amyloid deposition is comparatively smaller. The low expression of C3 and C5 and failure to upregulate C5 and downstream components differs from human AD brain and likely contributes to the lack of full complement activation in APP transgenic mice.

  17. Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes

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    Miklossy, J.; Miller, L.; Qing, H.; Radenovic, A.; Kis, A.; Vileno, B.; Laszlo, F.; Martins, R.N.; Waeber, G.; Mooser, V.; Bosman, F.; Khalili, K.; Darbinian, N.; McGeer, P.L.

    2008-08-25

    Strong epidemiologic evidence suggests an association between Alzheimer disease (AD) and type 2 diabetes. To determine if amyloid beta (A{beta}) and hyperphosphorylated tau occurs in type 2 diabetes, pancreas tissues from 21 autopsy cases (10 type 2 diabetes and 11 controls) were analyzed. APP and tau mRNAs were identified in human pancreas and in cultured insulinoma beta cells (INS-1) by RT-PCR. Prominent APP and tau bands were detected by Western blotting in pancreatic extracts. Aggregated A{beta}, hyperphosphorylated tau, ubiquitin, apolipoprotein E, apolipoprotein(a), IB1/JIP-1 and JNK1 were detected in Langerhans islets in type 2 diabetic patients. A{beta} was co-localized with amylin in islet amyloid deposits. In situ beta sheet formation of islet amyloid deposits was shown by infrared microspectroscopy (SIRMS). LPS increased APP in non-neuronal cells as well. We conclude that A{beta} deposits and hyperphosphorylated tau are also associated with type 2 diabetes, highlighting common pathogenetic features in neurodegenerative disorders, including AD and type 2 diabetes and suggesting that A{beta} deposits and hyperphosphorylated tau may also occur in other organs than the brain.

  18. Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage

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    Gordon Marcia N

    2004-12-01

    Full Text Available Abstract Background Anti-Aβ immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Aβ antibodies to 19- and 23-month old APP-transgenic mice. Methods We investigated the effects of weekly anti-Aβ antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. Results After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Aβ immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. Conclusions The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage.

  19. Immunolocalization of Kisspeptin Associated with AmyloidDeposits in the Pons of an Alzheimer’s Disease Patient

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    Amrutha Chilumuri

    2013-01-01

    Full Text Available The pons region of the Alzheimer’s disease (AD brain is one of the last to show amyloid-β (Aβ deposits and has been suggested to contain neuroprotective compounds. Kisspeptin (KP is a hormone that activates the hypothalamic-pituitary-gonadal axis and has been suggested to be neuroprotective against Aβ toxicity. The localization of KP, plus the established endogenous neuroprotective compounds corticotropin releasing hormone (CRH and catalase, in tissue sections from the pons region of a male AD subject has been determined in relation to Aβ deposits. Results showed Aβ deposits also stained with KP, CRH, and catalase antibodies. At high magnification the staining of deposits was either KP or catalase positive, and there was only a limited area of the deposits with KP-catalase colocalization. The CRH does not bind Aβ, whilst both KP and catalase can bind Aβ, suggesting that colocalization in Aβ deposits is not restricted to compounds that directly bind Aβ. The neuroprotective actions of KP, CRH, and catalase were confirmed in vitro, and fibrillar Aβ preparations were shown to stimulate the release of KP in vitro. In conclusion, neuroprotective KP, CRH, and catalase all colocalize with Aβ plaque-like deposits in the pons region from a male AD subject.

  20. Extramedullary plasmocytoma associated with a massive deposit of amyloid in the duodenum

    Institute of Scientific and Technical Information of China (English)

    Fabiana Pirani Carneiro; Maria de Nazareth Machado Sobreira; Livia Bravo Maia; Alesso Cervantes Sartorelli; Luiz Eduardo de Almeida Prado Franceschi; Mauro Brito Brandao; Bárbara Wosnjuk Calaca; Fernando Silva Lustosa; Joao Vieira Lopes

    2009-01-01

    We report a rare case of extramedullary plasmocytoma associated with a massive deposit of amyloid in the duodenum. A 72-year-old Japanese man was admitted to our hospital presenting with a 3-mo history of epigastric pain, vomiting and weight loss. On computed tomography (CT) a wall thickening of the fourth part of the duodenum was observed. Multiple biopsies obtained from the lesion showed infiltration of plasma cells and lymphocytes, but they were not conclusive. The patient underwent resection of the lesion and, on histopathological examination, the lesion consisted of a dense and diffuse infiltrate of plasma cells and a few admixed lymphocytes with reactive follicles extending to the muscular propria. An extensive deposition of amyloid was also observed. Immunohistochemical stains revealed that a few plasmacytoid cells showed λ light chain staining, though most were κ light chain positive. These cells also were positive for CD138 and CD56 but negative for CD20 and CD79. The findings were consistent with extramedullary plasmocytoma associated with a massive deposit of amyloid in duodenum. A subsequent workup for multiple myeloma was completely negative. The patient showed no signs of local recurrence or dissemination of the disease after 12 mo follow-up. Because of the association of plasmocytoma and amyloidosis, the patient must be followed up because of the possible systemic involvement of the neoplasm and amyloidosis in future.

  1. Topo-optical reactions for the identification of O-acyl sugars in amyloid deposits.

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    Richter, Susann; Makovitzky, Josef

    2009-01-01

    The aldehyde bisulfite toluidine blue (ABT) reaction with former saponification (KOH-ABT) and periodic acid-borohydride reduction-saponification (PB-KOH-ABT) were applied to sections of human amyloid deposits in the respiratory tract. The saponification-induced increase in ABT-reactivity was confined to the presence of O-acyl sugars associated with the amyloid fibrils. The anisotropic and metachromatic effect in the ABT and KOH-ABT reaction was reduced in the corresponding PB-KOH-ABT reaction, a difference attributed to the removal of staining due to neutral carbohydrate residues. Since the periodic acid-borohydride reduction abolishes all pre-existing ABT-reactivity of neutral sugar vicinal diols, the isolated KOH-effect could be shown using the PB-KOH-ABT reaction. By application of this sequence, the problem identifying small quantities of O-acyl sugars was solved. It is suggested that the KOH-effect depends upon the removal of O-acyl substituents located on the polyhydroxy side chain (C7, C8, C9) of sialic acid residues. An advantage of such topo-optical reactions over biochemical techniques is the exact localization of O-acyl sugars in tissue sites. By means of the KOH-ABT and PB-KOH-ABT reactions we have demonstrated, for the first time, that O-acyl sugars occur within amyloid deposits.

  2. Dissociation between brain amyloid deposition and metabolism in early mild cognitive impairment.

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    Liyong Wu

    Full Text Available BACKGROUND: The hypothetical model of dynamic biomarkers for Alzheimer's disease (AD describes high amyloid deposition and hypometabolism at the mild cognitive impairment (MCI stage. However, it remains unknown whether brain amyloidosis and hypometabolism follow the same trajectories in MCI individuals. We used the concept of early MCI (EMCI and late MCI (LMCI as defined by the Alzheimer's disease Neuroimaging Initiative (ADNI-Go in order to compare the biomarker profile between EMCI and LMCI. OBJECTIVES: To examine the global and voxel-based neocortical amyloid burden and metabolism among individuals who are cognitively normal (CN, as well as those with EMCI, LMCI and mild AD. METHODS: In the present study, 354 participants, including CN (n = 109, EMCI (n = 157, LMCI (n = 39 and AD (n = 49, were enrolled between September 2009 and November 2011 through ADNI-GO and ADNI-2. Brain amyloid load and metabolism were estimated using [(18F]AV45 and [(18F]fluorodeoxyglucose ([(18F]FDG PET, respectively. Uptake ratio images of [(18F]AV45 and [(18F]FDG were calculated by dividing the summed PET image by the median counts of the grey matter of the cerebellum and pons, respectively. Group differences of global [(18F]AV45 and [(18F]FDG were analyzed using ANOVA, while the voxel-based group differences were estimated using statistic parametric mapping (SPM. RESULTS: EMCI patients showed higher global [(18F]AV45 retention compared to CN and lower uptake compared to LMCI. SPM detected higher [(18F]AV45 uptake in EMCI compared to CN in the precuneus, posterior cingulate, medial and dorsal lateral prefrontal cortices, bilaterally. EMCI showed lower [(18F]AV45 retention than LMCI in the superior temporal, inferior parietal, as well as dorsal lateral prefrontal cortices, bilaterally. Regarding to the global [(18F]FDG, EMCI patients showed no significant difference from CN and a higher uptake ratio compared to LMCI. At the voxel level, EMCI showed higher metabolism

  3. Clinically different stages of Alzheimer's disease associated by amyloid deposition with [11C]-PIB PET imaging.

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    Hatashita, Shizuo; Yamasaki, Hidetomo

    2010-01-01

    We investigated whether [11C]-PIB PET detects underlying amyloid deposition at clinically different stages of Alzheimer's disease (AD) and preclinical dementia. The Japanese cohort of 214 subjects underwent cognitive testing and 60-min dynamic [11C]-PIB PET. [11C]-PIB data were acquired from 35-60 min after injection. Regions of interest were defined on co-registered MRI. Distribution volume ratios (DVR) of PIB retention were determined using Logan graphical analysis. All 56 patients with AD showed a robust increase in PIB retention in cortical areas (typical PIB AD-pattern). A mean DVR value in 11 patients with moderate AD (CDR: 2.1 ± 0.4) showed significantly higher PIB retention (2.38 ± 0.42, p differ from very mild AD. The prevalence of AD among the 53 amyloid positive patients aged 75 years or older increased greatly to 74% whereas that of amyloid positive HC decreased by only 9% and amyloid positive MCI by 17%. Prodromal AD and AD dementia is identified, based on cognitive function and amyloid deposition by PIB PET imaging. Further, the cortical amyloid deposition could be detected at preclinical stage of AD.

  4. Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models.

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    Minami, S Sakura; Min, Sang-Won; Krabbe, Grietje; Wang, Chao; Zhou, Yungui; Asgarov, Rustam; Li, Yaqiao; Martens, Lauren H; Elia, Lisa P; Ward, Michael E; Mucke, Lennart; Farese, Robert V; Gan, Li

    2014-10-01

    Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.

  5. DBA/2J genetic background exacerbates spontaneous lethal seizures but lessens amyloid deposition in a mouse model of Alzheimer's disease.

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    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.

  6. Monoclonal Gammopathy of Undetermined Significance with Amyloid Deposition in the Lung and Non-Amyloid Eosinophilic Deposition in the Brain: A Case Report

    Directory of Open Access Journals (Sweden)

    Francois Abi-Fadel

    2010-01-01

    Full Text Available Background. Monoclonal gammopathy of undetermined significance (MGUS is rarely complicated by amyloidosis. Case. A 66-year-old white male presented to the emergency room (ER after an unwitnessed fall and change in mental status. Patient was awake and alert but not oriented. There was no focal deficit on neurological exam. Past medical history (PMH included hypertension, hypercholesterolemia, aortic valve replacement (nonmetallic, incomplete heart block controlled by a pacemaker and IgG- IgA type Monoclonal Gammopathy of Undetermined Significance. The MGUS was diagnosed 9 months ago on serum protein electrophoresis (SPEP as patient was referred to the outpatient clinic for hyperglobulinemia on routine blood work. In ER, a head-computed tomography (CT revealed multiple parenchymal hemorrhagic lesions suspicious for metastases. A CT chest, abdomen and pelvis revealed numerous ground-glass and solid nodules in the lungs. Lower extremity duplex and transesophageal echocardiogram were negative. Serial blood cultures and serologies for cryptococcus and histoplasmosis, antineutrophil cytoplasmic antibody (ANCA, antinuclear antibody (ANA, rheumatoid factor (RF, cryoglobulin, and antiglomerular basement membrane (anti-GBM antibodies were all negative. CT guided lung biopsy was positive for Thioflavin T amyloid deposits. Brain biopsy was positive for eosinophilic material (similar to the lungs but negative for Thioflavin T stain. The patient's clinical status continued to deteriorate with cold cyanotic fingers developing on day 12 and a health care acquired pneumonia, respiratory failure, and fungemia on day 18. On day 29, family withdrew life support and denied any autopsies. Conclusion. Described is an atypical course of MGUS complicated by amyloidosis of the lung and nonamyloid eosinophilic deposition in the brain. As MGUS might be complicated by diseases such as amyloidosis and multiple myeloma, a scheduled follow-up of these patients is always

  7. In vivo evaluation of amyloid deposition and brain glucose metabolism of 5XFAD mice using positron emission tomography.

    Science.gov (United States)

    Rojas, Santiago; Herance, José Raúl; Gispert, Juan Domingo; Abad, Sergio; Torrent, Elia; Jiménez, Xavier; Pareto, Deborah; Perpiña, Unai; Sarroca, Sara; Rodríguez, Elisenda; Ortega-Aznar, Arantxa; Sanfeliu, Coral

    2013-07-01

    Positron emission tomography (PET) has been used extensively to evaluate the neuropathology of Alzheimer's disease (AD) in vivo. Radiotracers directed toward the amyloid deposition such as [(18)F]-FDDNP (2-(1-{6-[(2-[F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile) and [(11)C]-PIB (Pittsburg compound B) have shown exceptional value in animal models and AD patients. Previously, the glucose analogue [(18)F]-FDG (2-[(18)F]fluorodeoxyglucose) allowed researchers and clinicians to evaluate the brain glucose consumption and proved its utility for the early diagnosis and the monitoring of the progression of AD. Animal models of AD are based on the transgenic expression of different human mutant genes linked to familial AD. The novel transgenic 5XFAD mouse containing 5 mutated genes in its genome has been proposed as an AD model with rapid and massive cerebral amyloid deposition. PET studies performed with animal-dedicated scanners indicate that PET with amyloid-targeted radiotracers can detect the pathological amyloid deposition in transgenic mice and rats. However, in other studies no differences were found between transgenic mice and their wild type littermates. We sought to investigate in 5XFAD mice if the radiotracers [(11)C]-PIB, and [(18)F]-Florbetapir could quantify the amyloid deposition in vivo and if [(18)F]-FDG could do so with regard to glucose consumption. We found that 5XFAD animals presented higher cerebral binding of [(18)F]-Florbetapir, [(11)C]-PIB, and [(18)F]-FDG. These results support the use of amyloid PET radiotracers for the evaluation of AD animal models. Probably, the increased uptake observed with [(18)F]-FDG is a consequence of glial activation that occurs in 5XFAD mice.

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-09-15

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

  10. 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

  11. Amyloiddeposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression

    Science.gov (United States)

    Mormino, Elizabeth C.; Schultz, Aaron P.; Wigman, Sarah; Ward, Andrew M.; Larvie, Mykol; Amariglio, Rebecca E.; Marshall, Gad A.; Rentz, Dorene M.; Johnson, Keith A.; Sperling, Reisa A.

    2015-01-01

    Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity—consistent with findings in genetic at-risk populations—and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimer’s disease continuum. Here, we examine the contribution of amyloiddeposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model

  12. Amyloiddeposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression.

    Science.gov (United States)

    Huijbers, Willem; Mormino, Elizabeth C; Schultz, Aaron P; Wigman, Sarah; Ward, Andrew M; Larvie, Mykol; Amariglio, Rebecca E; Marshall, Gad A; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A

    2015-04-01

    Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity--consistent with findings in genetic at-risk populations--and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-β, which may be particularly important in prediction of progression along the Alzheimer's disease continuum. Here, we examine the contribution of amyloiddeposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-β status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-β positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-β negative patients with mild cognitive impairment. Longitudinally, amyloid-β positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model

  13. Modeling of age-dependent amyloid accumulation and γ-secretase inhibition of soluble and insoluble Aβ in a transgenic mouse model of amyloid deposition.

    Science.gov (United States)

    Parkinson, Joanna; Ploeger, Bart; Appelkvist, Paulina; Bogstedt, Anna; Dillner Bergstedt, Karin; Eketjäll, Susanna; Visser, Sandra A G

    2013-12-01

    According to the "amyloid hypothesis," accumulation of amyloid beta (Aβ) peptides in the brain is linked to the development of Alzheimer's disease. The aims of this investigation were to develop a model for the age-dependent amyloid accumulation and to quantify the age- and treatment-duration-dependent efficacy of the γ-secretase inhibitor MRK-560 in the Tg2576 transgenic mouse model of amyloid deposition. Soluble and insoluble Aβ40 and Aβ42 brain concentrations were compiled from multiple naïve, vehicle, and MRK-560-treated animals. The age of Tg2576 mice in the studies ranged between 3.5 and 26 months. Single doses of MRK-560 inhibited soluble Aβ40 levels in animals up to 9 months old. In contrast, MRK-560 did not cause significant acute effects on soluble Aβ40 levels in animals older than 13 months. Absolute levels of Aβ variants increased exponentially over age and reached a plateau at ∼20 months. In the final model, it was assumed that MRK-560 inhibited the Aβ production rate with an Aβ level-dependent IC50.The age-dependent increase in Aβ levels was best described by a logistic model that stimulated the production rate of soluble Aβ. The increase in insoluble Aβ was defined as a function of soluble Aβ by using a scaling factor and a different turnover rate. The turnover half-life for insoluble Aβ was estimated at 30 days, explaining that at least a 4-week treatment in young animals was required to demonstrate a reduction in insoluble Aβ. Taken together, the derived knowledge could be exploited for an improved design of new experiments in Tg2576 mice. PMID:25505567

  14. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy.

    Science.gov (United States)

    Keable, Abby; Fenna, Kate; Yuen, Ho Ming; Johnston, David A; Smyth, Neil R; Smith, Colin; Al-Shahi Salman, Rustam; Samarasekera, Neshika; Nicoll, James A R; Attems, Johannes; Kalaria, Rajesh N; Weller, Roy O; Carare, Roxana O

    2016-05-01

    Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. 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:26327684

  15. 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

    event in AD (Alzheimer's disease) synaptic dysfunctions. Structural alterations introduced by site-specific modifications linked to protein aging may affect Abeta production, polymerization and clearance, and therefore play a pivotal role in the pathogenesis of sporadic and genetic forms of AD. Early......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....... Since these modifications may affect folding and turnover, they reduce protein functionality over time and may be linked to pathological conditions. The present mini-review describes evidence of AAR and AAI involvement in the misfolding and brain accumulation of Abeta (amyloid beta-peptide), a central...

  16. Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech

    Directory of Open Access Journals (Sweden)

    Jennifer L. Whitwell

    2016-01-01

    Full Text Available Beta-amyloid (Aβ deposition can be observed in primary progressive aphasia (PPA and progressive apraxia of speech (PAOS. While it is typically associated with logopenic PPA, there are exceptions that make predicting Aβ status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Aβ deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified and PAOS (n = 42 subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Aβ was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Aβ (+ status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Aβ status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Aβ (+ status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Aβ (+ status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Aβ deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Aβ status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Aβ status in unclassified

  17. Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech.

    Science.gov (United States)

    Whitwell, Jennifer L; Weigand, Stephen D; Duffy, Joseph R; Strand, Edythe A; Machulda, Mary M; Senjem, Matthew L; Gunter, Jeffrey L; Lowe, Val J; Jack, Clifford R; Josephs, Keith A

    2016-01-01

    Beta-amyloid (Aβ) deposition can be observed in primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS). While it is typically associated with logopenic PPA, there are exceptions that make predicting Aβ status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Aβ deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified) and PAOS (n = 42) subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Aβ was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Aβ (+) status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Aβ status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Aβ (+) status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Aβ (+) status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Aβ deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Aβ status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Aβ status in unclassified PPA subjects

  18. Characteristics of glucose metabolism and amyloid deposition by positron emission tomography images in Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    纪勇

    2013-01-01

    Objective To investigate positron emission tomography (PET) image characteristics of glucose metabolism and amyloid deposition as demonstrated by fluorodeoxyglucose (18F-FDG) and Pittsburgh Compound B (PiB) in Alzheimer’s disease (AD) .Methods Patients with mild AD and moderate AD (n=6,each) were included in this study.6 healthy subjects were selected as normal controls.Cognitive function was assessed by the minimental state examination,Montreal Cognitive Assessment and Clinical Dementia Rating.Ventricular dilation,cor-

  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. Viscoelastic response of neural cells governed by the deposition of amyloid-β peptides (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 amyloid-β peptide (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.

  1. CCR5 deficiency accelerates lipopolysaccharide-induced astrogliosis, amyloid-beta deposit and impaired memory function.

    Science.gov (United States)

    Hwang, Chul Ju; Park, Mi Hee; Hwang, Jae Yeon; Kim, Ju Hwan; Yun, Na Young; Oh, Sang Yeon; Song, Ju Kyung; Seo, Hyun Ok; Kim, Yun-Bae; Hwang, Dae Yeon; Oh, Ki-Wan; Han, Sang-Bae; Hong, Jin Tae

    2016-03-15

    Chemokine receptors are implicated in inflammation and immune responses. Neuro-inflammation is associated with activation of astrocyte and amyloid-beta (Aβ) generations that lead to pathogenesis of Alzheimer disease (AD). Previous our study showed that deficiency of CC chemokine receptor 5 (CCR5) results in activation of astrocytes and Aβ deposit, and thus memory dysfunction through increase of CC chemokine receptor 2 (CCR2) expression. CCR5 knockout mice were used as an animal model with memory dysfunction. For the purpose LPS was injected i.p. daily (0.25 mg/kg/day). The memory dysfunctions were much higher in LPS-injected CCR5 knockout mice compared to CCR5 wild type mice as well as non-injected CCR5 knockout mice. Associated with severe memory dysfuction in LPS injected CCR5 knockout mice, LPS injection significant increase expression of inflammatory proteins, astrocyte activation, expressions of β-secretase as well as Aβ deposition in the brain of CCR5 knockout mice as compared with that of CCR5 wild type mice. In CCR5 knockout mice, CCR2 expressions were high and co-localized with GFAP which was significantly elevated by LPS. Expression of monocyte chemoattractant protein-1 (MCP-1) which ligands of CCR2 also increased by LPS injection, and increment of MCP-1 expression is much higher in CCR5 knockout mice. BV-2 cells treated with CCR5 antagonist, D-ala-peptide T-amide (DAPTA) and cultured astrocytes isolated from CCR5 knockout mice treated with LPS (1 μg/ml) and CCR2 antagonist, decreased the NF-ĸB activation and Aβ level. These findings suggest that the deficiency of CCR5 enhances response of LPS, which accelerates to neuro-inflammation and memory impairment.

  2. Cerebrolysin reduces amyloiddeposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction.

    Science.gov (United States)

    Xing, Shihui; Zhang, Jian; Dang, Chao; Liu, Gang; Zhang, Yusheng; Li, Jingjing; Fan, Yuhua; Pei, Zhong; Zeng, Jinsheng

    2014-02-15

    Focal cerebral infarction causes amyloid-β (Aβ) deposits and secondary thalamic neuronal degeneration. The present study aimed to determine the protective effects of Cerebrolysin on Aβ deposits and secondary neuronal damage in thalamus after cerebral infarction. At 24h after distal middle cerebral artery occlusion (MCAO), Cerebrolysin (5 ml/kg) or saline as control was once daily administered for consecutive 13 days by intraperitoneal injection. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunofluorescence at 14 days after MCAO. Aβ deposits, activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), apoptosis and autophagy were determined by TUNEL staining, immunofluorescence and immunoblot. The results showed that Cerebrolysin significantly improved sensory deficit compared to controls (pCerebrolysin, which was accompanied by decreases in neuronal loss and astroglial activation compared to controls (all p Cerebrolysin markedly inhibited cleaved caspase-3, conversion of LC3-II, downregulation of Bcl-2 and upregulation of Bax in the ipsilateral thalamus compared to controls (all pCerebrolysin reduces Aβ deposits, apoptosis and autophagy in the ipsilateral thalamus, which may be associated with amelioration of secondary thalamic damage and functional recovery after cerebral infarction. PMID:24315581

  3. Cerebrolysin reduces amyloiddeposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction.

    Science.gov (United States)

    Xing, Shihui; Zhang, Jian; Dang, Chao; Liu, Gang; Zhang, Yusheng; Li, Jingjing; Fan, Yuhua; Pei, Zhong; Zeng, Jinsheng

    2014-02-15

    Focal cerebral infarction causes amyloid-β (Aβ) deposits and secondary thalamic neuronal degeneration. The present study aimed to determine the protective effects of Cerebrolysin on Aβ deposits and secondary neuronal damage in thalamus after cerebral infarction. At 24h after distal middle cerebral artery occlusion (MCAO), Cerebrolysin (5 ml/kg) or saline as control was once daily administered for consecutive 13 days by intraperitoneal injection. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunofluorescence at 14 days after MCAO. Aβ deposits, activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), apoptosis and autophagy were determined by TUNEL staining, immunofluorescence and immunoblot. The results showed that Cerebrolysin significantly improved sensory deficit compared to controls (pCerebrolysin, which was accompanied by decreases in neuronal loss and astroglial activation compared to controls (all p Cerebrolysin markedly inhibited cleaved caspase-3, conversion of LC3-II, downregulation of Bcl-2 and upregulation of Bax in the ipsilateral thalamus compared to controls (all pCerebrolysin reduces Aβ deposits, apoptosis and autophagy in the ipsilateral thalamus, which may be associated with amelioration of secondary thalamic damage and functional recovery after cerebral infarction.

  4. Differences in functional brain connectivity alterations associated with cerebral amyloid deposition in amnestic mild cognitive impairment

    Directory of Open Access Journals (Sweden)

    Dahyun eYi

    2015-02-01

    Full Text Available Despite potential implications for the early detection of impending AD, very little is known about the differences of large scale brain networks between amnestic MCI (aMCI with high cerebral amyloid beta protein (Aβ deposition (i.e., aMCI+ and aMCI with no or very little Aβ deposition (i.e., aMCI-. We first aimed to extend the current literature on altering intrinsic functional connectivity (FC of the default mode network (DMN and salience network (SN from CN to AD dementia. Second, we further examined the differences of the DMN and the SN between aMCI-, aMCI+, and CN. Forty-three older adult (12 CN, 10 aMCI+, 10 aMCI-, and 11 AD dementia subjects were included. All participants received clinical and neuropsychological assessment, resting state functional MRI, structural MRI, and Pittsburgh compound-B-PET scans. FC data were preprocessed using Multivariate Exploratory Linear Optimized Decomposition into Independent Components of FSL. Group comparisons were carried out using the dual-regression approach. In addition, to verify presence of grey matter (GM volume changes with intrinsic functional network alterations, Voxel Based Morphometry was performed on the acquired T1-weighted data. As expected, AD dementia participants exhibited decreased FC in the DMN compared to CN (in precuneus and cingulate gyrus. The degree of alteration in the DMN in aMCI+ compared to CN was intermediate to that of AD. In contrast, aMCI- exhibited increased FC in the DMN compared to CN (in precuneus as well as aMCI+. In terms of the SN, aMCI- exhibited decreased FC compared to both CN and aMCI+ particularly in the inferior frontal gyrus. FC within the SN in aMCI+ and AD did not differ from CN. Compared to CN, aMCI- showed atrophy in bilateral superior temporal gyri whereas aMCI+ showed atrophy in right precuneus. The results indicate that despite of the similarity in cross-sectional cognitive features aMCI- has quite different functional brain connectivity compared to

  5. P-glycoprotein efflux and other factors limit brain amyloid beta reduction by beta-site amyloid precursor protein-cleaving enzyme 1 inhibitors in mice.

    Science.gov (United States)

    Meredith, Jere E; Thompson, Lorin A; Toyn, Jeremy H; Marcin, Lawrence; Barten, Donna M; Marcinkeviciene, Jovita; Kopcho, Lisa; Kim, Young; Lin, Alan; Guss, Valerie; Burton, Catherine; Iben, Lawrence; Polson, Craig; Cantone, Joe; Ford, Michael; Drexler, Dieter; Fiedler, Tracey; Lentz, Kimberley A; Grace, James E; Kolb, Janet; Corsa, Jason; Pierdomenico, Maria; Jones, Kelli; Olson, Richard E; Macor, John E; Albright, Charles F

    2008-08-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid beta (Abeta) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from AD patients, genetic analysis of mutations that cause early onset forms of AD, and preclinical studies. Based on this hypothesis, beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors are an attractive therapeutic approach for AD because cleavage of the APP by BACE1 is required to form Abeta. In this study, three potent BACE1 inhibitors are characterized. All three inhibitors decrease Abeta formation in cultured cells with IC(50) values less than 10 nM. Analysis of APP C-terminal fragments by immunoblotting and Abeta peptides by mass spectrometry showed that these inhibitors decreased Abeta by inhibiting BACE1. An assay for Abeta1-40 in mice was developed and used to show that these BACE1 inhibitors decreased plasma Abeta1-40, but not brain Abeta1-40, in wild-type mice. Because these BACE1 inhibitors were substrates for P-glycoprotein (P-gp), a member of the ATP-binding cassette superfamily of efflux transporters, these inhibitors were administered to P-gp knockout (KO) mice. These studies showed that all three BACE1 inhibitors decreased brain Abeta1-40 in P-gp KO mice, demonstrating that P-gp is a major limitation for development of BACE1 inhibitors to test the amyloid hypothesis. A comparison of plasma Abeta1-40 and brain Abeta1-40 dose responses for these three compounds revealed differences in relative ED(50) values, indicating that factors other than P-gp can also contribute to poor brain activity by BACE1 inhibitors.

  6. 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.

  7. Amyloid Deposits in the Bone Marrow of Patients with AL Amyloidosis Do Not Impact Stem Cell Mobilization or Engraftment

    OpenAIRE

    Cowan, Andrew J.; Seldin, David C.; Skinner, Martha; Quillen, Karen; Doros, Gheorghe; Tan, Josenia; O'Hara, Carl; Finn, Kathleen T.; Sanchorawala, Vaishali

    2012-01-01

    Amyloid deposits are often found in the bone marrow in patients with AL amyloidosis; we sought to determine whether this affects stem cell collection or engraftment following high dose melphalan and autologous stem cell transplantation (HDM/SCT). Data on 361 patients with AL amyloidosis who had Congo red staining of the pre-treatment bone marrow biopsy and underwent HDM/SCT from July 1994 to December 2011 were reviewed. Data were analyzed for stem cell yield, number of days of stem cell colle...

  8. Long-Term Interrelationship between Brain Metabolism and Amyloid Deposition in Mild Cognitive Impairment

    DEFF Research Database (Denmark)

    Kemppainen, Nina; Joutsa, Juho; Johansson, Jarkko;

    2015-01-01

    The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Nine MCI patients, who converted to AD between...

  9. Cutaneous lymphatic amyloid deposits in 'Hungarian-type' familial transthyretin amyloidosis : a case report

    NARCIS (Netherlands)

    Harkany, T.; Garzuly, F.; Csanaky, G.; Luiten, P.G.M.; Nyakas, C.; Linke, R.P.; Virágh, S.

    2002-01-01

    Multiple transthyretin (TTR) mutations have recently been identified and implicated in the development of familial systemic amyloidoses, but early diagnosis of these disorders is still largely unresolved. We investigated the presence and tissue distribution of TTR-derived amyloid in skin biopsies of

  10. IMPY, a potential β-amyloid imaging probe for detection of prion deposits in scrapie-infected mice

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2008-02-15

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

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

    OpenAIRE

    Ossenkoppele, Rik; Madison, Cindee,; Oh, Hwamee; Wirth, Miranka; van Berckel, Bart N. M.; Jagust, William J.

    2013-01-01

    A potential mechanism that enables intellectual preservation in cognitively normal elderly that harbor beta-amyloid (Aβ) pathology is heightened cerebral glucose metabolism. To investigate cross-sectional inter-relationships between Aβ, glucose metabolism, and cognition, 81 subjects (mean age: 75 ± 7 years) underwent [11C]Pittsburgh Compound-B and [18F]fluorodeoxyglucose positron emission tomography scans and neuropsychological testing. They were divided into low-Aβ (n = 53), intermediate-Aβ ...

  13. Rimmed vacuoles with beta-amyloid and ubiquitinated filamentous deposits in the muscles of patients with long-standing denervation (postpoliomyelitis muscular atrophy): similarities with inclusion body myositis.

    Science.gov (United States)

    Semino-Mora, C; Dalakas, M C

    1998-10-01

    In the chronically denervated muscles of patients with prior paralytic poliomyelitis, there are secondary myopathic features, including endomysial inflammation and rare vacuolated fibers. To assess the frequency and characteristics of the vacuoles and their similarities with those seen in inclusion body myositis (IBM), we examined 58 muscle biopsy specimens from patients with prior paralytic poliomyelitis for (1) the presence of rimmed vacuoles; (2) acid-phosphatase reactivity; (3) Congo-red-positive amyloid deposits; (4) electron microscopy, searching for tubulofilaments; and (5) immunoelectron microscopy, using antibodies against beta-amyloid and ubiquitin. We found vacuolated muscle fibers in 18 of 58 (31%) biopsies, with a mean frequency of 2.06 +/- 0.42 fibers per specimen. The vacuoles contained acid phosphatase-positive material in 6 of the 18 (33.30%) specimens and stained positive for Congo red in five (27.80%). By immunoelectron microscopy, the vacuoles contained 5.17 +/- 0.13 nm fibrils and 14.9 +/- 0.31 nm filaments that immunoreacted with antibodies to beta-amyloid and ubiquitin in a pattern identical to the one seen in IBM. We conclude that vacuolated muscle fibers containing filamentous inclusions positive for amyloid and ubiquitin are not unique to IBM and the other vacuolar myopathies but can also occur in a chronic neurogenic condition, such as postpoliomyelitis. The chronicity of the underlying disease, rather than the cause, may lead to vacuolar formation, amyloid deposition, and accumulation of ubiquitinated filaments.

  14. Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta

    DEFF Research Database (Denmark)

    Holton, J.L; Lashley, T.; Ghiso, J.;

    2002-01-01

    response using conventional techniques, immunohistochemistry, confocal microscopy, and immunoelectron microscopy. We showed that ADan is widely distributed in the central nervous system (CNS) in the leptomeninges, blood vessels, and parenchyma. A predominance of parenchymal pre-amyloid (non...

  15. Regional dynamics of amyloiddeposition in healthy elderly, mild cognitive impairment and Alzheimer's disease: a voxelwise PiB-PET longitudinal study.

    Science.gov (United States)

    Villain, Nicolas; Chételat, Gaël; Grassiot, Blandine; Bourgeat, Pierrick; Jones, Gareth; Ellis, Kathryn A; Ames, David; Martins, Ralph N; Eustache, Francis; Salvado, Olivier; Masters, Colin L; Rowe, Christopher C; Villemagne, Victor L

    2012-07-01

    Amyloiddeposition in Alzheimer's disease is thought to start while individuals are still cognitively unimpaired and it is hypothesized that after an early phase of fast accumulation, a plateau is reached by the time of cognitive decline. However, few longitudinal Pittsburgh compound B-positron emission tomography studies have tested this hypothesis, and with conflicting results. The purpose of this work is to further our understanding of the dynamics of amyloiddeposition in a large longitudinal cohort. A total of 32 patients with Alzheimer's disease, 49 subjects with mild cognitive impairment and 103 healthy controls underwent two Pittsburgh compound B-positron emission tomography scans 18 months apart. For each participant, a parametric map of Pittsburgh compound B-positron emission tomography rate of change was created [(follow-up scan - baseline scan)/follow-up duration] and entered in a voxelwise three-way analysis of covariance, with clinical status (healthy controls, mild cognitive impairment or Alzheimer's disease), disease progression (clinical conversion from healthy controls to mild cognitive impairment or Alzheimer's disease, or from mild cognitive impairment to Alzheimer's disease) and Pittsburgh compound B status (positive versus negative) as independent factors. Only a significant effect of the Pittsburgh compound B status was found: both Pittsburgh compound B-positive and -negative subjects showed a significant increase in amyloiddeposition, with this increase being significantly higher in Pittsburgh compound B-positive individuals. This finding suggests either that Pittsburgh compound B-negative individuals have slower rates of amyloid-β accumulation than positive, or that the proportion of individuals showing significant increase in amyloiddeposition, termed 'Pittsburgh compound B accumulators', is higher within the Pittsburgh compound B-positive group than within the Pittsburgh compound B-negative group. The bimodal

  16. Automated PET-only quantification of amyloid deposition with adaptive template and empirically pre-defined ROI

    Science.gov (United States)

    Akamatsu, G.; Ikari, Y.; Ohnishi, A.; Nishida, H.; Aita, K.; Sasaki, M.; Yamamoto, Y.; Sasaki, M.; Senda, M.

    2016-08-01

    Amyloid PET is useful for early and/or differential diagnosis of Alzheimer’s disease (AD). Quantification of amyloid deposition using PET has been employed to improve diagnosis and to monitor AD therapy, particularly in research. Although MRI is often used for segmentation of gray matter and for spatial normalization into standard Montreal Neurological Institute (MNI) space where region-of-interest (ROI) template is defined, 3D MRI is not always available in clinical practice. The purpose of this study was to examine the feasibility of PET-only amyloid quantification with an adaptive template and a pre-defined standard ROI template that has been empirically generated from typical cases. A total of 68 subjects who underwent brain 11C-PiB PET were examined. The 11C-PiB images were non-linearly spatially normalized to the standard MNI T1 atlas using the same transformation parameters of MRI-based normalization. The automatic-anatomical-labeling-ROI (AAL-ROI) template was applied to the PET images. All voxel values were normalized by the mean value of cerebellar cortex to generate the SUVR-scaled images. Eleven typical positive images and eight typical negative images were normalized and averaged, respectively, and were used as the positive and negative template. Positive and negative masks which consist of voxels with SUVR  ⩾1.7 were extracted from both templates. Empirical PiB-prone ROI (EPP-ROI) was generated by subtracting the negative mask from the positive mask. The 11C-PiB image of each subject was non-rigidly normalized to the positive and negative template, respectively, and the one with higher cross-correlation was adopted. The EPP-ROI was then inversely transformed to individual PET images. We evaluated differences of SUVR between standard MRI-based method and PET-only method. We additionally evaluated whether the PET-only method would correctly categorize 11C-PiB scans as positive or negative. Significant correlation was observed between the SUVRs

  17. Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice

    Directory of Open Access Journals (Sweden)

    Rogers Kathryn

    2012-12-01

    Full Text Available Abstract Background A hallmark of Alzheimer’s disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Aβ42 and Aβ40. Many drug discovery efforts have focused on decreasing the production of Aβ42 through γ-secretase inhibition. However, identification of γ-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of γ-secretase to shift Aβ production to favor shorter, less amyloidogenic peptides than Aβ42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called γ-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer’s disease. Results Here we describe EVP-0015962, a novel small molecule γ-secretase modulator. EVP-0015962 decreased Aβ42 in H4 cells (IC50 = 67 nM and increased the shorter Aβ38 by 1.7 fold at the IC50 for lowering of Aβ42. AβTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other γ-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a γ-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg decreased Aβ42 and did not alter AβTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Aβ deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation reduced Aβ aggregates, amyloid plaques, inflammatory markers, and cognitive deficits. Conclusions EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective γ-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Aβ42, attenuated memory deficits, and reduced Aβ plaque

  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. Comparing brain amyloid deposition, glucose metabolism, and atrophy in mild cognitive impairment with and without a family history of dementia.

    Science.gov (United States)

    Mosconi, Lisa; Andrews, Randolph D; Matthews, Dawn C

    2013-01-01

    This study compares the degree of brain amyloid-β (Aβ) deposition, glucose metabolism, and grey matter volume (GMV) reductions in mild cognitive impairment (MCI) patients overall and as a function of their parental history of dementia. Ten MCI with maternal history (MH), 8 with paternal history (PH), and 24 with negative family history (NH) received 11C-PiB and 18F-FDG PET and T1-MRI as part of the Alzheimer's Disease Neuroimaging Initiative. Statistical parametric mapping, voxel based morphometry, and Z-score mapping were used to compare biomarkers across MCI groups, and relative to 12 normal controls. MCI had higher PiB retention, hypometabolism, and GMV reductions in Alzheimer-vulnerable regions compared to controls. Biomarker abnormalities were more pronounced in MCI with MH than those with PH and NH. After partial volume correction of PET, Aβ load exceeded hypometabolism and atrophy with regard to the number of regions affected and magnitude of impairment in those regions. Hypometabolism exceeded atrophy in all MCI groups and exceeded Aβ load in medial temporal and posterior cingulate regions of MCI MH. While all three biomarkers were abnormal in MCI compared to controls, Aβ deposition was the most prominent abnormality, with MCI MH having the greatest degree of co-occurring hypometabolism.

  20. 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

  1. 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

  2. Limited Proteolysis Reveals That Amyloids from the 3D Domain-Swapping Cystatin B Have a Non-Native β-Sheet Topology.

    Science.gov (United States)

    Davis, Peter J; Holmes, David; Waltho, Jonathan P; Staniforth, Rosemary A

    2015-07-31

    3D domain-swapping proteins form multimers by unfolding and then sharing of secondary structure elements, often with native-like interactions. Runaway domain swapping is proposed as a mechanism for folded proteins to form amyloid fibres, with examples including serpins and cystatins. Cystatin C amyloids cause a hereditary form of cerebral amyloid angiopathy whilst cystatin B aggregates are found in cases of Unverricht-Lundborg Syndrome, a progressive form of myoclonic epilepsy. Under conditions that favour fibrillisation, cystatins populate stable 3D domain-swapped dimers both in vitro and in vivo that represent intermediates on route to the formation of fibrils. Previous work on cystatin B amyloid fibrils revealed that the α-helical region of the protein becomes disordered and identified the conservation of a continuous 20-residue elongated β-strand (residues 39-58), the latter being a salient feature of the dimeric 3D domain-swapped structure. Here we apply limited proteolysis to cystatin B amyloid fibrils and show that not only the α-helical N-terminal of the protein (residues 1-35) but also the C-terminal of the protein (residues 80-98) can be removed without disturbing the underlying fibril structure. This observation is incompatible with previous models of cystatin amyloid fibrils where the β-sheet is assumed to retain its native antiparallel arrangement. We conclude that our data favour a more generic, at least partially parallel, arrangement for cystatin β-sheet structure in mature amyloids and propose a model that remains consistent with available data for amyloids from either cystatin B or cystatin C.

  3. Self-assembling and self-limiting monolayer deposition

    Science.gov (United States)

    Foest, Rüdiger; Schmidt, Martin; Gargouri, Hassan

    2014-02-01

    Effects of spatial ordering of molecules on surfaces are commonly utilized to deposit ultra-thin films with a thickness of a few nm. In this review paper, several methods are discussed, that are distinguished from other thin film deposition processes by exactly these effects that lead to self-assembling and self-limiting layer growth and eventually to coatings with unique and fascinating properties and applications in micro-electronics, optics, chemistry, or biology. Traditional methods for the formation of self-assembled films of ordered organic molecules, such as the Langmuir-Blodgett technique along with thermal atomic layer deposition (ALD) of inorganic molecules are evaluated. The overview is complemented by more recent developments for the deposition of organic or hybrid films by molecular layer deposition. Particular attention is given to plasma assisted techniques, either as a preparative, supplementary step or as inherent part of the deposition as in plasma enhanced ALD or plasma assisted, repeated grafting deposition. The different methods are compared and their film formation mechanisms along with their advantages are presented from the perspective of a plasma scientist. The paper contains lists of established film compounds and a collection of the relevant literature is provided for further reading.

  4. Relationships between sleep quality and brain volume, metabolism, and amyloid deposition in late adulthood.

    Science.gov (United States)

    Branger, Pierre; Arenaza-Urquijo, Eider M; Tomadesso, Clémence; Mézenge, Florence; André, Claire; de Flores, Robin; Mutlu, Justine; de La Sayette, Vincent; Eustache, Francis; Chételat, Gaël; Rauchs, Géraldine

    2016-05-01

    Recent studies in mouse models of Alzheimer's disease (AD) and in humans suggest that sleep disruption and amyloid-beta (Aβ) accumulation are interrelated, and may, thus, exacerbate each other. We investigated the association between self-reported sleep variables and neuroimaging data in 51 healthy older adults. Participants completed a questionnaire assessing sleep quality and quantity and underwent positron emission tomography scans using [18F]florbetapir and [18F]fluorodeoxyglucose and an magnetic resonance imaging scan to measure Aβ burden, hypometabolism, and atrophy, respectively. Longer sleep latency was associated with greater Aβ burden in prefrontal areas. Moreover, the number of nocturnal awakenings was negatively correlated with gray matter volume in the insular region. In asymptomatic middle-aged and older adults, lower self-reported sleep quality was associated with greater Aβ burden and lower volume in brain areas relevant in aging and AD, but not with glucose metabolism. These results highlight the potential relevance of preserving sleep quality in older adults and suggest that sleep may be a factor to screen for in individuals at risk for AD.

  5. Scaling behavior of deposition models with limited downward mobility

    International Nuclear Information System (INIS)

    We have studied the interface-width scaling behavior of deposition models in which limited downward mobility is introduced. In all the models studied here, there is a maximum allowed slope for the interface at which the growth velocity is zero. The Kardar-Parisi-Zhang equation is resummed in order to show explicitly this slope constraint, but still incorporates parameters λ measuring the slope dependence of the growth velocity, ν measuring the surface tension, and D measuring the noise amplitude. Increasing mobility naturally smooths the interface, and is associated with a decrease in the magnitude of λeff=λD1/2/ν3/2. A detailed study of a bridge-site deposition model, with one hop of probability p, shows that |λ| increases with p. From an independent assessment of noise-amplitude behavior, we can conclude that ν must also increase with p to ensure the required λeff behavior. Direct determination of ν via the Wolf-Tang procedure of imposing inhomogeneity on some length scale L supports this conclusion. (However ν depends on the inhomogeneity strength, which should be chosen small, and on L.) We comment on anticipated behavior of similar limited-mobility models in d≥2 dimensions, and compare with behavior of limited-mobility ballistic deposition and noise-reduced deposition models

  6. Lithium treatment of APPSwDI/NOS2-/- mice leads to reduced hyperphosphorylated tau, increased amyloid deposition and altered inflammatory phenotype.

    Directory of Open Access Journals (Sweden)

    Tiffany L Sudduth

    Full Text Available Lithium is an anti-psychotic that has been shown to prevent the hyperphosphorylation of tau protein through the inhibition of glycogen-synthase kinase 3-beta (GSK3β. We recently developed a mouse model that progresses from amyloid pathology to tau pathology and neurodegeneration due to the genetic deletion of NOS2 in an APP transgenic mouse; the APPSwDI/NOS2-/- mouse. Because this mouse develops tau pathology, amyloid pathology and neuronal loss we were interested in the effect anti-tau therapy would have on amyloid pathology, learning and memory. We administered lithium in the diets of APPSwDI/NOS2-/- mice for a period of eight months, followed by water maze testing at 12 months of age, immediately prior to sacrifice. We found that lithium significantly lowered hyperphosphorylated tau levels as measured by Western blot and immunocytochemistry. However, we found no apparent neuroprotection, no effect on spatial memory deficits and an increase in histological amyloid deposition. Aβ levels measured biochemically were unaltered. We also found that lithium significantly altered the neuroinflammatory phenotype of the brain, resulting in enhanced alternative inflammatory response while concurrently lowering the classical inflammatory response. Our data suggest that lithium may be beneficial for the treatment of tauopathies but may not be beneficial for the treatment of Alzheimer's disease.

  7. 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

  8. PiB fails to map amyloid deposits in cerebral cortex of aged dogs with canine cognitive dysfunction

    Directory of Open Access Journals (Sweden)

    Rikke eFast

    2013-12-01

    Full Text Available Dogs with Canine Cognitive Dysfunction (CCD accumulate amyloid beta (Aβ in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer’s disease (AD, the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest to the understanding of AD. However, the sensitivity of the biomarker Pittsburgh Compound B (PiB to the presence of Aβ in humans and in other mammalian species is in doubt. To test the sensitivity and assess the distribution of Aβ in dog brain, we mapped the brains of dogs with signs of CCD (n=16 and a control group (n=4 of healthy dogs with radioactively labeled PiB ([11C]PiB. Structural MRI brain scans were obtained from each dog. Tracer washout analysis yielded parametric maps of PIB retention in brain. In the CCD group, dogs had significant retention of [11C]PiB in the cerebellum, compared to the cerebral cortex. Retention in the cerebellum is at variance with evidence from brains of humans with AD. To confirm the lack of sensitivity, we stained two dog brains with the immunohistochemical marker 6E10, which is sensitive to the presence of both Aβ and Aβ precursor protein (AβPP. The 6E10 stain revealed intracellular material positive for Aβ or AβPP, or both, in Purkinje cells. The brains of the two groups of dogs did not have significantly different patterns of [11C]PiB binding, suggesting that the material detected with 6E10 is AβPP rather than Aβ. As the comparison with the histological images revealed no correlation between the [11C]PiB and Aβ and AβPP deposits in post-mortem brain, the marked intracellular staining implies intracellular involvement of amyloid processing in the dog brain. We conclude that PET maps of [11C]PiB retention in brain of dogs with CCD fundamentally differ from the images obtained in most humans with AD.

  9. Brain Amyloid Deposition and Longitudinal Cognitive Decline in Nondemented Older Subjects: Results from a Multi-Ethnic Population.

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    Yian Gu

    Full Text Available We aimed to whether the abnormally high amyloid-β (Aβ level in the brain among apparently healthy elders is related with subtle cognitive deficits and/or accelerated cognitive decline.A total of 116 dementia-free participants (mean age 84.5 years of the Washington Heights Inwood Columbia Aging Project completed 18F-Florbetaben PET imaging. Positive or negative cerebral Aβ deposition was assessed visually. Quantitative cerebral Aβ burden was calculated as the standardized uptake value ratio in pre-established regions of interest using cerebellar cortex as the reference region. Cognition was determined using a neuropsychological battery and selected tests scores were combined into four composite scores (memory, language, executive/speed, and visuospatial using exploratory factor analysis. We examined the relationship between cerebral Aβ level and longitudinal cognition change up to 20 years before the PET scan using latent growth curve models, controlling for age, education, ethnicity, and Apolipoprotein E (APOE genotype.Positive reading of Aβ was found in 41 of 116 (35% individuals. Cognitive scores at scan time was not related with Aβ. All cognitive scores declined over time. Aβ positive reading (B = -0.034, p = 0.02 and higher Aβ burden in temporal region (B = -0.080, p = 0.02 were associated with faster decline in executive/speed. Stratified analyses showed that higher Aβ deposition was associated with faster longitudinal declines in mean cognition, language, and executive/speed in African-Americans or in APOE ε4 carriers, and with faster memory decline in APOE ε4 carriers. The associations remained significant after excluding mild cognitive impairment participants.High Aβ deposition in healthy elders was associated with decline in executive/speed in the decade before neuroimaging, and the association was observed primarily in African-Americans and APOE ε4 carriers. Our results suggest that measuring cerebral Aβ may give us

  10. Imaging of amyloid deposition in human brain using positron emission tomography and [{sup 18}F]FACT: comparison with [{sup 11}C]PIB

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Hiroshi [National Institute of Radiological Sciences, Molecular Imaging Center, Chiba (Japan); National Institute of Radiological Sciences, Biophysics Program, Molecular Imaging Center, Chiba (Japan); Shinotoh, Hitoshi; Shimada, Hitoshi; Miyoshi, Michie; Takano, Harumasa; Takahashi, Hidehiko; Arakawa, Ryosuke; Kodaka, Fumitoshi; Ono, Maiko; Eguchi, Yoko; Higuchi, Makoto; Fukumura, Toshimitsu; Suhara, Tetsuya [National Institute of Radiological Sciences, Molecular Imaging Center, Chiba (Japan); Yanai, Kazuhiko; Okamura, Nobuyuki [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan)

    2014-04-15

    The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The {sup 18}F-labeled amyloid tracer, [{sup 18}F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1, 3-benzoxazol-6-yl)oxy ]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [ {sup 11}C ]Pittsburgh compound B (PIB) and [ {sup 18}F ]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared. Two PET scans, one of each with [ {sup 11}C ]PIB and [ {sup 18}F ]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation. No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [ {sup 18}F ]FACT studies without partial volume correction, while significant differences were observed in [ {sup 11}C ]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [ {sup 18}F ]FACT studies as well as [ {sup 11}C ]PIB. Relatively lower uptakes of [ {sup 11}C ]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [ {sup 18}F ]FACT. Relatively higher uptake of [ {sup 11}C ]PIB in distribution was observed in the frontal and parietal cortices. Since [ {sup 18}F ]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [ {sup 11}C ]PIB and [ {sup 18}F ]FACT might be due to differences

  11. 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.

  12. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation

    International Nuclear Information System (INIS)

    Familial amyloid polyneuropathy (FAP) associated with transthyretin (TTR) mutations is the commonest type of hereditary amyloidosis. Plasma TTR is produced almost exclusively in the liver and orthotopic liver transplantation is the only available treatment, although the clinical outcome varies. Serum amyloid P component (SAP) scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo, but it has not previously been used to study the outcome of visceral amyloid deposits in FAP following liver transplantation. Whole body scintigraphy following injection of iodine-123 labelled SAP was performed in 17 patients with FAP associated with TTR Met30 and in five asymptomatic gene carriers. Follow-up studies were performed in ten patients, eight of whom had undergone orthotopic liver transplantation 1-5 years beforehand. There was abnormal uptake of 123I-SAP in all FAP patients, including the kidneys in each case, the spleen in five cases and the adrenal glands in three cases. Renal amyloid deposits were also present in three of the asymptomatic carriers. Follow-up studies 1-5 years after liver transplantation showed that there had been substantial regression of the visceral amyloid deposits in two patients and modest improvement in three cases. The amyloid deposits were unchanged in two patients. In conclusion, 123I-SAP scintigraphy identified unsuspected visceral amyloid in each patient with FAP due to TTR Met30. The universal presence of renal amyloid probably underlies the high frequency of renal failure that occurs in FAP following liver transplantation. The variable capacity of patients to mobilise amyloid deposits following liver transplantation may contribute to their long-term clinical outcome. (orig.)

  13. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Rydh, A.; Hietala, S.O.; Aahlstroem, K.R. [Department of Diagnostic Radiology, University Hospital of Northern Sweden, Umeaa (Sweden); Suhr, O. [Department of Internal Medicine, University Hospital of Northern Sweden, Umeaa (Sweden); Pepys, M.B.; Hawkins, P.N. [Immunological Medicine Unit, Department of Medicine, Imperial College School of Medicine, London (United Kingdom)

    1998-07-01

    Familial amyloid polyneuropathy (FAP) associated with transthyretin (TTR) mutations is the commonest type of hereditary amyloidosis. Plasma TTR is produced almost exclusively in the liver and orthotopic liver transplantation is the only available treatment, although the clinical outcome varies. Serum amyloid P component (SAP) scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo, but it has not previously been used to study the outcome of visceral amyloid deposits in FAP following liver transplantation. Whole body scintigraphy following injection of iodine-123 labelled SAP was performed in 17 patients with FAP associated with TTR Met30 and in five asymptomatic gene carriers. Follow-up studies were performed in ten patients, eight of whom had undergone orthotopic liver transplantation 1-5 years beforehand. There was abnormal uptake of {sup 123}I-SAP in all FAP patients, including the kidneys in each case, the spleen in five cases and the adrenal glands in three cases. Renal amyloid deposits were also present in three of the asymptomatic carriers. Follow-up studies 1-5 years after liver transplantation showed that there had been substantial regression of the visceral amyloid deposits in two patients and modest improvement in three cases. The amyloid deposits were unchanged in two patients. In conclusion, {sup 123}I-SAP scintigraphy identified unsuspected visceral amyloid in each patient with FAP due to TTR Met30. The universal presence of renal amyloid probably underlies the high frequency of renal failure that occurs in FAP following liver transplantation. The variable capacity of patients to mobilise amyloid deposits following liver transplantation may contribute to their long-term clinical outcome. (orig.) With 2 figs., 2 tabs., 22 refs.

  14. Is the wash-off process of road-deposited sediment source limited or transport limited?

    Science.gov (United States)

    Zhao, Hongtao; Chen, Xuefei; Hao, Shaonan; Jiang, Yan; Zhao, Jiang; Zou, Changliang; Xie, Wenxia

    2016-09-01

    An in-depth understanding of the road-deposited sediments (RDS) wash-off process is essential to estimation of urban surface runoff pollution load and to designing methods to minimize the adverse impacts on the receiving waters. There are two debatable RDS wash-off views: source limited and transport limited. The RDS build-up and wash-off process was characterized to explore what determines the wash-off process to be source limited or transport limited based on twelve RDS sampling activities on an urban road in Beijing. The results showed that two natural rain events (2.0mm and 23.2mm) reduced the total RDS mass by 30%-40%, and that finer particles (wash-off load. Both single- and multi-rain events caused the RDS particle grain size to become coarser, while dry days made the RDS particle grain size finer. These findings indicated that the bulk RDS particles wash-off tends to be transport limited, but that finer particles tend to be source limited. To further explore and confirm the results of the field experiment, a total of 40 simulated rain events were designed to observe the RDS wash-off with different particle size fractions. The finer particles have a higher wash-off percentage (Fw) than the coarser particles, and the Fw values provide a good view to characterize the wash-off process. The key conclusions drawn from the combined field and simulated experiments data are: (i) Finer and coarser particle wash-off processes tend to be source limited and transport limited, respectively. (ii) The source and transport limited processes occur during the initial period (the first flush) and later periods, respectively. (iii) The smaller and larger rain events tend to be transport limited and source limited, respectively. Overall, the wash-off process is generally a combination of source and transport limited processes. PMID:27135567

  15. In vivo detection of amyloiddeposits 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 amyloiddeposits 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.

  16. In vivo detection of amyloiddeposits 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 amyloiddeposits 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

  17. 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

  18. Diagnostic utility and limitations of glutamine synthetase and serum amyloid-associated protein immunohistochemistry in the distinction of focal nodular hyperplasia and inflammatory hepatocellular adenoma.

    Science.gov (United States)

    Joseph, Nancy M; Ferrell, Linda D; Jain, Dhanpat; Torbenson, Michael S; Wu, Tsung-Teh; Yeh, Matthew M; Kakar, Sanjay

    2014-01-01

    Inflammatory hepatocellular adenoma can show overlapping histological features with focal nodular hyperplasia, including inflammation, fibrous stroma, and ductular reaction. Expression of serum amyloid-associated protein in inflammatory hepatocellular adenoma and map-like pattern of glutamine synthetase in focal nodular hyperplasia can be helpful in this distinction, but the pitfalls and limitations of these markers have not been established. Morphology and immunohistochemistry were analyzed in 54 inflammatory hepatocellular adenomas, 40 focal nodular hyperplasia, and 3 indeterminate lesions. Morphological analysis demonstrated that nodularity, fibrous stroma, dystrophic blood vessels, and ductular reaction were more common in focal nodular hyperplasia, while telangiectasia, hemorrhage, and steatosis were more common in inflammatory hepatocellular adenoma, but there was frequent overlap of morphological features. The majority of inflammatory hepatocellular adenomas demonstrated perivascular and/or patchy glutamine synthetase staining (73.6%), while the remaining cases had diffuse (7.5%), negative (3.8%), or patchy pattern of staining (15%) that showed subtle differences from the classic map-like staining pattern and was designated as pseudo map-like staining. Positive staining for serum amyloid-associated protein was seen in the majority of inflammatory hepatocellular adenomas (92.6%) and in the minority of focal nodular hyperplasia (17.5%). The glutamine synthetase staining pattern was map-like in 90% of focal nodular hyperplasia cases, with the remaining 10% of cases showing pseudo map-like staining. Three cases were labeled as indeterminate and showed focal nodular hyperplasia-like morphology but lacked map-like glutamine synthetase staining pattern; these cases demonstrated a patchy pseudo map-like glutamine synthetase pattern along with the expression of serum amyloid-associated protein. Our results highlight the diagnostic errors that can be caused by variant

  19. {beta} - amyloid imaging probes

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Jae Min [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    Imaging distribution of {beta} - amyloid plaques in Alzheimer's disease is very important for early and accurate diagnosis. Early trial of the {beta} -amyloid plaques includes using radiolabeled peptides which can be only applied for peripheral {beta} - amyloid plaques due to limited penetration through the blood brain barrier (BBB). Congo red or Chrysamine G derivatives were labeled with Tc-99m for imaging {beta} - amyloid plaques of Alzheimer patient's brain without success due to problem with BBB penetration. Thioflavin T derivatives gave breakthrough for {beta} - amyloid imaging in vivo, and a benzothiazole derivative [C-11]6-OH-BTA-1 brought a great success. Many other benzothiazole, benzoxazole, benzofuran, imidazopyridine, and styrylbenzene derivatives have been labeled with F-18 and I-123 to improve the imaging quality. However, [C-11]6-OH-BTA-1 still remains as the best. However, short half-life of C-11 is a limitation of wide distribution of this agent. So, it is still required to develop an Tc-99m, F-18 or I-123 labeled agent for {beta} - amyloid imaging agent.

  20. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study

    International Nuclear Information System (INIS)

    Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (Aβ) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and Aβ deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis. PET imaging with the amyloid plaque tracer 11C-AZD2184 and the astroglial tracer 11C-deuterium-L-deprenyl (11C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for Aβ deposition and astrocytosis by in vitro autoradiography using 3H-AZD2184, 3H-Pittsburgh compound B (PIB) and 3H-L-deprenyl and immunostaining performed with antibodies for Aβ42 and glial fibrillary acidic protein (GFAP) in sagittal brain sections. 11C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal 11C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography 3H-AZD2184 and 3H-PIB binding confirmed the in vivo findings with 11C-AZD2184 and demonstrated age-dependent increases in Aβ deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in 3H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more Aβ42 deposits in the cortex and hippocampus and more GFAP+ reactive astrocytes in the hippocampus at 18-24 months than at 6 months in APPswe

  1. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study

    Energy Technology Data Exchange (ETDEWEB)

    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

    Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (Aβ) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and Aβ deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis. PET imaging with the amyloid plaque tracer {sup 11}C-AZD2184 and the astroglial tracer {sup 11}C-deuterium-L-deprenyl ({sup 11}C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for Aβ deposition and astrocytosis by in vitro autoradiography using {sup 3}H-AZD2184, {sup 3}H-Pittsburgh compound B (PIB) and {sup 3}H-L-deprenyl and immunostaining performed with antibodies for Aβ{sub 42} and glial fibrillary acidic protein (GFAP) in sagittal brain sections. {sup 11}C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal {sup 11}C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography {sup 3}H-AZD2184 and {sup 3}H-PIB binding confirmed the in vivo findings with {sup 11}C-AZD2184 and demonstrated age-dependent increases in Aβ deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in {sup 3}H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more Aβ{sub 42} deposits in the cortex and hippocampus and more

  2. Effect of chronic intermittent hypoxia on the expression of Nip3, cell apoptosis, β-amyloid protein deposit in mice brain cortex

    Institute of Scientific and Technical Information of China (English)

    ZENG Yi-ming; CAI Kai-jin; CHEN Xiao-yong; WU Minx-ia; LIN Xi

    2009-01-01

    Background Chronic intermittent hypoxia (CIH) is the most important pathophysiologic feature of sleep apnea syndrome (SAS). To explore the relationship between SAS and dementia, the effects of CIH on the expression of Nip3, neuron apoptosis andβ-amyloid protein deposit in the brain cortex of the frontal lobe of mice were evaluated in this study. Methods Thirty male ICR mice were divided into four groups: control group (A, n=-10, sham hypoxia/reoxygenation), 2 weeks CIH group (B, n=-5), 4 weeks CIH group (C, n=-5), and 8 weeks CIH group (D, n=10). The ICR mice were placed in a chamber and exposed to intermittent hypoxia (oxygen concentration changed periodically from (21.72±0.55)% to (6.84±0.47)% every two minutes, eight hours per day). Neuron apoptosis of the cortex of the frontal lobe was detected by means of terminal deoxy-nucleotidyl transferase-mediated in situ end labeling (TUNEL). Immunohistochemical staining was performed for measuring expression of Nip3 and β-amyloid protein. The ultrastructure of neurons was observed under a transmission electron microscope. Results TUNEL positive neurons in each square millimeter in the cortex of the frontal lobe were categorized by median or Ri into group A (1,5.5), group B (133, 13), group C (252, 21), and group D (318, 24). There were significant differences among the above four groups (P=0.000). The significance test was performed between the control group and each CIH group respectively: group A and B (P>0.05); group A and C (P 0.05); groups A and C (P<0.005); and groups A and D (P<0.005). There was no significant difference between groups B and C, groups B and D, and groups C and D. The expression of Nip3 was closely correlated with neuron apoptosis in the brain (P <0.05). The expression ofβ-amyloid protein in the brain of mice was negative in all CIH groups and the control group. Ultrastructure observation showed karyopyknosis of nucleus, swelling of chondriosomes, deposit of lipofuscins and degeneration of

  3. Transmissible amyloid.

    Science.gov (United States)

    Tjernberg, L O; Rising, A; Johansson, J; Jaudzems, K; Westermark, P

    2016-08-01

    There are around 30 human diseases associated with protein misfolding and amyloid formation, each one caused by a certain protein or peptide. Many of these diseases are lethal and together they pose an enormous burden to society. The prion protein has attracted particular interest as being shown to be the pathogenic agent in transmissible diseases such as kuru, Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Whether similar transmission could occur also in other amyloidoses such as Alzheimer's disease, Parkinson's disease and serum amyloid A amyloidosis is a matter of intense research and debate. Furthermore, it has been suggested that novel biomaterials such as artificial spider silk are potentially amyloidogenic. Here, we provide a brief introduction to amyloid, prions and other proteins involved in amyloid disease and review recent evidence for their potential transmission. We discuss the similarities and differences between amyloid and silk, as well as the potential hazards associated with protein-based biomaterials. PMID:27002185

  4. Kinetic studies with iodine-123-labeled serum amyloid P component in patients with systemic AA and AL amyloidosis and assessment of clinical value

    NARCIS (Netherlands)

    Jager, PL; Hazenberg, BPC; Franssen, EJF; Limburg, PC; van Rijswijk, MH; Piers, DA

    1998-01-01

    In systemic amyloidosis, widespread amyloid deposition interferes with organ function, frequently with fatal consequences. Diagnosis rests on demonstrating amyloid deposits in the tissues, traditionally with histology although scintigraphic imaging with radiolabeled serum amyloid P component (SAP) h

  5. The effect of 18F-florbetapir dose reduction on region-based classification of cortical amyloid deposition

    Energy Technology Data Exchange (ETDEWEB)

    Herholz, K.; Evans, R.; Anton-Rodriguez, J.; Hinz, R.; Matthews, J.C. [University of Manchester, Wolfson Molecular Imaging Centre and Manchester Academic Health Science Centre, Manchester, England (United Kingdom)

    2014-11-15

    There are specific dose recommendations for diagnostic amyloid PET imaging with 18F-florbetapir, but they may not apply to research studies using regional quantitative analysis. We, therefore, studied the effect of tracer dose reduction on the discriminative power of regional analysis. Using bootstrap resampling of list-mode data from 18F-florbetapir scans, a total of 800 images were reconstructed for four different dosage levels: 100, 50, 20, and 10 %. The effect of the injected dose on the variation of measured radiotracer uptake was determined in large cortical regions defined on co-registered and segmented magnetic resonance images. The impact of the observed variation on the discrimination between normal controls and patients with AD was then assessed using data in a cohort study described by Fleisher et al. (Arch Neurol 68(11):1404-1411, 2011). The coefficient of variance for the cortex to cerebellum uptake ratio increased from 0.9 % at full dose of 300 MBq to 2.5 % at 10 % of this dose, but was still small compared to biological variation. It, therefore, had very little impact on discrimination between AD and elderly controls. The original area under the ROC curve was 0.881, decreasing to 0.878 at 10 % of full dose. Original sensitivity for discrimination between AD and controls was 82.0 %, while specificity was 77.3 %; these decreased to 81.8 and 77.1 %, respectively, at the reduced dose. However, the number of subjects within the classification border zone between proven amyloid pathology and young healthy controls increased substantially by 7 to 14 %. A substantial reduction of tracer dose increases uncertainty at the classification border zone while still providing good discrimination between AD patients and controls when using activity data from cortical regions defined on co-registered and segmented MR scans. (orig.)

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-07-15

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

  7. PiB fails to map amyloid deposits in cerebral cortex of aged dogs with Canine Cognitive Dysfunction

    DEFF Research Database (Denmark)

    Fast, Rikke; Rodell, Anders; Gjedde, Albert;

    2013-01-01

    to the understanding of AD. However, the sensitivity of the biomarker Pittsburgh Compound B (PiB) to the presence of Aβ in humans and in other mammalian species is in doubt. To test the sensitivity and assess the distribution of Aβ in dog brain, we mapped the brains of dogs with signs of CCD (n = 16) and a control......]PiB in the cerebellum, compared to the cerebral cortex. Retention in the cerebellum is at variance with evidence from brains of humans with AD. To confirm the lack of sensitivity, we stained two dog brains with the immunohistochemical marker 6E10, which is sensitive to the presence of both Aβ and Aβ precursor protein......Dogs with Canine Cognitive Dysfunction (CCD) accumulate amyloid beta (Aβ) in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer's disease (AD), the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest...

  8. A Novel liposomal nanoparticle for the imaging of amyloid plaque by MRI

    OpenAIRE

    Tanifum, Eric A; Ghaghada, Ketan; Vollert, Craig; Head, Elizabeth; Eriksen, Jason L.; Annapragada, Ananth

    2016-01-01

    Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy....

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-08-10

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

  10. Backfilling of KBS-3V deposition tunnels - possibilities and limitations

    Energy Technology Data Exchange (ETDEWEB)

    Wimelius, Hans (Swedish Nuclear Fuel and Waste Management Co., Stockholm (Sweden)); Pusch, Roland (Geodevelopment International AB, Lund (Sweden))

    2008-12-15

    By definition for the SKB repository concept, the backfill of KBS-3V deposition tunnels must be so designed that transport of dissolved matter is controlled by diffusion and not by advective water flow. This requires that the hydraulic conductivity of the backfill does not exceed about E-10 m/s. The backfilling materials also have to adequately resist compression caused by upward expansion of the buffer. It must also exert an effective pressure of at least 100 kPa on the rock in order to provide support to the rock and minimize spalling of the rock. These criteria are fulfilled by several approaches and options for backfill materials, placed and compacted layer wise or in the form of blocks of compacted clay powder. Based on the experience from comprehensive lab studies and considering practical issues, SKB has selected a concept where the major part of the backfill consists of stacked blocks that are surrounded by clay pellets. Using this concept a basis for a detailed evaluation, a study of three different techniques for placing the blocks has been undertaken. The three block placement techniques examined are the 'Block', 'Robot', and 'Module' methods. They involve different block sizes and techniques for handling and placing the blocks but the same way of preparing the foundation bed of the blocks and placing the pellet filling. The blasted tunnels have a varying cross section, caused by the orientation of the blast-holes. This requires that a varying fraction of blocks be installed in the backfilling along the blasted tunnel interval if sufficiently high density and low hydraulic conductivity is to be achieved. The efficiency of filling will depend on the type of clay used in the blocks. For example, using Friedland clay for block preparation, the filling efficiency must be 80% while it can be reduced to 60% if more smectite-rich clay is used. The use of a clay with high smectite content increases margins and is concluded to be

  11. Plasma-enhanced chemical vapor deposition for YBCO film fabrication of superconducting fault-current limiter

    Energy Technology Data Exchange (ETDEWEB)

    Jun, Byung Hyuk; Kim, Chan Joong

    2006-05-15

    Since the high-temperature superconductor of oxide type was founded, many researches and efforts have been performed for finding its application field. The YBCO superconducting film fabricated on economic metal substrate with uniform critical current density is considered as superconducting fault-current limiter (SFCL). There are physical and chemical processes to fabricate superconductor film, and it is understood that the chemical methods are more economic to deposit large area. Among them, chemical vapor deposition (CVD) is a promising deposition method in obtaining film uniformity. To solve the problems due to the high deposition temperature of thermal CVD, plasma-enhanced chemical vapor deposition (PECVD) is suggested. This report describes the principle and fabrication trend of SFCL, example of YBCO film deposition by PECVD method, and principle of plasma deposition.

  12. Traumatic brain injury accelerates amyloiddeposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Shishido, Hajime; Kishimoto, Yasushi; Kawai, Nobuyuki; Toyota, Yasunori; Ueno, Masaki; Kubota, Takashi; Kirino, Yutaka; Tamiya, Takashi

    2016-08-26

    Several pathological and epidemiological studies have demonstrated a possible relationship between traumatic brain injury (TBI) and Alzheimer's disease (AD). However, the exact contribution of TBI to AD onset and progression is unclear. Hence, we examined AD-related histopathological changes and cognitive impairment after TBI in triple transgenic (3×Tg)-AD model mice. Five- to seven-month-old 3×Tg-AD model mice were subjected to either TBI by the weight-drop method or a sham treatment. In the 3×Tg-AD mice subjected to TBI, the spatial learning was not significantly different 7 days after TBI compared to that of the sham-treated 3×Tg-AD mice. However, 28 days after TBI, the 3×Tg-AD mice exhibited significantly lower spatial learning than the sham-treated 3×Tg-AD mice. Correspondingly, while a few amyloid-β (Aβ) plaques were observed in both sham-treated and TBI-treated 3×Tg-AD mouse hippocampus 7 days after TBI, the Aβ deposition was significantly greater in 3×Tg-AD mice 28 days after TBI. Thus, we demonstrated that TBI induced a significant increase in hippocampal Aβ deposition 28 days after TBI compared to that of the control animals, which was associated with worse spatial learning ability in 3×Tg-AD mice. The present study suggests that TBI could be a risk factor for accelerated AD progression, particularly when genetic and hereditary predispositions are involved. PMID:27373531

  13. Comparing amyloiddeposition, neuroinflammation, glucose metabolism, and mitochondrial complex I activity in brain: a PET study in aged monkeys

    Energy Technology Data Exchange (ETDEWEB)

    Tsukada, Hideo; Nishiyama, Shingo; Ohba, Hiroyuki; Kanazawa, Masakatsu; Kakiuchi, Takeharu; Harada, Norihiro [Hamamatsu Photonics K.K., Central Research Laboratory, Shizuoka (Japan)

    2014-11-15

    The aim of the present study was to compare amyloid-β (Aβ) deposition, translocator protein (TSPO) activity, regional cerebral metabolic rate of glucose (rCMRglc), and mitochondrial complex I (MC-I) activity in the brain of aged monkeys. PET scans with {sup 11}C-PIB (Aβ), {sup 18}F-BCPP-EF (MC-I), {sup 11}C-DPA-713 (TSPO), and {sup 18}F-FDG (rCMRglc) were performed in aged monkeys (Macaca mulatta) in the conscious state and under isoflurane anaesthesia. {sup 11}C-PIB binding to Aβ and {sup 11}C-DPA-713 binding to TSPO were evaluated in terms of standard uptake values (SUV). The total volume of distribution (V{sub T}) of {sup 18}F-BCPP-EF and rCMRglc with {sup 18}F-FDG were calculated using arterial blood sampling. Isoflurane did not affect MC-I activity measured in terms of {sup 18}F-BCPP-EF uptake in living brain. There was a significant negative correlation between {sup 18}F-BCPP-EF binding (V{sub T}) and {sup 11}C-PIB uptake (SUVR), and there was a significant positive correlation between {sup 11}C-DPA-713 uptake (SUV) and {sup 11}C-PIB uptake. In contrast, there was no significant correlation between rCMRglc ratio and {sup 11}C-PIB uptake. {sup 18}F-BCPP-EF could be a potential PET probe for quantitative imaging of impaired MC-I activity that is correlated with Aβ deposition in the living brain. (orig.)

  14. Extrahepatic production of acute phase serum amyloid A

    OpenAIRE

    Upragarin, N.; Landman, W.J.M.; Gaastra, W; Gruys, E.

    2005-01-01

    Amyloidosis is a group of diseases characterized by the extracellular deposition of protein that contains non-branching, straight fibrils on electron microscopy (amyloid fibrils) that have a high content of ß-pleated sheet conformation. Various biochemically distinct proteins can undergo transformation into amyloid fibrils. The precursor protein of amyloid protein A (AA) is the acute phase protein serum amyloid A (SAA). The concentration of SAA in plasma increa...

  15. STIMULATED PLATELETS RELEASE AMYLOID β–PROTEIN PRECURSOR

    OpenAIRE

    Cole, Gregory M.; Galasko, Douglas; Shapiro, I. Paul; Saitoh, Tsunao

    1990-01-01

    Human platelets can be stimulated by thrombin or ionomycin to secrete soluble truncated amyloid β–protein precursor and particulate membrane fragments which contain C-terminal and N-terminal immunoreactive amyloid β–protein precursor. This suggests a possible circulating source of β–protein in serum which may play a role in the formation of amyloid deposits. The release of soluble amyloid β-protein precursor could be involved in normal platelet physiology.

  16. Imbalanced atmospheric nitrogen and phosphorus depositions in China: Implications for nutrient limitation

    Science.gov (United States)

    Zhu, Jianxing; Wang, Qiufeng; He, Nianpeng; Smith, Melinda D.; Elser, James J.; Du, Jiaqiang; Yuan, Guofu; Yu, Guirui; Yu, Qiang

    2016-06-01

    Atmospheric wet nitrogen (N) and phosphorus (P) depositions are important sources of bioavailable N and P, and the input of N and P and their ratios significantly influences nutrient availability and balance in terrestrial as well as aquatic ecosystems. Here we monitored atmospheric P depositions by measuring monthly dissolved P concentration in rainfall at 41 field stations in China. Average deposition fluxes of N and P were 13.69 ± 8.69 kg N ha-1 a-1 (our previous study) and 0.21 ± 0.17 kg P ha-1 a-1, respectively. Central and southern China had higher N and P deposition rates than northwest China, northeast China, Inner Mongolia, or Qinghai-Tibet. Atmospheric N and P depositions showed strong seasonal patterns and were dependent upon seasonal precipitation. Fertilizer and energy consumption were significantly correlated with N deposition but less correlated with P deposition. The N:P ratios of atmospheric wet deposition (with the average of 77 ± 40, by mass) were negatively correlated with current soil N:P ratios in different ecological regions, suggesting that the imbalanced atmospheric N and P deposition will alter nutrient availability and strengthen P limitation, which may further influence the structure and function of terrestrial ecosystems. The findings provide the assessments of both wet N and P deposition and their N:P ratio across China and indicate potential for strong impacts of atmospheric deposition on broad range of terrestrial ecosystems.

  17. Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure

    Energy Technology Data Exchange (ETDEWEB)

    Altman, Robin [Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine; Ly, Sonny [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Science Directorate; Hilt, Silvia [Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine; Petrlova, Jitka [Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine; Maezawa, Izumi [Univ. of California Davis, Sacramento, CA (United States). MIND Inst. and Dept. of Pathology and Laboratory Medicine; Kálai, Tamás [Univ. of Pecs (Hungary). Inst. of Organic and Medicinal Chemistry; Hideg, Kálmán [Univ. of Pecs (Hungary). Inst. of Organic and Medicinal Chemistry; Jin, Lee-Way [Univ. of California Davis, Sacramento, CA (United States). MIND Inst. and Dept. of Pathology and Laboratory Medicine; Laurence, Ted A. [Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine; Voss, John C. [Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine

    2015-12-01

    Alzheimer’s disease is characterized by the presence of extracellular plaques comprised of amyloid beta (Aβ) peptides. Soluble oligomers of the Aβ peptide underlie a cascade of neuronal loss and dysfunction associated with Alzheimer's disease. Single particle analyses of Aβ oligomers in solution by fluorescence correlation spectroscopy (FCS) were used to provide real-time descriptions of how spin-labeled fluorenes (SLFs; bi-functional small molecules that block the toxicity of Aβ) prevent and disrupt oligomeric assemblies of Aβ in solution. The FCS results, combined with electron paramagnetic resonance spectroscopy and circular dichroism spectroscopy, demonstrate SLFs can inhibit the growth of Aβ oligomers and disrupt existing oligomers while retaining Aβ in a largely disordered state. Furthermore, while the ability of SLF to block Aβ toxicity correlates with a reduction in oligomer size, our results suggest the conformation of Aβ within the oligomer determines the toxicity of the species. Attenuation of Aβ toxicity, which has been associated primarily with the soluble oligomeric form, can be achieved through redistribution of the peptides into smaller oligomers and arrest of the fractional increase in beta secondary structure.

  18. Amyloid Goiter Secondary to Ulcerative Colitis

    Directory of Open Access Journals (Sweden)

    Bunyamin Aydin

    2016-01-01

    Full Text Available Diffuse amyloid goiter (AG is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn’s disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis.

  19. Amyloid Goiter Secondary to Ulcerative Colitis.

    Science.gov (United States)

    Aydin, Bunyamin; Koca, Yavuz Savas; Koca, Tugba; Yildiz, Ihsan; Gerek Celikden, Sevda; Ciris, Metin

    2016-01-01

    Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis. PMID:27051538

  20. Partial Volume Correction in Quantitative Amyloid Imaging

    Science.gov (United States)

    Su, Yi; Blazey, Tyler M.; Snyder, Abraham Z.; Raichle, Marcus E.; Marcus, Daniel S.; Ances, Beau M.; Bateman, Randall J.; Cairns, Nigel J.; Aldea, Patricia; Cash, Lisa; Christensen, Jon J.; Friedrichsen, Karl; Hornbeck, Russ C.; Farrar, Angela M.; Owen, Christopher J.; Mayeux, Richard; Brickman, Adam M.; Klunk, William; Price, Julie C.; Thompson, Paul M.; Ghetti, Bernardino; Saykin, Andrew J.; Sperling, Reisa A.; Johnson, Keith A.; Schofield, Peter R.; Buckles, Virginia; Morris, John C.; Benzinger, Tammie. LS.

    2014-01-01

    Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. As positron emission tomography (PET) scanners have limited spatial resolution, measured signals are distorted by partial volume effects. Various techniques have been proposed for correcting partial volume effects, but there is no consensus as to whether these techniques are necessary in amyloid imaging, and, if so, how they should be implemented. We evaluated a two-component partial volume correction technique and a regional spread function technique using both simulated and human Pittsburgh compound B (PiB) PET imaging data. Both correction techniques compensated for partial volume effects and yielded improved detection of subtle changes in PiB retention. However, the regional spread function technique was more accurate in application to simulated data. Because PiB retention estimates depend on the correction technique, standardization is necessary to compare results across groups. Partial volume correction has sometimes been avoided because it increases the sensitivity to inaccuracy in image registration and segmentation. However, our results indicate that appropriate PVC may enhance our ability to detect changes in amyloid deposition. PMID:25485714

  1. Nutrient availability and phytoplankton nutrient limitation across a gradient of atmospheric nitrogen deposition

    Science.gov (United States)

    Elser, J.J.; Kyle, M.; Steuer, L.; Nydick, K.R.; Baron, J.S.

    2009-01-01

    Atmospheric nitrogen (N) deposition to lakes and watersheds has been increasing steadily due to various anthropogenic activities. Because such anthropogenic N is widely distributed, even lakes relatively removed from direct human disturbance are potentially impacted. However, the effects of increased atmospheric N deposition on lakes are not well documented, We examined phytoplankton biomass, the absolute and relative abundance of limiting nutrients (N and phosphorus [P]), and phytoplankton nutrient limitation in alpine lakes of the Rocky Mountains of Colorado (USA) receiving elevated (>6 kg N??ha-1??yr-1) or low (atmospheric N deposition. Highdeposition lakes had higher NO3-N and total N concentrations and higher total N : total P ratios. Concentrations of chlorophyll and seston carbon (C) were 2-2.5 times higher in highdeposition relative to low-deposition lakes, while high-deposition lakes also had higher seston C:N and C:P (but not N:P) ratios. Short-term enrichment bioassays indicated a qualitative shift in the nature of phytoplankton nutrient limitation due to N deposition, as highdeposition lakes had an increased frequency of primary P limitation and a decreased frequency and magnitude of response to N and to combined N and P enrichment. Thus elevated atmospheric N deposition appears to have shifted nutrient supply from a relatively balanced but predominantly N-deficient regime to a more consistently P-limited regime in Colorado alpine lakes. This adds to accumulating evidence that sustained N deposition may have important effects on lake phytoplankton communities and plankton-based food webs by shifting the quantitative and qualitative nature of nutrient limitation. ?? 2009 by the Ecological Society of America.

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

    Directory of Open Access Journals (Sweden)

    G. D. Rabinovici

    2009-01-01

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

  3. Vaccination with a non-human random sequence amyloid oligomer mimic results in improved cognitive function and reduced plaque deposition and micro hemorrhage in Tg2576 mice

    Directory of Open Access Journals (Sweden)

    Rasool Suhail

    2012-08-01

    Full Text Available Abstract Background It is well established that vaccination of humans and transgenic animals against fibrillar Aβ prevents amyloid accumulation in plaques and preserves cognitive function in transgenic mouse models. However, autoimmune side effects have halted the development of vaccines based on full length human Aβ. Further development of an effective vaccine depends on overcoming these side effects while maintaining an effective immune response. Results We have previously reported that the immune response to amyloid oligomers is largely directed against generic epitopes that are common to amyloid oligomers of many different proteins and independent of a specific amino acid sequence. Here we have examined whether we can exploit this generic immune response to develop a vaccine that targets amyloid oligomers using a non-human random sequence amyloid oligomer. In order to study the effect of vaccination against generic oligomer epitopes, a random sequence oligomer (3A was selected as it forms oligomers that react with the oligomer specific A11 antibody. Oligomer mimics from 3A peptide, Aβ, islet amyloid polypeptide (IAPP, and Aβ fibrils were used to vaccinate Tg2576 mice, which develop a progressive accumulation of plaques and cognitive impairment. Vaccination with the 3A random sequence antigen was just as effective as vaccination with the other antigens in improving cognitive function and reducing total plaque load (Aβ burden in the Tg2576 mouse brains, but was associated with a much lower incidence of micro hemorrhage than Aβ antigens. Conclusion These results shows that the amyloid Aβ sequence is not necessary to produce a protective immune response that specifically targets generic amyloid oligomers. Using a non-human, random sequence antigen may facilitate the development of a vaccine that avoids autoimmune side effects.

  4. Self-limiting atomic layer deposition of conformal nanostructured silver films

    Science.gov (United States)

    Golrokhi, Zahra; Chalker, Sophia; Sutcliffe, Christopher J.; Potter, Richard J.

    2016-02-01

    The controlled deposition of ultra-thin conformal silver nanoparticle films is of interest for applications including anti-microbial surfaces, plasmonics, catalysts and sensors. While numerous techniques can produce silver nanoparticles, few are able to produce highly conformal coatings on high aspect ratio surfaces, together with sub-nanometre control and scalability. Here we develop a self-limiting atomic layer deposition (ALD) process for the deposition of conformal metallic silver nanoparticle films. The films have been deposited using direct liquid injection ALD with ((hexafluoroacetylacetonato)silver(I)(1,5-cyclooctadiene)) and propan-1-ol. An ALD temperature window between 123 and 128 °C is identified and within this range self-limiting growth is confirmed with a mass deposition rate of ∼17.5 ng/cm2/cycle. The effects of temperature, precursor dose, co-reactant dose and cycle number on the deposition rate and on the properties of the films have been systematically investigated. Under self-limiting conditions, films are metallic silver with a nano-textured surface topography and nanoparticle size is dependent on the number of ALD cycles. The ALD reaction mechanisms have been elucidated using in-situ quartz crystal microbalance (QCM) measurements, showing chemisorption of the silver precursor, followed by heterogeneous catalytic dehydrogenation of the alcohol to form metallic silver and an aldehyde.

  5. Simulation Study of Heat Flux Deposition Pattern on the Surface of HT-7 Toroidal Limiters

    Institute of Scientific and Technical Information of China (English)

    GAO Feng; CHEN Junling; LI Jiangang; DING Rui

    2008-01-01

    The heat flux deposition pattern on the toroidal limiters installed in HT-7 was simulated with ANSYS code. The simulation model was established with the ripple of the magnetic field. The heat deposition pattern and temperature distribution on the surface of the toroidal limiters were obtained. A comparison of the results obtained with and without the shaped tiles, used to reduce the heat flux on the leading edge of the limiters, was made. The maximum heat load allowed at the leading edge was about 1.8 MW/m2 because of the poor power removing capacity on the ends of the limiters. This approach can also be applied to other devices with a limiter configuration in a circular cross-section shape.

  6. Amyloid deposition detected with florbetapir F 18 (18F-AV-45) is related to lower episodic memory performance in clinically normal older individuals

    Science.gov (United States)

    Sperling, Reisa A.; Johnson, Keith A.; Doraiswamy, P. Murali; Reiman, Eric M.; Fleisher, Adam S.; Sabbagh, Marwan; Sadowsky, Carl; Carpenter, Alan; Davis, Mat; Lu, Ming; Flitter, Matthew; Joshi, Abhinay; Clark, Christopher M.; Grundman, Michael; Mintun, Mark; Skovronsky, Daniel; Pontecorvo, Michael

    2012-01-01

    The objective of this study was to evaluate the relationship of amyloid burden, as assessed by florbetapir F 18 (18F-AV-45) amyloid PET, and cognition in healthy older control subjects (HC). Seventy-eight HC subjects were assessed with a brief cognitive test battery and PET imaging with florbetapir F 18. A standard uptake value ratio (SUVr) was computed for mean data from six cortical regions using a whole cerebellum reference region. Scans were also visually rated as amyloid positive (Aβ+) or amyloid negative (Aβ−) by three readers. Higher SUVr correlated with lower immediate memory (r=−0.33; p=0.003) and delayed recall scores (r=−0.25; p=0.027). Performance on immediate recall was also lower in the visually rated Aβ+ compared to Aβ− HC (p=0.04), with a similar trend observed in delayed recall (p=0.06). These findings support the hypothesis that higher amyloid burden is associated with lower memory performance among clinically normal older subjects. Longitudinal follow-up is ongoing to determine whether florbetapir F 18 may also predict subsequent cognitive decline. PMID:22878163

  7. 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.

  8. Extraskeletal problems and amyloid.

    Science.gov (United States)

    Drüeke, T B

    1999-12-01

    The major clinical manifestations of dialysis-associated A beta 2M amyloidosis are chronic arthralgias, destructive arthropathy and the carpal tunnel syndrome. For dialysis patients who have been maintained on renal replacement therapy for more than 10-15 years, this complication may become a major physical handicap. It may even be life-threatening in some instances due to cervical cord compression. Amyloid deposits in joint areas precede clinical symptoms and signs by several years. Systemic deposits may also occur but their clinical manifestations are infrequent. The diagnosis of dialysis arthropathy associated with beta 2-microglobulin-associated (A beta 2M) amyloidosis mostly relies on indirect clinical and radiological evidence. Histologic proof is rarely obtained in vivo. The pathogenesis of the disease is complex. It includes reduced elimination of beta 2M and potentially also as impaired degradation of A beta 2M as well as enhanced production of A beta 2M amyloid fibrils. Non enzymatic modifications of beta 2M probably play a role, including beta 2M protein modification with advanced glycation end-products (AGE) and advanced oxidation protein products. Modified beta 2M, collagen and proteoglycans appear actively involved in the induction of a local inflammatory response and beta 2M amyloid formation. There is also evidence in favor of treatment-related factors such as the type of hemodialysis membrane and the purity of dialysis water. Hopefully, the translation of our improving knowledge of all the factors involved will lead to a better treatment and eventually to the prevention of this dramatic complication of dialysis.

  9. Studies of amyloid toxicity in Drosophila models and effects of the BRICHOS domain

    OpenAIRE

    Hermansson Wik, Erik

    2015-01-01

    Amyloid diseases involve specific protein misfolding events and formation of fibrillar deposits. The symptoms of these diseases are broad and dependent on site of accumulation, with different amyloid proteins depositing in specific tissues or systematically. One such protein is transthyretin (TTR) associated with senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy. We show that the glycosaminoglycan heparan sulfate (HS) can be co-loc...

  10. Beta-amyloid deposition and cognitive function in patients with major depressive disorder with different subtypes of mild cognitive impairment: {sup 18}F-florbetapir (AV-45/Amyvid) PET study

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Kuan-Yi; Liu, Chia-Yih; Chen, Chia-Hsiang; Lee, Chin-Pang [Chang Gung Memorial Hospital and Chang Gung University, Department of Psychiatry, Tao-Yuan (China); Chen, Cheng-Sheng [Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Department of Psychiatry, Kaohsiung (China); Hsiao, Ing-Tsung; Hsieh, Chia-Ju; Yen, Tzu-Chen; Lin, Kun-Ju [Chang Gung Memorial Hospital, Department of Nuclear Medicine and Molecular Imaging Center, Kuei Shan Hsiang, Taoyuan (China); Chang Gung University, Department of Medical Imaging and Radiological Sciences and Healthy Aging Research Center, Tao-Yuan (China)

    2016-06-15

    The objective of this study was to evaluate the amyloid burden, as assessed by {sup 18}F-florbetapir (AV-45/Amyvid) positron emission tomography PET, in patients with major depressive disorder (MDD) with different subtypes of mild cognitive impairment (MCI) and the relationship between amyloid burden and cognition in MDD patients. The study included 55 MDD patients without dementia and 21 healthy control subjects (HCs) who were assessed using a comprehensive cognitive test battery and {sup 18}F-florbetapir PET imaging. The standardized uptake value ratios (SUVR) in eight cortical regions using the whole cerebellum as reference region were determined and voxel-wise comparisons between the HC and MDD groups were performed. Vascular risk factors, serum homocysteine level and the apolipoprotein E (ApoE) genotype were also determined. Among the 55 MDD patients, 22 (40.0 %) had MCI, 12 (21.8 %) non-amnestic MCI (naMCI) and 10 (18.2 %) amnestic MCI (aMCI). The MDD patients with aMCI had the highest relative {sup 18}F-florbetapir uptake in all cortical regions, and a significant difference in relative {sup 18}F-florbetapir uptake was found in the parietal region as compared with that in naMCI subjects (P < 0.05) and HCs (P < 0.01). Voxel-wise analyses revealed significantly increased relative {sup 18}F-florbetapir uptake in the MDD patients with aMCI and naMCI in the frontal, parietal, temporal and occipital areas (P < 0.005). The global cortical SUVR was significantly negatively correlated with MMSE score (r = -0.342, P = 0.010) and memory function (r = -0.328, P = 0.015). The negative correlation between the global SUVR and memory in the MDD patients remained significant in multiple regression analyses that included age, educational level, ApoE genotype, and depression severity (β = -3.607, t = -2.874, P = 0.006). We found preliminary evidence of brain beta-amyloid deposition in MDD patients with different subtypes of MCI. Our findings in MDD patients support the

  11. Molecular mechanisms of amyloid self-regulation

    OpenAIRE

    Landreh, Michael

    2012-01-01

    Amyloid is associated with both pathological protein deposits and the formation of functional protein structures. Therefore, several strategies have evolved to control the formation or inhibition of amyloid in vivo. In this thesis, three separate systems were investigated in which amyloidogenic protein segments are coupled to regulatory elements that prevent or promote fibrillation. We describe the molecular mechanism for how (a) a propeptide segment prevents the uncontrolled a...

  12. Large area deposition of YBCO thick films for applications in resistive fault current limiting devices

    International Nuclear Information System (INIS)

    The preparation of the switching element of a resistive superconducting fault current limiter requires the up-scaling of deposition techniques for thin YBa2Cu3O7-x (YBCO) films to large areas and high film thicknesses. For a projected 100 kVA limiter model an area of about 400 cm2 and a film thickness of up to 5 μm will be necessary, depending on the material properties like critical current density jc and normal state resistivity ρn. Within a joint project various deposition methods including pulsed laser deposition (PLD), magnetron sputtering (MS), thermal evaporation (TE) and plasma flash evaporation (PFE) are evaluated as possible candidates for the operation of deposition systems capable of coating 20 x 20 cm2 substrates. Both single crystalline wafers and polycrystalline ceramic plates are considered as substrates. To achieve high jc on polycrystalline substrate materials an additional zirconia buffer layer consisting of biaxially orientated crystallites has to be prepared by ion beam assisted deposition (IBAD). In small samples with IBAD buffer critical currents above 105 A cm-2 with a maximum of 1 x 106 A cm-2 have been achieved. The presently available sample sizes depend on the installed systems for YBCO and buffer deposition, respectively and on the commercial availability of the substrate material. The largest samples which have been prepared and characterised have sizes of 1 x 25 cm2 and 5 x 5 cm2 for PLD, 10 x 10 cm2 for TE and IBAD, 2 in. (1 in.=2.54 cm) diameter for MS, and 3 x 7 cm2 for PFE. The corresponding highest film thicknesses are 4.5 μm for PLD, 1.4 μm for TE, 1.6 μm for IBAD and 0.4 μm for MS. (orig.)

  13. 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).

  14. Plaque deposition dependent decrease in 5-HT2A serotonin receptor in AbetaPPswe/PS1dE9 amyloid overexpressing mice

    DEFF Research Database (Denmark)

    Holm, Peter; Ettrup, Anders; Klein, Anders B;

    2010-01-01

    -HT2A receptor regulation in double transgenic AbetaPPswe/PS1dE9 mice which display excess production of Abeta and age-dependent increase in amyloid plaques. Three different age-groups, 4-month-old, 8- month-old, and 11-month-old were included in the study. [3H]-MDL100907, [3H]-escitalopram, and [11C...

  15. Islet amyloid polypeptide-induced membrane leakage involves uptake of lipids by forming amyloid fibers.

    Science.gov (United States)

    Sparr, Emma; Engel, Maarten F M; Sakharov, Dmitri V; Sprong, Mariette; Jacobs, Jet; de Kruijff, Ben; Höppener, Jo W M; Killian, J Antoinette

    2004-11-01

    Fibril formation of islet amyloid polypeptide (IAPP) is associated with cell death of the insulin-producing pancreatic beta-cells in patients with Type 2 Diabetes Mellitus. A likely cause for the cytotoxicity of human IAPP is that it destroys the barrier properties of the cell membrane. Here, we show by fluorescence confocal microscopy on lipid vesicles that the process of hIAPP amyloid formation is accompanied by a loss of barrier function, whereby lipids are extracted from the membrane and taken up in the forming amyloid deposits. No membrane interaction was observed when preformed fibrils were used. It is proposed that lipid uptake from the cell membrane is responsible for amyloid-induced membrane damage and that this represents a general mechanism underlying the cytotoxicity of amyloid forming proteins. PMID:15527771

  16. Modeling the Aggregation Propensity and Toxicity of Amyloid-β Variants

    DEFF Research Database (Denmark)

    Tiwari, Manish Kumar; Kepp, Kasper Planeta

    2015-01-01

    Protein aggregation is a hallmark of many neurodegenerative disorders. Alzheimer’s disease (AD) is directly linked to deposits of amyloid-β (Aβ) derived from the amyloid-β protein precursor (AβPP), and multiple experimental studies have investigated the aggregation behavior of these amyloids...

  17. Amyloid-beta Positron Emission Tomography Imaging Probes : A Critical Review

    NARCIS (Netherlands)

    Kepe, Vladimir; Moghbel, Mateen C.; Langstrom, Bengt; Zaidi, Habib; Vinters, Harry V.; Huang, Sung-Cheng; Satyamurthy, Nagichettiar; Doudet, Doris; Mishani, Eyal; Cohen, Robert M.; Hoilund-Carlsen, Poul F.; Alavi, Abass; Barrio, Jorge R.

    2013-01-01

    The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-beta deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-beta plaques are currently at various stages of FDA approval. However, a

  18. Cardiac resynchronization therapy in a patient with amyloid cardiomyopathy.

    Science.gov (United States)

    Zizek, David; Cvijić, Marta; Zupan, Igor

    2013-06-01

    Cardiac involvement in systemic light chain amyloidosis carries poor prognosis. Amyloid deposition in the myocardium can alter regional left ventricular contraction and cause dyssynchrony. Cardiac resynchronization therapy (CRT) is an effective treatment strategy for patients with advanced heart failure and echocardiographic dyssynchrony. We report a clinical and echocardiographic response of a patient with amyloid cardiomyopathy, treated with a combination of chemotherapy and CRT.

  19. Quench Limit Calculation for Steady State Heat Deposits in LHC Inner Triplet Magnets

    CERN Document Server

    Cerutti, F; Esposito, L S; Siemko, A; Bocian, D

    2012-01-01

    In hadron colliders such as the LHC, the energy deposited in the superconductors by the particles lost from the beams or coming from the collision debris may provoke quenches detrimental to the accelerator operation. A Network Model is used to simulate the thermodynamic behavior of the superconducting magnets. In previous papers the validations of network model with measurements performed in the CERN and Fermilab magnet test facilities were presented. This model was subsequently used for thermal analysis of the current LHC inner triplet quadrupole magnets for beam energy of 3.5 TeV and 7.0 TeV. The detailed study of helium cooling channels efficiency for energy deposits simulated with FLUKA was performed. The expected LHC inner triplet magnets quench limit is presented.

  20. Identification of a Common Binding Mode for Imaging Agents to Amyloid Fibrils from Molecular Dynamics Simulations

    DEFF Research Database (Denmark)

    Skeby, Katrine Kirkeby; Sørensen, Jesper; Schiøtt, Birgit

    2013-01-01

    Amyloid diseases are characterized by the misfolding and deposition of proteins in the body in the form of insoluble amyloid fibrils. Alzheimer’s disease and type 2 diabetes mellitus are two examples of amyloid diseases which are closely related both with respect to the atomic structures of the a......Amyloid diseases are characterized by the misfolding and deposition of proteins in the body in the form of insoluble amyloid fibrils. Alzheimer’s disease and type 2 diabetes mellitus are two examples of amyloid diseases which are closely related both with respect to the atomic structures...... of the amyloid fibrils and the disease pathology. Alzheimer’s disease is very difficult to diagnose, and much research is being performed to develop noninvasive diagnostic methods, such as imaging with small-molecule agents. The interactions between amyloid fibrils and imaging agents are challenging to examine...

  1. 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.

  2. Nitrogen deposition effects on subalpine grassland: The role of nutrient limitations and changes in mycorrhizal abundance

    Science.gov (United States)

    Blanke, Verena; Bassin, Seraina; Volk, Matthias; Fuhrer, Jürg

    2012-11-01

    To better understand how increasing atmospheric nitrogen (N) deposition may affect subalpine grassland, we carried out a nutrient addition experiment in the Swiss Alps. N addition (+N) was combined with phosphorus (P) addition (+P) to determine nutrient limitations in plant functional groups. To examine responses of arbuscular mycorrhizal fungi (AMF) and AMF effects on plant growth, in-growth cores containing local plant species (phytometers) were inserted, and in half of them the external mycelium was disrupted weekly to impede mycorrhizal functioning. At harvest, aboveground biomass and element concentrations of the established vegetation were measured, as well as phytometer shoot and root mass, and the percentage of root length colonized (%RLC) by AMF. Only productivity of grasses increased under +N and +P, while other groups showed no or negative growth responses. +P decreased %RLC in all phytometers, whereas +N increased %RLC in the most abundant grass species, and reduced the relative abundance of arbuscules to total intraradical mycelium in the other species. Weekly destruction of the external mycelium reduced %RLC in most species, but did not affect plant biomass. The results suggest that increased N deposition in such N- and P-co-limited grassland will lead to shifts in plant functional group composition due to differences in the plants' nutrient demand, that +N will affect AMF abundance and mutualistic functioning, but that changes in AMF abundance may not considerably affect plant growth.

  3. The Effect of Glycosaminoglycans (GAGs on Amyloid Aggregation and Toxicity

    Directory of Open Access Journals (Sweden)

    Clara Iannuzzi

    2015-02-01

    Full Text Available Amyloidosis is a protein folding disorder in which normally soluble proteins are deposited extracellularly as insoluble fibrils, impairing tissue structure and function. Charged polyelectrolytes such as glycosaminoglycans (GAGs are frequently found associated with the proteinaceous deposits in tissues of patients affected by amyloid diseases. Experimental evidence indicate that they can play an active role in favoring amyloid fibril formation and stabilization. Binding of GAGs to amyloid fibrils occurs mainly through electrostatic interactions involving the negative polyelectrolyte charges and positively charged side chains residues of aggregating protein. Similarly to catalyst for reactions, GAGs favor aggregation, nucleation and amyloid fibril formation functioning as a structural templates for the self-assembly of highly cytotoxic oligomeric precursors, rich in β-sheets, into harmless amyloid fibrils. Moreover, the GAGs amyloid promoting activity can be facilitated through specific interactions via consensus binding sites between amyloid polypeptide and GAGs molecules. We review the effect of GAGs on amyloid deposition as well as proteins not strictly related to diseases. In addition, we consider the potential of the GAGs therapy in amyloidosis.

  4. The minimum detection limits of RDX and TNT deposited on various surfaces as determined by ion mobility spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Rodacy, P.

    1993-08-01

    An Ion Mobility Spectrometer (IMS) was used to determine the detection limits of RDX and TNT on six different substrates. The preparation of the explosive deposits on the surfaces is examined as well as effects due to the size, uniformity, method of application, and time that a deposit has been on a surface. Sampling methods are discussed along with effects of the surface topology. The transfer of explosives from a hand to a surface, and methods to reduce the detection limits are presented.

  5. Contagious deposition of seeds in spider monkeys' sleeping trees limits effective seed dispersal in fragmented landscapes.

    Directory of Open Access Journals (Sweden)

    Arturo González-Zamora

    Full Text Available The repeated use of sleeping sites by frugivorous vertebrates promotes the deposition and aggregation of copious amounts of seeds in these sites. This spatially contagious pattern of seed deposition has key implications for seed dispersal, particularly because such patterns can persist through recruitment. Assessing the seed rain patterns in sleeping sites thus represents a fundamental step in understanding the spatial structure and regeneration of plant assemblages. We evaluated the seed rain produced by spider monkeys (Ateles geoffroyi in latrines located beneath 60 sleeping trees in two continuous forest sites (CFS and three forest fragments (FF in the Lacandona rainforest, Mexico. We tested for differences among latrines, among sites, and between forest conditions in the abundance, diversity (α-, β- and, γ-components and evenness of seed assemblages. We recorded 45,919 seeds ≥ 5 mm (in length from 68 species. The abundance of seeds was 1.7 times higher in FF than in CFS, particularly because of the dominance of a few plant species. As a consequence, community evenness tended to be lower within FF. β-diversity of common and dominant species was two times greater among FF than between CFS. Although mean α-diversity per latrine did not differ among sites, the greater β-diversity among latrines in CFS increased γ-diversity in these sites, particularly when considering common and dominant species. Our results support the hypothesis that fruit scarcity in FF can 'force' spider monkeys to deplete the available fruit patches more intensively than in CFS. This feeding strategy can limit the effectiveness of spider monkeys as seed dispersers in FF, because (i it can limit the number of seed dispersers visiting such fruit patches; (ii it increases seed dispersal limitation; and (iii it can contribute to the floristic homogenization (i.e., reduced β-diversity among latrines in fragmented landscapes.

  6. Contemporary treatment of amyloid heart disease.

    Science.gov (United States)

    Palecek, Tomas; Fikrle, Michal; Nemecek, Eduard; Bauerova, Lenka; Kuchynka, Petr; Louch, William E; Spicka, Ivan; Rysava, Romana

    2015-01-01

    The amyloidoses represent a group of diseases characterized by extracellular deposition of abnormal protein, amyloid, which is formed by insoluble extracellular fibrils in β-pleated sheets. Although cardiac involvement may occur in all types of amyloidoses, clinically relevant amyloid cardiomyopathy is a typical feature of AL amyloidosis and transthyretin-related amyloidoses. Congestive heart failure represents the commonest manifestation of amyloid heart disease. Noninvasive imaging techniques, especially echocardiography and cardiac magnetic resonance, play a major role in the diagnosis of amyloid cardiomyopathy; however, histological confirmation and exact typing of amyloid deposits is necessary whether in extracardiac location or directly in the myocardium. Early diagnosis of amyloid heart disease is of utmost importance as the presence and especially the severity of cardiac involvement generally drives the prognosis of affected subjects and plays a major role in determining the intensity of specific treatment, namely in AL amyloidosis. The management of patients with amyloid heart disease is complex. Loop diuretics together with aldosterone antagonists represent the basis for influencing signs of congestion. In AL amyloidosis, high-dose chemotherapy followed by autologous stem cell transplantation is generally considered to be a front-line treatment option, if the disease is diagnosed at its early stage. The combination of mephalan with dexamethasone has been the standard therapy for severely affected individuals; however, the combinations with several novel agents including immunomodulatory drugs and bortezomibe have been tested in clinical trials with promising results. New therapeutic substances with the potential to slow or even stop the progression of transthyretin-related amyloidosis are also extensively studied. PMID:25483951

  7. Is amyloid A (AA) amyloidosis always secondary?

    OpenAIRE

    Maury, C P; Törnroth, T; Wegelius, O

    1985-01-01

    The case is reported of a patient with systemic AA amyloidosis associated with non-specific mesenteric lymphadenitis and chronic sideropenia. Renal, small bowel, and rectal biopsies showed amyloid deposits containing AA protein, as defined by potassium permanganate sensitivity and by reactivity with AA antiserum. Reversal of the nephrotic syndrome occurred during steroid-azathioprine therapy.

  8. On performance limitations and property correlations of Al-doped ZnO deposited by radio-frequency sputtering

    DEFF Research Database (Denmark)

    Crovetto, Andrea; Ottsen, Tobias Sand; Stamate, Eugen;

    2016-01-01

    The electrical properties of RF-sputtered Al-doped ZnO are often spatially inhomogeneous and strongly dependent on deposition parameters. In this work, we study the mechanisms that limit the minimum resistivity achievable under different deposition regimes. In a low- and intermediate-pressure reg......The electrical properties of RF-sputtered Al-doped ZnO are often spatially inhomogeneous and strongly dependent on deposition parameters. In this work, we study the mechanisms that limit the minimum resistivity achievable under different deposition regimes. In a low- and intermediate......-pressure regime, we find a generalized dependence of the electrical properties, grain size, texture, and Al content on compressive stress, regardless of sputtering pressure or position on the substrate. In a high-pressure regime, a porous microstructure limits the achievable resistivity and causes it to increase...

  9. Islet amyloid polypeptide in pancreatic islets from type 2 diabetic subjects

    OpenAIRE

    Tomita, Tatsuo

    2012-01-01

    Aims/hypothesis: Islet amyloid polypeptide (IAPP) is a chief constituent of amyloid deposits in pancreatic islets, characteristic histopathology for type 2 diabetes. The goal of this study was to analyze islet cell composition in diabetic islets for the process of transforming water-soluble IAPP in β-cells to water-insoluble amyloid deposits by Immunocytochemical staining using different dilutions of anti-IAPP antibody. IAPP in β-cell granules may initiate β-cell necrosis through apoptosis to...

  10. Prions, amyloids, and RNA: Pieces of a puzzle.

    Science.gov (United States)

    Nizhnikov, Anton A; Antonets, Kirill S; Bondarev, Stanislav A; Inge-Vechtomov, Sergey G; Derkatch, Irina L

    2016-05-01

    Amyloids are protein aggregates consisting of fibrils rich in β-sheets. Growth of amyloid fibrils occurs by the addition of protein molecules to the tip of an aggregate with a concurrent change of a conformation. Thus, amyloids are self-propagating protein conformations. In certain cases these conformations are transmissible / infectious; they are known as prions. Initially, amyloids were discovered as pathological extracellular deposits occurring in different tissues and organs. To date, amyloids and prions have been associated with over 30 incurable diseases in humans and animals. However, a number of recent studies demonstrate that amyloids are also functionally involved in a variety of biological processes, from biofilm formation by bacteria, to long-term memory in animals. Interestingly, amyloid-forming proteins are highly overrepresented among cellular factors engaged in all stages of mRNA life cycle: from transcription and translation, to storage and degradation. Here we review rapidly accumulating data on functional and pathogenic amyloids associated with mRNA processing, and discuss possible significance of prion and amyloid networks in the modulation of key cellular functions. PMID:27248002

  11. Pharmacokinetics of [{sup 18}F]flutemetamol in wild-type rodents and its binding to beta amyloid deposits in a mouse model of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Snellman, Anniina; Lopez-Picon, Francisco R.; Haaparanta-Solin, Merja [University of Turku, MediCity/PET Preclinical Laboratory, Turku PET Centre, Turku (Finland); Rokka, Johanna; Eskola, Olli [University of Turku, Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, Turku (Finland); Wilson, Ian; Farrar, Gill [GE Healthcare Medical Diagnostics, Little Chalfont, Buckinghamshire (United Kingdom); Scheinin, Mika [University of Turku, Department of Pharmacology, Drug Development and Therapeutics, Turku (Finland); Turku University Hospital, Unit of Clinical Pharmacology, Turku (Finland); Solin, Olof [University of Turku, Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, Turku (Finland); Aabo Akademi University, Accelerator Laboratory, Turku PET Centre, Turku (Finland); Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland)

    2012-11-15

    The aim of this study was to investigate the potential of [{sup 18}F]flutemetamol as a preclinical PET tracer for imaging {beta}-amyloid (A{beta}) deposition by comparing its pharmacokinetics to those of [{sup 11}C]Pittsburgh compound B ([{sup 11}C]PIB) in wild-type Sprague Dawley rats and C57Bl/6N mice. In addition, binding of [{sup 18}F]flutemetamol to A{beta} deposits was studied in the Tg2576 transgenic mouse model of Alzheimer's disease. [{sup 18}F]Flutemetamol biodistribution was evaluated using ex vivo PET methods and in vivo PET imaging in wild-type rats and mice. Metabolism and binding of [{sup 11}C]PIB and [{sup 18}F]flutemetamol to plasma proteins were analysed using thin-layer chromatography and ultrafiltration methods, respectively. Radiation dose estimates were calculated from rat ex vivo biodistribution data. The binding of [{sup 18}F]flutemetamol to A{beta} deposits was also studied using ex vivo and in vitro autoradiography. The location of A{beta} deposits in the brain was determined with thioflavine S staining and immunohistochemistry. The pharmacokinetics of [{sup 18}F]flutemetamol resembled that of [{sup 11}C]PIB in rats and mice. In vivo studies showed that both tracers readily entered the brain, and were excreted via the hepatobiliary pathway in both rats and mice. The metabolism of [{sup 18}F]flutemetamol into radioactive metabolites was faster than that of [{sup 11}C]PIB. [{sup 18}F]Flutemetamol cleared more slowly from the brain than [{sup 11}C]PIB, particularly from white matter, in line with its higher lipophilicity. Effective dose estimates for [{sup 11}C]PIB and [{sup 18}F]flutemetamol were 2.28 and 6.65 {mu}Sv/MBq, respectively. Autoradiographs showed [{sup 18}F]flutemetamol binding to fibrillar A{beta} deposits in the brain of Tg2576 mice. Based on its pharmacokinetic profile, [{sup 18}F]flutemetamol showed potential as a PET tracer for preclinical imaging. It showed good brain uptake and was bound to A{beta} deposits in the

  12. 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

  13. Neuropsychological Effects of Cerebral Amyloid Angiopathy.

    Science.gov (United States)

    Schrag, Matthew; Kirshner, Howard

    2016-08-01

    Cerebral amyloid angiopathy is a condition of the cerebral arterioles and to a lesser extent capillaries and veins, wherein beta-amyloid is deposited. In arterioles, this preferentially targets vascular smooth muscle cells and in the later stages undermines the stability of the vessel. This condition is frequently comorbid with Alzheimer's disease and its role in cognitive impairment and dementia is a topic of considerable recent research. This article reviews recent literature which confirms that CAA independently contributes to cognitive impairment by potentiating the neurodegeneration of Alzheimer's disease, by predisposing to microhemorrhagic and microischemic injury to the brain parenchyma, and by interfering with the autoregulation of CNS blood flow. In this review, we discuss the clinical presentation of cerebral amyloid angiopathy, with a focus on the neuropsychological manifestations of this vasculopathy. PMID:27357378

  14. Fibrillar dimer formation of islet amyloid polypeptides

    Energy Technology Data Exchange (ETDEWEB)

    Chiu, Chi-cheng [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States); de Pablo, Juan J. [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-05-08

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  15. Fibrillar dimer formation of islet amyloid polypeptides

    Science.gov (United States)

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-09-01

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 - 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 - 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  16. SPECT imaging of peripheral amyloid in mice by targeting hyper-sulfated heparan sulfate proteoglycans with specific scFv antibodies.

    NARCIS (Netherlands)

    Wall, J.S.; Richey, T.; Stuckey, A.; Donnell, R.; Oosterhof, A.; Kuppevelt, T. van; Smits, N.C.; Kennel, S.J.

    2012-01-01

    INTRODUCTION: Amyloid deposits are associated with a broad spectrum of disorders including monoclonal gammopathies, chronic inflammation, and Alzheimer's disease. In all cases, the amyloid pathology contains, in addition to protein fibrils, a plethora of associated molecules, including high concentr

  17. Increased brain amyloid deposition in patients with a lifetime history of major depression: evidenced on {sup 18}F-florbetapir (AV-45/Amyvid) positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Kuan-Yi; Chen, Chia-Hsiang; Liu, Chia-Yih [Chang Gung Memorial Hospital and Chang Gung University, Department of Psychiatry, Tao-Yuan (China); Hsiao, Ing-Tsung; Hsieh, Chia-Ju [Chang Gung Memorial Hospital, Department of Nuclear Medicine and Molecular Imaging Center, Tao-Yuan (China); Chang Gung University, Department of Medical Imaging and Radiological Sciences and Healthy Aging Research Center, Tao-Yuan (China); Chen, Cheng-Sheng [Kaohsiung Medical University Hospital, Department of Psychiatry, Kaohsiung (China); Wai, Yau-Yau [Chang Gung Memorial Hospital, Department of Radiology, Tao-Yuan (China); Chang, Chee-Jen [Chang Gung University, Graduate Institute of Clinical Medical Science, Tao-Yuan (China); Chang Gung University, Clinical Informatics and Medical Statistics Research Center, Tao-Yuan (China); Chang Gung Memorial Hospital, Biostatistical Center for Clinical Research, Tao-Yuan (China); Tseng, Hsiao-Jung [Chang Gung Memorial Hospital, Biostatistical Center for Clinical Research, Tao-Yuan (China); Yen, Tzue-Chen; Lin, Kun-Ju [Chang Gung University, Department of Medical Imaging and Radiological Sciences and Healthy Aging Research Center, Tao-Yuan (China); Chang Gung Memorial Hospital, Department of Nuclear Medicine and Molecular Imaging Center, Tao-Yuan (China)

    2014-04-15

    The literature suggests that a history of depression is associated with an increased risk of developing Alzheimer's disease (AD). The aim of this study was to examine brain amyloid accumulation in patients with lifetime major depression using {sup 18}F-florbetapir (AV-45/Amyvid) PET imaging in comparison with that in nondepressed subjects. The study groups comprised 25 depressed patients and 11 comparison subjects who did not meet the diagnostic criteria for AD or amnestic mild cognitive impairment. Vascular risk factors, homocysteine and apolipoprotein E (ApoE) genotype were also examined. The standard uptake value ratio (SUVR) of each volume of interest was analysed using whole the cerebellum as the reference region. Patients with a lifetime history of major depression had higher {sup 18}F-florbetapir SUVRs in the precuneus (1.06 ± 0.08 vs. 1.00 ± 0.06, p = 0.045) and parietal region (1.05 ± 0.08 vs. 0.98 ± 0.07, p = 0.038) than the comparison subjects. Voxel-wise analysis revealed a significantly increased SUVR in depressed patients in the frontal, parietal, temporal and occipital areas (p < 0.01). There were no significant associations between global {sup 18}F-florbetapir SUVRs and prior depression episodes, age at onset of depression, or time since onset of first depression. Increased {sup 18}F-florbetapir binding values were found in patients with late-life major depression relative to comparison subjects in specific brain regions, despite no differences in age, sex, education, Mini Mental Status Examination score, vascular risk factor score, homocysteine and ApoE ε4 genotype between the two groups. A longitudinal follow-up study with a large sample size would be worthwhile. (orig.)

  18. Increased brain amyloid deposition in patients with a lifetime history of major depression: evidenced on 18F-florbetapir (AV-45/Amyvid) positron emission tomography

    International Nuclear Information System (INIS)

    The literature suggests that a history of depression is associated with an increased risk of developing Alzheimer's disease (AD). The aim of this study was to examine brain amyloid accumulation in patients with lifetime major depression using 18F-florbetapir (AV-45/Amyvid) PET imaging in comparison with that in nondepressed subjects. The study groups comprised 25 depressed patients and 11 comparison subjects who did not meet the diagnostic criteria for AD or amnestic mild cognitive impairment. Vascular risk factors, homocysteine and apolipoprotein E (ApoE) genotype were also examined. The standard uptake value ratio (SUVR) of each volume of interest was analysed using whole the cerebellum as the reference region. Patients with a lifetime history of major depression had higher 18F-florbetapir SUVRs in the precuneus (1.06 ± 0.08 vs. 1.00 ± 0.06, p = 0.045) and parietal region (1.05 ± 0.08 vs. 0.98 ± 0.07, p = 0.038) than the comparison subjects. Voxel-wise analysis revealed a significantly increased SUVR in depressed patients in the frontal, parietal, temporal and occipital areas (p 18F-florbetapir SUVRs and prior depression episodes, age at onset of depression, or time since onset of first depression. Increased 18F-florbetapir binding values were found in patients with late-life major depression relative to comparison subjects in specific brain regions, despite no differences in age, sex, education, Mini Mental Status Examination score, vascular risk factor score, homocysteine and ApoE ε4 genotype between the two groups. A longitudinal follow-up study with a large sample size would be worthwhile. (orig.)

  19. Effect of wall conditions on the self-limiting deposition of metal oxides by pulsed plasma-enhanced chemical vapor deposition

    International Nuclear Information System (INIS)

    Pulsed plasma-enhanced chemical vapor deposition has been engineered to deliver self-limiting growth (i.e., ∼A /pulse) of metal oxides such as Ta2O5 and Al2O3. In this process the reactor walls are alternately exposed to atomic oxygen and metal precursors. The degree of adsorption in the latter step can dramatically influence both deposition rates and film quality. The impact of precursor adsorption on the plasma and gas-phase composition in these systems was quantified using optical emission spectroscopy and quadrupole mass spectrometry, respectively. It is shown that the time scale for a complete adsorption on the chamber walls is much greater than gas-phase residence times. Adsorbed compounds significantly alter the reactor composition, particularly at the initiation of each plasma pulse. As a consequence, careful attention must be paid to reactor design and operation to control deposition rates and maintain film quality

  20. Hereditary Amyloid Cardiomyopathy Caused by a Variant Apolipoprotein A1

    OpenAIRE

    Hamidi Asl, Ladan; Liepnieks, Juris J.; Hamidi Asl, Kamran; Uemichi, Tomoyuki; Moulin, Georges; Desjoyaux, Emmanuel; Loire, Robert; Delpech, Marc; Grateau, Gilles; Benson, Merrill D.

    1999-01-01

    Autosomal dominant hereditary amyloidosis with a unique cutaneous and cardiac presentation and death from heart failure by the sixth or seventh decade was found to be associated with a previously unreported point mutation (thymine to cytosine, nt 1389) in exon 4 of the apolipoprotein A1 (apoA1) gene. The predicted substitution of proline for leucine at amino acid position 90 was confirmed by structural analysis of amyloid protein isolated from cardiac deposits of amyloid. The subunit protein ...

  1. Cardiac and pleuropulmonary AL amyloid imaging with technetium-99m labelled aprotinin

    Energy Technology Data Exchange (ETDEWEB)

    Aprile, C. [Dept. of Nuclear Medicine, Fondazione Clinica del Lavoro-IRCCS, Pavia (Italy); Marinone, G. [Inst. of Clinical Medicine II and Research Lab. Biotechnology, Policlinico S. Matteo-IRCCS, Pavia (Italy); Saponaro, R. [Dept. of Nuclear Medicine, Fondazione Clinica del Lavoro-IRCCS, Pavia (Italy); Bonino, C. [SORIN Biomedica, Saluggia VC (Italy); Merlini, G. [Inst. of Clinical Medicine II and Research Lab. Biotechnology, Policlinico S. Matteo-IRCCS, Pavia (Italy)

    1995-12-01

    Antiproteases are known to be present in amyloid deposits. We evaluated the possibility of using an anti-serine protease (aprotinin) labelled with technetium-99m (TcA), usually employed as a cortical renal tracer, for the imaging of amyloid deposits. Because of the known high uptake of TcA by the kidneys, we limited our analysis to extra-abdominal amyloid localizations. We report the scintigraphic findings observed in 24 patients with light chain amyloidosis (AL) and one with a hereditary form who were known or suspected to have extra-abdominal involvement. Planar scans obtained 100 min after i.v. TcA administration showed myocardial accumulation in 11 patients, pleuropulmonary accumulation in nine, pericardial accumulation in two and localization in the neck region (thyroid, salivary glands and tongue) in eight. TcA scintigraphy was negative in five patients without clinical or laboratory evidence of extra-abdominal involvement, as well as in 12 control group patients with cardiac and renal diseases. These preliminary results indicate TcA to be a low-cost, readily available radiopharmaceutical for imaging of extra-abdominal involvement in AL type amyloidosis. (orig.)

  2. Amyloid in biopsies of the gastrointestinal tract-a retrospective observational study on 542 patients.

    Science.gov (United States)

    Freudenthaler, Sophie; Hegenbart, Ute; Schönland, Stefan; Behrens, Hans-Michael; Krüger, Sandra; Röcken, Christoph

    2016-05-01

    In this retrospective observational study, we investigated the histopathological and demographic characteristics of amyloid in gastrointestinal biopsies. From the Amyloid Registry Kiel, we retrieved all cases with amyloid in biopsies of the stomach, duodenum, small intestine, large intestine, and rectum submitted for tertiary referral between January 2003 and April 2013. Amyloid was identified by Congo red staining in combination with polarization microscopy and classified by immunohistochemistry. The TTR-genotype was assessed in 56 patients. Amyloid type was correlated with demographic patient characteristics. Six hundred sixty-three biopsies from 542 patients were retrieved. Amyloid was found in each biopsy as vascular and/or interstitial amyloid deposits. Biopsies were obtained from the colon [254 biopsies (38.3 %)], stomach, [153 (23.1 %)], rectum [112 (16.9 %)], duodenum [105 (15.8 %)], and jejunum/ileum [39 (5.9 %)]. ALλ amyloid was found in 286 (52.8 %), ATTR in 88 (16.2 %), ALκ in 74 (13.7 %), AA in 58 (10.7 %), and ApoAI amyloid in 4 (0.7 %) patients. The remaining 21 cases were ALys amyloid in 4 (0.7 %), AL n.o.s. in 14 (2.6 %), and mixed type amyloidosis in 3 (0.6 %). The amyloid of 11 (2.0 %) cases remained unclassified. The median age of the patients was 68 years. Men [332 (61.7 %)] were significantly more prevalent than women [206 (38.3 %); p < 0.001]. TTR mutations were found in 24 % of the patients with ATTR amyloidosis. The median age, the histoanatomical distribution (proximal to distal; mucosal to submucosal), and the deposition pattern (vascular/interstitial) varied between different amyloid types. Amyloid in gastrointestinal biopsies mainly affects male elderly patients and shows amyloid-type-specific demographic patient characteristics. PMID:26915034

  3. Visualisation of the deposited layer on the toroidal pumped limiter of Tore Supra using IR data during disruptions

    Energy Technology Data Exchange (ETDEWEB)

    Corre, Y.; Brosset, C.; Dufour, E.; Guilhem, D.; Lowry, C.; Mitteau, R.; Monier-Garbet, P.; Pegourie, B.; Tsitrone, E.; Vallet, S

    2005-07-01

    We propose here to visualize the deposited layer on the toroidal pump limiter (TPL) using IR data during disruptions. The area size and shape are, and this is the main advantage of using IR data during disruptions, investigated during the experimental campaigns. The IR system allows 2 dimensional measurement of temperature over a 60 degrees toroidal section of the actively cooled TPL located at the bottom of the vacuum vessel of Tore-Supra. It appears that IR monitoring during disruption is a powerful tool to visualize the deposited layer. The general pattern of the deposited layer viewed on the TPL is more or less constant on the centimeter scale over about 4000 pulses. The surfaces of the thickest and moderate deposition zone have been estimated to be in total onto the entire TPL about 0.4 and 0.22 m{sup 2} respectively. The thickest deposition zone shows different thermal intensities for a given heat flux possibly related to the thickness and/or the adhesion of the surface layer. Sharp heating and cooling time constant in the moderate deposition zone are indication of a very thin and well attached surface layer.

  4. Contagious Deposition of Seeds in Spider Monkeys' Sleeping Trees Limits Effective Seed Dispersal in Fragmented Landscapes

    OpenAIRE

    Arturo González-Zamora; Víctor Arroyo-Rodríguez; Federico Escobar; Matthias Rös; Ken Oyama; Guillermo Ibarra-Manríquez; Stoner, Kathryn E.; Colin A Chapman

    2014-01-01

    The repeated use of sleeping sites by frugivorous vertebrates promotes the deposition and aggregation of copious amounts of seeds in these sites. This spatially contagious pattern of seed deposition has key implications for seed dispersal, particularly because such patterns can persist through recruitment. Assessing the seed rain patterns in sleeping sites thus represents a fundamental step in understanding the spatial structure and regeneration of plant assemblages. We evaluated the seed rai...

  5. Cerebral amyloid angiopathy

    Science.gov (United States)

    ... Fenichel GM, Jankovic J, Mazziotta JC, eds. Bradley's Neurology in Clinical Practice . 6th ed. Philadelphia, PA: Elsevier ... al. Course of cerebral amyloid angiopathy-related inflammation. Neurology. 2007;68:1411-1416. PMID: 17452586 www.ncbi. ...

  6. Experimentally Derived Structural Constraints for Amyloid Fibrils of Wild-Type Transthyretin

    OpenAIRE

    Bateman, David A.; Tycko, Robert; Wickner, Reed B.

    2011-01-01

    Transthyretin (TTR) is a largely β-sheet serum protein responsible for transporting thyroxine and vitamin A. TTR is found in amyloid deposits of patients with senile systemic amyloidosis. TTR mutants lead to familial amyloidotic polyneuropathy and familial amyloid cardiomyopathy, with an earlier age of onset. Studies of amyloid fibrils of familial amyloidotic polyneuropathy mutant TTR suggest a structure similar to the native state with only a simple opening of a β-strand-loop-strand region e...

  7. Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein

    OpenAIRE

    Park, Laibaik; Zhou, Ping; Pitstick, Rose; Capone, Carmen; Anrather, Josef; Norris, Erin H.; Younkin, Linda; Younkin, Steven; Carlson, George; McEwen, Bruce S.; Iadecola, Costantino

    2008-01-01

    Alterations in cerebrovascular regulation related to vascular oxidative stress have been implicated in the mechanisms of Alzheimer's disease (AD), but their role in the amyloid deposition and cognitive impairment associated with AD remains unclear. We used mice overexpressing the Swedish mutation of the amyloid precursor protein (Tg2576) as a model of AD to examine the role of reactive oxygen species produced by NADPH oxidase in the cerebrovascular alterations, amyloid deposition, and behavio...

  8. In silico and in vitro studies to elucidate the role of Cu2+ and galanthamine as the limiting step in the amyloid beta (1-42) fibrillation process.

    Science.gov (United States)

    Hernández-Rodríguez, Maricarmen; Correa-Basurto, José; Benitez-Cardoza, Claudia G; Resendiz-Albor, Aldo Arturo; Rosales-Hernández, Martha C

    2013-10-01

    The formation of fibrils and oligomers of amyloid beta (Aβ) with 42 amino acid residues (Aβ 1-42 ) is the most important pathophysiological event associated with Alzheimer's disease (AD). The formation of Aβ fibrils and oligomers requires a conformational change from an α-helix to a β-sheet conformation, which is encouraged by the formation of a salt bridge between Asp 23 or Glu 22 and Lys 28. Recently, Cu(2+) and various drugs used for AD treatment, such as galanthamine (Reminyl(®) ), have been reported to inhibit the formation of Aβ fibrils. However, the mechanism of this inhibition remains unclear. Therefore, the aim of this work was to explore how Cu(2+) and galanthamine prevent the formation of Aβ1-42 fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that Aβ1-42 acquires a characteristic U-shape before the α-helix to β-sheet conformational change. The formation of a salt bridge between Asp 23 and Lys 28 was also observed beginning at 5 ns. However, the MD simulations of Aβ 1-42 in the presence of Cu(2+) or galanthamine demonstrated that both ligands prevent the formation of the salt bridge by either binding to Glu 22 and Asp 23 (Cu(2+) ) or to Lys 28 (galanthamine), which prevents Aβ 1-42 from adopting the U-characteristic conformation that allows the amino acids to transition to a β-sheet conformation. The docking results revealed that the conformation obtained by the MD simulation of a monomer from the 1Z0Q structure can form similar interactions to those obtained from the 2BGE structure in the oligomers. The in vitro studies demonstrated that Aβ remains in an unfolded conformation when Cu(2+) and galanthamine are used. Then, ligands that bind Asp 23 or Glu 22 and Lys 28 could therefore be used to prevent β turn formation and, consequently, the formation of Aβ fibrils.

  9. Adolescent exposure to MDMA induces dopaminergic toxicity in substantia nigra and potentiates the amyloid plaque deposition in the striatum of APPswe/PS1dE9 mice.

    Science.gov (United States)

    Abad, Sonia; Ramon, Carla; Pubill, David; Camarasa, Jorge; Camins, Antonio; Escubedo, Elena

    2016-09-01

    MDMA is one of the most used drugs by adolescents and its consumption has been associated with many psychobiological problems, among them psychomotor problems. Moreover, some authors described that early exposure to MDMA may render the dopaminergic neurons more vulnerable to the effects of future neurotoxic insults. Alzheimer disease (AD) is the main cause of dementia in the elderly and a percentage of the patients have predisposition to suffer nigrostriatal alterations, developing extrapyramidal signs. Nigrostriatal dysfunction in the brain of aged APPswe/PS1dE9 (APP/PS1), a mouse model of familiar AD (FAD), has also been described. The aim of the present study was to investigate the consequences of adolescent exposure to MDMA in APP/PS1 mice, on nigrostriatal function on early adulthood. We used a MDMA schedule simulating weekend binge abuse of this substance. Our MDMA schedule produced a genotype-independent decrease in dopaminergic neurons in the substantia nigra that remained at least 3months. Shortly after the injury, wild-type animals showed a decrease in the locomotor activity and apparent DA depletion in striatum, however in the APP/PS1 mice neither the locomotor activity nor the DA levels were modified, but a reduction in dopamine transporter (DAT) expression and a higher levels of oxidative stress were observed. We found that these disturbances are age-related characteristics that this APP/PS1 mice develops spontaneously much later. Therefore, MDMA administration seems to anticipate the striatal dopaminergic dysfunction in this FAD model. The most important outcome lies in a potentiation, by MDMA, of the amyloid beta deposition in the striatum. PMID:27344237

  10. De novo Amyloid Proteins from Designed Combinatorial Libraries

    Science.gov (United States)

    West, Michael W.; Wang, Weixun; Patterson, Jennifer; Mancias, Joseph D.; Beasley, James R.; Hecht, Michael H.

    1999-09-01

    Amyloid deposits are associated with several neurodegenerative diseases, including Alzheimer's disease and the prion diseases. The amyloid fibrils isolated from these different diseases share similar structural features. However, the protein sequences that assemble into these fibrils differ substantially from one disease to another. To probe the relationship between amino acid sequence and the propensity to form amyloid, we studied a combinatorial library of sequences designed de novo. All sequences in the library were designed to share an identical pattern of alternating polar and nonpolar residues, but the precise identities of these side chains were not constrained and were varied combinatorially. The resulting proteins self-assemble into large oligomers visible by electron microscopy as amyloid-like fibrils. Like natural amyloid, the de novo fibrils are composed of β -sheet secondary structure and bind the diagnostic dye, Congo red. Thus, binary patterning of polar and nonpolar residues arranged in alternating periodicity can direct protein sequences to form fibrils resembling amyloid. The model amyloid fibrils assemble and disassemble reversibly, providing a tractable system for both basic studies into the mechanisms of fibril assembly and the development of molecular therapies that interfere with this assembly.

  11. The Role of Deposition in Limiting the Hazard Extent of Dense-Gas Plumes

    Energy Technology Data Exchange (ETDEWEB)

    Dillon, M B

    2008-05-11

    Accidents that involve large (multi-ton) releases of toxic industrial chemicals and form dense-gas clouds often yield far fewer fatalities, casualties and environmental effects than standard assessment and emergency response models predict. This modeling study, which considers both dense-gas turbulence suppression and deposition to environmental objects (e.g. buildings), demonstrates that dry deposition to environmental objects may play a significant role in reducing the distance at which adverse impacts occur - particularly under low-wind, stable atmospheric conditions which are often considered to be the worst-case scenario for these types of releases. The degree to which the released chemical sticks to (or reacts with) environmental surfaces is likely a key parameter controlling hazard extents. In all modeled cases, the deposition to vertical surfaces of environmental objects (e.g. building walls) was more efficient in reducing atmospheric chemical concentrations than deposition to the earth's surface. This study suggests that (1) hazard extents may vary widely by release environment (e.g. grasslands vs. suburbia) and release conditions (e.g. sunlight or humidity may change the rate at which chemicals react with a surface) and (2) greenbelts (or similar structures) may dramatically reduce the impacts of large-scale releases. While these results are demonstrated to be qualitatively consistent with the downwind extent of vegetation damage in two chlorine releases, critical knowledge gaps exist and this study provides recommendations for additional experimental studies.

  12. The Role of Deposition in Limiting the Hazard Extent of Dense-Gas Plumes

    Energy Technology Data Exchange (ETDEWEB)

    Dillon, M B

    2008-01-29

    Accidents involving release of large (multi-ton) quantities of toxic industrial chemicals often yield far fewer fatalities and causalities than standard, widely-used assessment and emergency response models predict. While recent work has suggested that models should incorporate the protection provided by buildings, more refined health effect methodologies, and more detailed consideration of the release process; investigations into the role of deposition onto outdoor surfaces has been lacking. In this paper, we examine the conditions under which dry deposition may significantly reduce the extent of the downwind hazard zone. We provide theoretical arguments that in congested environments (e.g. suburbs, forests), deposition to vertical surfaces (such as building walls) may play a significant role in reducing the hazard zone extent--particularly under low-wind, stable atmospheric conditions which are often considered to be the worst-case scenario for these types of releases. Our analysis suggests that in these urban or suburban environments, the amount of toxic chemicals lost to earth's surface is typically a small fraction of overall depositional losses. For isothermal gases such as chlorine, the degree to which the chemicals stick to (or react with) surfaces (i.e. surface resistance) is demonstrated to be a key parameter controlling hazard extent (the maximum distance from the release at which hazards to human health are expected). This analysis does not consider the depositional effects associated with particulate matter or gases that undergo significant thermal change in the atmosphere. While no controlled experiments were available to validate our hypothesis, our analysis results are qualitatively consistent with the observed downwind extent of vegetation damage in two chlorine accidents.

  13. Inhibition of amyloid fibril formation of human amylin by N-alkylated amino acid and alpha-hydroxy acid residue containing peptides

    NARCIS (Netherlands)

    Rijkers, DTS; Hoppener, JWM; Posthuma, G; Lips, CJM; Liskamp, RMJ

    2002-01-01

    Amyloid deposits are formed as a result of uncontrolled aggregation of (poly)peptides or proteins. Today several diseases are known, for example Alzheimer's disease, Creutzfeldt-Jakob disease, mad cow disease, in which amyloid formation is involved. Amyloid fibrils are large aggregates of beta-pleat

  14. Size-Limited Penetration of Nanoparticles into Porcine Respiratory Mucus after Aerosol Deposition.

    Science.gov (United States)

    Murgia, Xabier; Pawelzyk, Paul; Schaefer, Ulrich F; Wagner, Christian; Willenbacher, Norbert; Lehr, Claus-Michael

    2016-04-11

    We investigated the rheological properties and the penetration of differently sized carboxylated nanoparticles in pig pulmonary mucus, on different distance and time scales. Nanoparticles were either mechanically mixed into the mucus samples or deposited as an aerosol, the latter resembling a more physiologically relevant delivery scenario. After mechanical dispersion, 500 nm particles were locally trapped; a fraction of carboxylated tracer particles of 100 or 200 nm in diameter could however freely diffuse in these networks over distances of approximately 20 μm. In contrast, after aerosol deposition on top of the mucus layer only particles with a size of 100 nm were able to penetrate into mucus, suggesting the presence of smaller pores at the air-mucus interface compared to within mucus. These findings are relevant to an understanding of the fate of potentially harmful aerosol particles, such as pathogens, pollutants, and other nanomaterials after incidental inhalation, as well as for the design of pulmonary drug delivery systems. PMID:26957140

  15. Amyloid Fibril Solubility

    CERN Document Server

    Rizzi, L G

    2015-01-01

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain side-chain interactions, backbone hydrogen bonding and temperature affect amyloid fibril solubility, which might prove a powerful tool to design protein fibrils with desired solubility and aggregation properties in general.

  16. 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...

  17. Neurotrophic and Neurotoxic Effects of Amyloid |beta Protein: Reversal by Tachykinin Neuropeptides

    Science.gov (United States)

    Yankner, Bruce A.; Duffy, Lawrence K.; Kirschner, Daniel A.

    1990-10-01

    The amyloid β protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid β protein was neurotrophic to undifferentiated hippocampal neurons at low concentrations and neurotoxic to mature neurons at higher concentrations. In differentiated neurons, amyloid β protein caused dendritic and axonal retraction followed by neuronal death. A portion of the amyloid β protein (amino acids 25 to 35) mediated both the trophic and toxic effects and was homologous to the tachykinin neuropeptide family. The effects of the amyloid β protein were mimicked by tachykinin antagonists and completely reversed by specific tachykinin agonists. Thus, the amyloid β protein could function as a neurotrophic factor for differentiating neurons, but at high concentrations in mature neurons, as in Alzheimer's disease, could cause neuronal degeneration.

  18. Depletion of spleen macrophages delays AA amyloid development: a study performed in the rapid mouse model of AA amyloidosis.

    Directory of Open Access Journals (Sweden)

    Katarzyna Lundmark

    Full Text Available AA amyloidosis is a systemic disease that develops secondary to chronic inflammatory diseases Macrophages are often found in the vicinity of amyloid deposits and considered to play a role in both formation and degradation of amyloid fibrils. In spleen reside at least three types of macrophages, red pulp macrophages (RPM, marginal zone macrophages (MZM, metallophilic marginal zone macrophages (MMZM. MMZM and MZM are located in the marginal zone and express a unique collection of scavenger receptors that are involved in the uptake of blood-born particles. The murine AA amyloid model that resembles the human form of the disease has been used to study amyloid effects on different macrophage populations. Amyloid was induced by intravenous injection of amyloid enhancing factor and subcutaneous injections of silver nitrate and macrophages were identified with specific antibodies. We show that MZMs are highly sensitive to amyloid and decrease in number progressively with increasing amyloid load. Total area of MMZMs is unaffected by amyloid but cells are activated and migrate into the white pulp. In a group of mice spleen macrophages were depleted by an intravenous injection of clodronate filled liposomes. Subsequent injections of AEF and silver nitrate showed a sustained amyloid development. RPMs that constitute the majority of macrophages in spleen, appear insensitive to amyloid and do not participate in amyloid formation.

  19. Urea-induced denaturation of apolipoprotein serum amyloid A reveals marginal stability of hexamer

    Science.gov (United States)

    Wang, Limin; Colón, Wilfredo

    2005-01-01

    Serum Amyloid A (SAA) is an acute phase reactant protein that is predominantly found bound to high-density lipoprotein in plasma. Upon inflammation, the plasma concentration of SAA can increase dramatically, occasionally leading to the development of amyloid A (AA) amyloidosis, which involves the deposition of SAA amyloid fibrils in major organs. We previously found that the murine isoform SAA2.2 exists in aqueous solution as a hexamer containing a central channel. Here we show using various biophysical and biochemical techniques that the SAA2.2 hexamer can be totally dissociated into monomer by ~2 M urea, with the concerted loss of its α-helical structure. However, limited trypsin proteolysis experiments in urea showed a conserved digestion profile, suggesting the preservation of major backbone topological features in the urea-denatured state of SAA2.2. The marginal stability of hexameric SAA2.2 and the presence of residual structure in the denatured monomeric protein suggest that both forms may interconvert in vivo to exert different functions to meet the various needs during normal physiological conditions and in response to inflammatory stimuli. PMID:15937280

  20. Atomic layer deposition-Sequential self-limiting surface reactions for advanced catalyst "bottom-up" synthesis

    Science.gov (United States)

    Lu, Junling; Elam, Jeffrey W.; Stair, Peter C.

    2016-06-01

    Catalyst synthesis with precise control over the structure of catalytic active sites at the atomic level is of essential importance for the scientific understanding of reaction mechanisms and for rational design of advanced catalysts with high performance. Such precise control is achievable using atomic layer deposition (ALD). ALD is similar to chemical vapor deposition (CVD), except that the deposition is split into a sequence of two self-limiting surface reactions between gaseous precursor molecules and a substrate. The unique self-limiting feature of ALD allows conformal deposition of catalytic materials on a high surface area catalyst support at the atomic level. The deposited catalytic materials can be precisely constructed on the support by varying the number and type of ALD cycles. As an alternative to the wet-chemistry based conventional methods, ALD provides a cycle-by-cycle "bottom-up" approach for nanostructuring supported catalysts with near atomic precision. In this review, we summarize recent attempts to synthesize supported catalysts with ALD. Nucleation and growth of metals by ALD on oxides and carbon materials for precise synthesis of supported monometallic catalyst are reviewed. The capability of achieving precise control over the particle size of monometallic nanoparticles by ALD is emphasized. The resulting metal catalysts with high dispersions and uniformity often show comparable or remarkably higher activity than those prepared by conventional methods. For supported bimetallic catalyst synthesis, we summarize the strategies for controlling the deposition of the secondary metal selectively on the primary metal nanoparticle but not on the support to exclude monometallic formation. As a review of the surface chemistry and growth behavior of metal ALD on metal surfaces, we demonstrate the ways to precisely tune size, composition and structure of bimetallic metal nanoparticles. The cycle-by-cycle "bottom up" construction of bimetallic (or multiple

  1. Limits of carrier mobility in Sb-doped SnO2 conducting films deposited by reactive sputtering

    Directory of Open Access Journals (Sweden)

    B. Bissig

    2015-06-01

    Full Text Available Electron transport in Sb-doped SnO2 (ATO films is studied to unveil the limited carrier mobility observed in sputtered films as compared to other deposition methods. Transparent and conductive ATO layers are deposited from metallic tin targets alloyed with antimony in oxygen atmosphere optimized for reactive sputtering. The carrier mobility decreases from 24 cm2 V−1 s−1 to 6 cm2 V−1 s−1 when increasing the doping level from 0 to 7 at. %, and the lowest resistivity of 1.8 × 10−3 Ω cm corresponding to the mobility of 12 cm2 V−1 s−1 which is obtained for the 3 at. % Sb-doped ATO. Temperature-dependent Hall effect measurements and near-infrared reflectance measurements reveal that the carrier mobility in sputtered ATO is limited by ingrain scattering. In contrast, the mobility of unintentionally doped SnO2 films is determined mostly by the grain boundary scattering. Both limitations should arise from the sputtering process itself, which suffers from the high-energy-ion bombardment and yields polycrystalline films with small grain size.

  2. Different responses of two Mosla species to potassium limitation in relation to acid rain deposition

    Institute of Scientific and Technical Information of China (English)

    Meng WANG; Bao-jing GU; Ying GE; Zhen LIU; De-an JIANG; Scott X. CHANG; Jie CHANG

    2009-01-01

    The increasingly serious problem of acid rain is leading to increased potassium (K) loss from soils, and in our field investigation, we found that even congenerically relative Mosla species show different tolerance to K-deficiency. A hydroponic study was conducted on the growth of two Mosla species and their morphological, physiological and stoichiometric traits in response to limited (0.35 mmol K/L), normal (3.25 mmol K/L) and excessive (6.50 mmol K/L) K concentrations. Mosla hang-chowensis is an endangered plant, whereas Mosla dianthera a widespread weed. In the case of M. hangchowensis, in comparison with normal K concentration, K-limitation induced a significant reduction in net photosynthetic rate (Pn), soluble protein content, and superoxide dismutase (SOD) activity, but an increase in malondialdehyde (MDA) concentration. However, leaf mass ratio (LMR) and root mass ratio (RMR) were changed little by K-limitation. In contrast, for M. dianthera, K-limitation had little effect on Pn, soluble protein content, SOD activity, and MDA concentration, but increased LMR and RMR. Critical values of N (nitrogen):K and K:P (phosphorus) ratios in the shoots indicated that limitation in acquiring K occurred under K-limited conditions for M. hangchowensis but not for M. dianthera. We found that low K content in natural habitats was a restrictive factor in the growth and distribution of M. hangchowensis, and soil K-deficiency caused by acid rain worsened the situation of M. hangchowensis, while M. dianthera could well acclimate to the increasing K-deficiency. We suggest that controlling the acid rain and applying K fertilizers may be an effective way to rescue the endangered M. hangchowensis.

  3. Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Kosicka, Iga

    2014-01-01

    Diabetes mellitus type II is a metabolic disease affecting millions of people worldwide. The disease is associated with occurence of insoluble, fibrillar, protein aggregates in islets of Langerhans in the pancreas - islet amyloid. The main constituent of these protein fibers is the human islet...

  4. Amyloid-β positron emission tomography imaging probes

    DEFF Research Database (Denmark)

    Kepe, Vladimir; Moghbel, Mateen C; Långström, Bengt;

    2013-01-01

    , a number of factors appear to preclude these probes from clinical utilization. As the available "amyloid specific" positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate...... on their significance has emerged. The aim of this review is to identify and discuss critically the scientific issues contributing to the extensive inconsistencies reported in the literature on their purported in vivo amyloid specificity and potential utilization in patients....

  5. Study of heat flux deposition on the limiter of the Tore Supra tokamak

    Energy Technology Data Exchange (ETDEWEB)

    Carpentier, S., E-mail: sophie.carpentier@cea.f [Ass. Euratom-CEA, DSM/IRFM, CEA Cadarache, F-13108 Saint-Paul-Lez-Durance (France); Corre, Y.; Chantant, M.; Daviot, R.; Dunand, G.; Gardarein, J.-L.; Gunn, J.; Kocan, M. [Ass. Euratom-CEA, DSM/IRFM, CEA Cadarache, F-13108 Saint-Paul-Lez-Durance (France); Le Niliot, C. [Ecole Polytechnique Universitaire de Marseille, I.U.S.T.I, UMR CNRS No 6595, Technopole de Chateau Gombert, F-13453 Marseille (France); Mitteau, R.; Moncada, V.; Monier-Garbet, P.; Pegourie, B.; Pocheau, C.; Reichle, R. [Ass. Euratom-CEA, DSM/IRFM, CEA Cadarache, F-13108 Saint-Paul-Lez-Durance (France); Rigollet, F. [Ecole Polytechnique Universitaire de Marseille, I.U.S.T.I, UMR CNRS No 6595, Technopole de Chateau Gombert, F-13453 Marseille (France); Saint-Laurent, F.; Travere, J.-M.; Tsitrone, E. [Ass. Euratom-CEA, DSM/IRFM, CEA Cadarache, F-13108 Saint-Paul-Lez-Durance (France)

    2009-06-15

    On the limiter of Tore Supra, the heat loads map computed from deconvolution of IR surface temperatures shows good agreement with calorimetry measurements. This experimental heat pattern allows deducing the heat fluxes in the scrape-off layer using a 3D magnetic calculation and assuming only parallel heat transport along field lines. This calculation leads to an underestimation of the power circulating in the edge plasma according to the power balance, similarly to RFA measurements. The comparison between experimental heat loads on the limiter and modelling also shows a spreading of heat fluxes near the LCFS that cannot be explained only by parallel transport in the SOL.

  6. Enoxaparin treatment administered at both early and late stages of amyloid beta deposition improves cognition of APPswe/PS1dE9 mice with differential effects on brain A beta levels.

    NARCIS (Netherlands)

    Timmer, N.M.; Dijk, L. van; Zee, C.E.E.M. van der; Kiliaan, A.J.; Waal, R.M.W. de; Verbeek, M.M.

    2010-01-01

    Enoxaparin (Enox), a low molecular weight heparin, has been shown to lower brain amyloid beta (A beta) load in a mouse model for Alzheimer's disease. However, the effect of Enox on cognition was not studied. Therefore, we examined the effect of peripheral Enox treatment on cognition and brain A beta

  7. Thermal Stability Threshold for Amyloid Formation in Light Chain Amyloidosis

    Directory of Open Access Journals (Sweden)

    Tanya L. Poshusta

    2013-11-01

    Full Text Available Light chain (AL amyloidosis is a devastating disease characterized by amyloid deposits formed by immunoglobulin light chains. Current available treatments involve conventional chemotherapy and autologous stem cell transplant. We have recently concluded a phase III trial comparing these two treatments. AL amyloidosis patients who achieve hematological complete response (CR do not necessarily achieve organ response regardless of the treatment they received. In order to investigate the possible correlation between amyloid formation kinetics and organ response, we selected AL amyloidosis patients from the trial with kidney involvement and CR after treatment. Six patients were selected and their monoclonal immunoglobulin light chains were characterized. The proteins showed differences in their stability and their kinetics of amyloid formation. A correlation was detected at pH 7.4, showing that less stable proteins are more likely to form amyloid fibrils. AL-T03 is too unstable to form amyloid fibrils at pH 7.4. This protein was found in the only patient in the study that had organ response, suggesting that partially folded species are required for amyloid formation to occur in AL amyloidosis.

  8. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Helen P McWilliams-Koeppen

    Full Text Available Light chain (AL amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(PH-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. These data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.

  9. B-Amyloid Precursor Protein Staining of the Brain in Sudden Infant and Early Childhood Death

    DEFF Research Database (Denmark)

    Jensen, Lisbeth Lund; Banner, Jytte; Ulhøi, Benedicte Parm;

    2013-01-01

    To develop and validate a scoring method for assessing β-amyloid precursor protein (APP) staining in cerebral white matter and to investigate the occurrence, amount and deposition pattern based on the cause of death in infants and young children.......To develop and validate a scoring method for assessing β-amyloid precursor protein (APP) staining in cerebral white matter and to investigate the occurrence, amount and deposition pattern based on the cause of death in infants and young children....

  10. Hot wire chemical vapor deposition: limits and opportunities of protecting the tungsten catalyzer from silicide with a cavity

    Energy Technology Data Exchange (ETDEWEB)

    Frigeri, P.A. [Dept. de Fisica Aplicada i Optica, Universitat de Barcelona, Barcelona-08028 (Spain); Nos, O., E-mail: oriol_nos@ub.ed [Dept. de Fisica Aplicada i Optica, Universitat de Barcelona, Barcelona-08028 (Spain); Ecotecnia (ALSTOM Group) (Spain); Bengoechea, S.; Frevert, C.; Asensi, J.M.; Bertomeu, J. [Dept. de Fisica Aplicada i Optica, Universitat de Barcelona, Barcelona-08028 (Spain)

    2009-04-30

    Hot Wire Chemical Vapor Deposition (HW-CVD) is one of the most promising techniques for depositing the intrinsic microcrystalline silicon layer for the production of micro-morph solar cells. However, the silicide formation at the colder ends of the tungsten wire drastically reduces the lifetime of the catalyzer, thus limiting its industrial exploitation. A simple but interesting strategy to decrease the silicide formation is to hide the electrical contacts of the catalyzer in a long narrow cavity which reduces the probability of the silane molecules to reach the colder ends of the wire. In this paper, the working mechanism of the cavity is elucidated. Measurements of the thickness profile of the silicon deposited in the internal walls of the cavity have been compared with those predicted using a simple diffusion model based on the assumption of Knudsen flow. A lifetime study of the protected and unprotected wires has been carried out. The different mechanisms which determine the deterioration of the catalyzer have been identified and discussed.

  11. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme.

    Science.gov (United States)

    Inestrosa, N C; Alvarez, A; Pérez, C A; Moreno, R D; Vicente, M; Linker, C; Casanueva, O I; Soto, C; Garrido, J

    1996-04-01

    Acetylcholinesterase (AChE), an important component of cholinergic synapses, colocalizes with amyloid-beta peptide (A beta) deposits of Alzheimer's brain. We report here that bovine brain AChE, as well as the human and mouse recombinant enzyme, accelerates amyloid formation from wild-type A beta and a mutant A beta peptide, which alone produces few amyloid-like fibrils. The action of AChE was independent of the subunit array of the enzyme, was not affected by edrophonium, an active site inhibitor, but it was affected by propidium, a peripheral anionic binding site ligand. Butyrylcholinesterase, an enzyme that lacks the peripheral site, did not affect amyloid formation. Furthermore, AChE is a potent amyloid-promoting factor when compared with other A beta-associated proteins. Thus, in addition to its role in cholinergic synapses, AChE may function by accelerating A beta formation and could play a role during amyloid deposition in Alzheimer's brain.

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

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Emily B.; Williams, Angela [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Heidel, Eric [Department of Surgery, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Macy, Sallie [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Kennel, Stephen J. [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Department of Radiology, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Wall, Jonathan S., E-mail: jwall@utmck.edu [Department of Medicine, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States); Department of Radiology, University of Tennessee Graduate School of Medicine, 1924 Alcoa Highway, Knoxville, TN 37922 (United States)

    2013-06-21

    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

  13. A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization.

    Directory of Open Access Journals (Sweden)

    Robert A Orlando

    Full Text Available Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD. The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved

  14. Amyloid Aggregation and Membrane Disruption by Amyloid Proteins

    Science.gov (United States)

    Ramamoorthy, Ayyalusamy

    2013-03-01

    Amyloidogenesis has been the focus of intense basic and clinical research, as an increasing number of amyloidogenic proteins have been linked to common and incurable degenerative diseases including Alzheimer's, type II diabetes, and Parkinson's. Recent studies suggest that the cell toxicity is mainly due to intermediates generated during the assembly process of amyloid fibers, which have been proposed to attack cells in a variety of ways. Disruption of cell membranes is believed to be one of the key components of amyloid toxicity. However, the mechanism by which this occurs is not fully understood. Our research in this area is focused on the investigation of the early events in the aggregation and membrane disruption of amyloid proteins, Islet amyloid polypeptide protein (IAPP, also known as amylin) and amyloid-beta peptide, on the molecular level. Structural insights into the mechanisms of membrane disruption by these amyloid proteins and the role of membrane components on the membrane disruption will be presented.

  15. Amyloids here, amyloids there…What’s wrong with them?

    OpenAIRE

    Gharibyan, Anna

    2012-01-01

    Amyloid formation is inherent property of proteins which under certain circumstances can become a pathologic feature of a group of diseases called amyloidosis. There are about 30 known human amyloidosis and more than 27 identified proteins involved in these pathologies.  Besides these proteins, there are a growing number of proteins non-related to diseases shown to form amyloid-like structures in vitro, which make them excellent tools for studying amyloid formation mechanisms, physicochemical...

  16. Current and future treatment of amyloid diseases.

    Science.gov (United States)

    Ankarcrona, M; Winblad, B; Monteiro, C; Fearns, C; Powers, E T; Johansson, J; Westermark, G T; Presto, J; Ericzon, B-G; Kelly, J W

    2016-08-01

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment. PMID:27165517

  17. Endocytosed 2-Microglobulin Amyloid Fibrils Induce Necrosis and Apoptosis of Rabbit Synovial Fibroblasts by Disrupting Endosomal/Lysosomal Membranes: A Novel Mechanism on the Cytotoxicity of Amyloid Fibrils.

    Directory of Open Access Journals (Sweden)

    Tadakazu Okoshi

    Full Text Available Dialysis-related amyloidosis is a major complication in long-term hemodialysis patients. In dialysis-related amyloidosis, β2-microglobulin (β2-m amyloid fibrils deposit in the osteoarticular tissue, leading to carpal tunnel syndrome and destructive arthropathy with cystic bone lesions, but the mechanism by which these amyloid fibrils destruct bone and joint tissue is not fully understood. In this study, we assessed the cytotoxic effect of β2-m amyloid fibrils on the cultured rabbit synovial fibroblasts. Under light microscopy, the cells treated with amyloid fibrils exhibited both necrotic and apoptotic changes, while the cells treated with β2-m monomers and vehicle buffer exhibited no morphological changes. As compared to β2-m monomers and vehicle buffer, β2-m amyloid fibrils significantly reduced cellular viability as measured by the lactate dehydrogenase release assay and the 3-(4,5-di-methylthiazol-2-yl-2,5-diphenyltetrazolium bromide reduction assay and significantly increased the percentage of apoptotic cells as measured by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method. β2-m amyloid fibrils added to the medium adhered to cell surfaces, but did not disrupt artificial plasma membranes as measured by the liposome dye release assay. Interestingly, when the cells were incubated with amyloid fibrils for several hours, many endosomes/lysosomes filled with amyloid fibrils were observed under confocal laser microscopy and electron microscopy, Moreover, some endosomal/lysosomal membranes were disrupted by intravesicular fibrils, leading to the leakage of the fibrils into the cytosol and adjacent to mitochondria. Inhibition of actin-dependent endocytosis by cytochalasin D attenuated the toxicity of amyloid fibrils. These results suggest that endocytosed β2-m amyloid fibrils induce necrosis and apoptosis by disrupting endosomal/lysosomal membranes, and this novel mechanism on the cytotoxicity of amyloid

  18. Effects of moxa and cigarette smoke on behavioral changes and brainβamyloid deposition in apoli-poprotein E-deficient mice%艾烟与香烟对载脂蛋白E基因敲除小鼠学习记忆功能与海马β淀粉样蛋白沉淀的影响

    Institute of Scientific and Technical Information of China (English)

    刘钧天; 崔莹雪; 黄玉海; 黄畅; 黄剑; 赵百孝; 韩丽; 杨佳; 王磊

    2015-01-01

    Objective To investigate the influence of moxa smoke and cigarette smoke on the apo-lipoprotein E-deficient ( ApoE-/-) male mice’ learning and memory ability andβamyloid deposition in brain hippocampus. Method 13 eight weeks old C57BL/6 mice were assigned to control group;27 eight weeks old ApoE-/- mice were randomly divided into 3 groups ( n=9/group): model group, moxa smoke group, cigarette smoke group. Mice in the two smoke groups were exposed to smoke, which concentration is con-trolled within 5~15 mg/m3;mice in model group and control group were exposed to normal air. The step-down test was conducted in the 13th week. Level ofβamyloid deposition was determined by congo red stai-ning. Results Compared with the model group, mice in control group, moxa smoke group and cigarette smoke group showed decreased learning latency, increased memory latency and made less mistakes in the step-down test (P< 0. 05). Compared with the model group,βamyloid deposition of control group, moxa smoke group and cigarette smoke group was significantly decreased ( P< 0. 05 ) . Conclusion Our find-ings suggest that moxa smoke may have effect on protecting nerve function and anti-aging by reducing the deposition of β amyloid in hippocampus.%目的:观察艾烟与香烟对载脂蛋白E基因敲除( apolipoprotein E-deficient,ApoE-/-)小鼠学习记忆能力与海马β淀粉样蛋白(β-Amyloid)沉淀的影响。方法将13只8周龄C57BL/6小鼠作为空白对照组,27只同龄ApoE-/-小鼠随机分为ApoE-/-模型组、艾烟组、香烟组。香烟与艾烟组小鼠分别暴露于5~15 mg/m3的香烟与艾烟环境。各组小鼠每天干预20分钟,每周6天,共干预12周。于第13周进行行为学测试,之后处死动物、取材,对其脑组织海马中Aβ沉淀进行刚果红染色。结果与模型组对比,空白对照组、艾烟组、香烟组小鼠均表现出学习潜伏期缩短,记忆潜伏期增长,记忆错误次数减少,差别有统计学意义( P<0.05)

  19. Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy

    Science.gov (United States)

    Dierksen, Gregory; Betensky, Rebecca; Gidicsin, Christopher; Halpin, Amy; Becker, Alex; Carmasin, Jeremy; Ayres, Alison; Schwab, Kristin; Viswanathan, Anand; Salat, David; Rosand, Jonathan; Johnson, Keith A.; Greenberg, Steven M.

    2012-01-01

    Objective: We aimed to determine whether amyloid imaging can help predict the location and number of future hemorrhages in cerebral amyloid angiopathy (CAA). Methods: We performed a longitudinal cohort study of 11 patients with CAA without dementia who underwent serial brain MRIs after baseline amyloid imaging with Pittsburgh compound B (PiB). Mean distribution volume ratio (DVR) of PiB was determined at the sites of new micro/macrobleeds identified on follow-up MRI and compared with PiB retention at “simulated” hemorrhages, randomly placed in the same subjects using a probability distribution map of CAA-hemorrhage location. Mean PiB retention at the sites of observed new bleeds was also compared to that in shells concentrically surrounding the bleeds. Finally the association between number of incident bleeds and 3 regional amyloid measures were obtained. Results: Nine of 11 subjects had at least one new microbleed on follow-up MRI (median 4, interquartile range [IQR] 1–9) and 2 had 5 new intracerebral hemorrhages. Mean DVR was greater at the sites of incident bleeds (1.34, 95% confidence interval [CI] 1.23–1.46) than simulated lesions (1.14, 95% CI 1.07–1.22, p < 0.0001) in multivariable models. PiB retention decreased with increasing distance from sites of observed bleeds (p < 0.0001). Mean DVR in a superior frontal/parasagittal region of interest correlated independently with number of future hemorrhages after adjustment for relevant covariates (p = 0.003). Conclusions: Our results provide direct evidence that new CAA-related hemorrhages occur preferentially at sites of increased amyloid deposition and suggest that PiB-PET imaging may be a useful tool in prediction of incident hemorrhages in patients with CAA. PMID:22786597

  20. Clinical use of amyloid-positron emission tomography neuroimaging: Practical and bioethical considerations.

    Science.gov (United States)

    Witte, Michael M; Foster, Norman L; Fleisher, Adam S; Williams, Monique M; Quaid, Kimberly; Wasserman, Michael; Hunt, Gail; Roberts, J Scott; Rabinovici, Gil D; Levenson, James L; Hake, Ann Marie; Hunter, Craig A; Van Campen, Luann E; Pontecorvo, Michael J; Hochstetler, Helen M; Tabas, Linda B; Trzepacz, Paula T

    2015-09-01

    Until recently, estimation of β-amyloid plaque density as a key element for identifying Alzheimer's disease (AD) pathology as the cause of cognitive impairment was only possible at autopsy. Now with amyloid-positron emission tomography (amyloid-PET) neuroimaging, this AD hallmark can be detected antemortem. Practitioners and patients need to better understand potential diagnostic benefits and limitations of amyloid-PET and the complex practical, ethical, and social implications surrounding this new technology. To complement the practical considerations, Eli Lilly and Company sponsored a Bioethics Advisory Board to discuss ethical issues that might arise from clinical use of amyloid-PET neuroimaging with patients being evaluated for causes of cognitive decline. To best address the multifaceted issues associated with amyloid-PET neuroimaging, we recommend this technology be used only by experienced imaging and treating physicians in appropriately selected patients and only in the context of a comprehensive clinical evaluation with adequate explanations before and after the scan. PMID:27239516

  1. In vivo amyloid aggregation kinetics tracked by time-lapse confocal microscopy in real-time.

    Science.gov (United States)

    Villar-Piqué, Anna; Espargaró, Alba; Ventura, Salvador; Sabate, Raimon

    2016-01-01

    Amyloid polymerization underlies an increasing number of human diseases. Despite this process having been studied extensively in vitro, aggregation is a difficult process to track in vivo due to methodological limitations and the slow kinetics of aggregation reactions in cells and tissues. Herein we exploit the amyloid properties of the inclusions bodies (IBs) formed by amyloidogenic proteins in bacteria to address the kinetics of in vivo amyloid aggregation. To this aim we used time-lapse confocal microscopy and a fusion of the amyloid-beta peptide (A β42) with a fluorescent reporter. This strategy allowed us to follow the intracellular kinetics of amyloid-like aggregation in real-time and to discriminate between variants exhibiting different in vivo aggregation propensity. Overall, the approach opens the possibility to assess the impact of point mutations as well as potential anti-aggregation drugs in the process of amyloid formation in living cells.

  2. Low-temperature self-limiting atomic layer deposition of wurtzite InN on Si(100

    Directory of Open Access Journals (Sweden)

    Ali Haider

    2016-04-01

    Full Text Available In this work, we report on self-limiting growth of InN thin films at substrate temperatures as low as 200 °C by hollow-cathode plasma-assisted atomic layer deposition (HCPA-ALD. The precursors used in growth experiments were trimethylindium (TMI and N2 plasma. Process parameters including TMI pulse time, N2 plasma exposure time, purge time, and deposition temperature have been optimized for self-limiting growth of InN with in ALD window. With the increase in exposure time of N2 plasma from 40 s to 100 s at 200 °C, growth rate showed a significant decrease from 1.60 to 0.64 Å/cycle. At 200 °C, growth rate saturated as 0.64 Å/cycle for TMI dose starting from 0.07 s. Structural, optical, and morphological characterization of InN were carried out in detail. X-ray diffraction measurements revealed the hexagonal wurtzite crystalline structure of the grown InN films. Refractive index of the InN film deposited at 200 °C was found to be 2.66 at 650 nm. 48 nm-thick InN films exhibited relatively smooth surfaces with Rms surface roughness values of 0.98 nm, while the film density was extracted as 6.30 g/cm3. X-ray photoelectron spectroscopy (XPS measurements depicted the peaks of indium, nitrogen, carbon, and oxygen on the film surface and quantitative information revealed that films are nearly stoichiometric with rather low impurity content. In3d and N1s high-resolution scans confirmed the presence of InN with peaks located at 443.5 and 396.8 eV, respectively. Transmission electron microscopy (TEM and selected area electron diffraction (SAED further confirmed the polycrystalline structure of InN thin films and elemental mapping revealed uniform distribution of indium and nitrogen along the scanned area of the InN film. Spectral absorption measurements exhibited an optical band edge around 1.9 eV. Our findings demonstrate that HCPA-ALD might be a promising technique to grow crystalline wurtzite InN thin films at low substrate temperatures.

  3. Cerebral Amyloid Angiopathy Burden Associated with Leukoaraiosis:a PET/MRI Study

    Science.gov (United States)

    Gurol, M. Edip; Viswanathan, Anand; Gidicsin, Christopher; Hedden, Trey; Ramirez-Martinez, Sergi; Dumas, Andrew; Vashkevich, Anastasia; Ayres, Alison M.; Auriel, Eitan; van Etten, Ellis; Becker, Alex; Carmasin, Jeremy; Schwab, Kristin; Rosand, Jonathan; Johnson, Keith A.; Greenberg, Steven M.

    2013-01-01

    Objective We hypothesized that vascular amyloid contributes to chronic brain ischemia, therefore amyloid burden measured by Pittsburgh Compound B retention on PET (PiB-PET) would correlate with the extent of MRI white matter hyperintensities (WMHor leukoaraiosis) in patients with high vascular amyloid deposition (Cerebral Amyloid Angiopathy, CAA) but not high parenchymal amyloid deposition (Alzheimer’s Disease, AD; Mild Cognitive Impairment, MCI) or healthy elderly (HE). Methods Fourty-two non-demented CAA patients, 50 HE subjects and 43 AD/MCI patients had brain MRI and PiB-PET. Multivariate linear regression was used to assess the independent association between PiB retention and WMD volume controlling for age, gender, apolipoprotein E genotype, and vascular risk factors within each group. Results CAA patients were younger than HE and AD (68±10 vs 73.3±7 and 74±7.4, p<0.01) but had higher amounts of WMH (medians: 21ml vs 3.2ml and 10.8ml respectively, p<0.05 for both comparisons). Global PiB retention and WMH showed strong correlation (rho=0.52, p<0.001) in the CAA group but not in HE or AD. These associations did not change in the multivariate models. Lobar microbleed count, another marker of CAA severity also remained as an independent predictor of WMH volume. Interpretation Our results indicate that amyloid burden in CAA subjects (with primarily vascular amyloid) but not AD subjects (with primarily parenchymal amyloid) independently correlate with WMH volume. These findings support the idea that vascular amyloid burden directly contributes to chronic cerebral ischemia and highlights the possible utility of amyloid imaging as a marker of CAA severity. PMID:23424091

  4. 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.

  5. Hacking the code of amyloid formation: the amyloid stretch hypothesis.

    Science.gov (United States)

    Pastor, M Teresa; Esteras-Chopo, Alexandra; Serrano, Luis

    2007-01-01

    Many research efforts in the last years have been directed towards understanding the factors determining protein misfolding and amyloid formation. Protein stability and amino acid composition have been identified as the two major factors in vitro. The research of our group has been focused on understanding the relationship between amino acid sequence and amyloid formation. Our approach has been the design of simple model systems that reproduce the biophysical properties of natural amyloids. An amyloid sequence pattern was extracted that can be used to detect amyloidogenic hexapeptide stretches in proteins. We have added evidence supporting that these amyloidogenic stretches can trigger amyloid formation by nonamyloidogenic proteins. Some experimental results in other amyloid proteins will be analyzed under the conclusions obtained in these studies. Our conclusions together with evidences from other groups suggest that amyloid formation is the result of the interplay between a decrease of protein stability, and the presence of highly amyloidogenic regions in proteins. As many of these results have been obtained in vitro, the challenge for the next years will be to demonstrate their validity in in vivo systems.

  6. Exons 16 and 17 of the amyloid precursor protein gene in familial inclusion body myopathy.

    Science.gov (United States)

    Sivakumar, K; Cervenáková, L; Dalakas, M C; Leon-Monzon, M; Isaacson, S H; Nagle, J W; Vasconcelos, O; Goldfarb, L G

    1995-08-01

    Accumulation of beta-amyloid protein (A beta) occurs in some muscle fibers of patients with inclusion body myopathy and resembles the type of amyloid deposits seen in the affected tissues of patients with Alzheimer's disease and cerebrovascular amyloidosis. Because mutations in exons 16 and 17 of the beta-amyloid precursor protein (beta APP) gene on chromosome 21 have been identified in patients with early-onset familial Alzheimer's disease and Dutch-type cerebrovascular amyloidosis, we searched for mutations of the same region in patients with familial inclusion body myopathy. Sequencing of both alleles in 8 patients from four unrelated families did not reveal any mutations in these exons. The amyloid deposition in familial forms of inclusion body myopathy may be either due to errors in other gene loci, or it is secondary reflecting altered beta APP metabolism or myocyte degeneration and cell membrane degradation.

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

    Directory of Open Access Journals (Sweden)

    Mathieu D. Santin

    2016-03-01

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

  8. Divalent cation tolerance protein binds to β-secretase and inhibits the processing of amyloid precursor protein

    Institute of Scientific and Technical Information of China (English)

    Runzhong Liu; Haibo Hou; Xuelian Yi; Shanwen Wu; Huan Zeng

    2013-01-01

    The deposition of amyloid-beta is a pathological hallmark of Alzheimer's disease. Amyloid-beta is derived from amyloid precursor protein through sequential proteolytic cleavages by β-secretase (beta-site amyloid precursor protein-cleaving enzyme 1) and γ-secretase. To further elucidate the roles of beta-site amyloid precursor protein-cleaving enzyme 1 in the development of Alzheimer's disease, a yeast two-hybrid system was used to screen a human embryonic brain cDNA library for proteins directly interacting with the intracellular domain of beta-site amyloid precursor protein-cleaving enzyme 1. A potential beta-site amyloid precursor protein-cleaving enzyme 1- interacting protein identified from the positive clones was divalent cation tolerance protein. Immunoprecipitation studies in the neuroblastoma cell line N2a showed that exogenous divalent cation tolerance protein interacts with endogenous beta-site amyloid precursor protein-cleaving enzyme 1. The overexpression of divalent cation tolerance protein did not affect beta-site amyloid precursor protein-cleaving enzyme 1 protein levels, but led to increased amyloid precursor protein levels in N2a/APP695 cells, with a concomitant reduction in the processing product amyloid precursor protein C-terminal fragment, indicating that divalent cation tolerance protein inhibits the processing of amyloid precursor protein. Our experimental findings suggest that divalent cation tolerance protein negatively regulates the function of beta-site amyloid precursor protein-cleaving enzyme 1. Thus, divalent cation tolerance protein could play a protective role in Alzheimer's disease.

  9. LRP1 in Brain Vascular Smooth Muscle Cells Mediates Local Clearance of Alzheimer's Amyloid

    OpenAIRE

    Kanekiyo, Takahisa; Liu, Chia-Chen; Shinohara, Mitsuru; Li, Jie; Bu, Guojun

    2012-01-01

    Impaired clearance of amyloid-β (Aβ) is a major pathogenic event for Alzheimer’s disease (AD). Aβ depositions in brain parenchyma as senile plaques and along cerebrovasculature as cerebral amyloid angiopathy (CAA) are hallmarks of AD. A major pathway that mediates brain Aβ clearance is the cerebrovascular system where Aβ is eliminated through the blood-brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An Aβ clearance receptor, the low-...

  10. Late-onset familial amyloid polyneuropathy (FAP) Val30Met without family history.

    OpenAIRE

    Rudolph, Thomas; Kurz, Martin Wilhelm; Farbu, Elisabeth

    2009-01-01

    Familial amyloid polyneuropathy (FAP) is rare and most commonly caused by the Val30Met mutation of the transthyretin (TTR) gene. Beside polyneuropathy, other complications due to amyloid deposits occur, but may vary in phenotype. The mutation tends to occur in endemic clusters. We describe a 65-year-old man from a non-endemic FAPVal30Met area who developed a progressive generalized painless axonal sensorimotor polyneuropathy with mild autonomic involvement and absent FAP symptoms in the famil...

  11. Skin deposits in hereditary cystatin C amyloidosis

    DEFF Research Database (Denmark)

    Benedikz, Eirikur; Blöndal, H; Gudmundsson, G

    1990-01-01

    Clinically normal skin from 47 individuals aged 9-70 years was investigated. Cystatin C amyloid deposits were found in various locations of the skin by light and/or electron microscopy, in all 12 patients with a clinical history of hereditary cystatin C amyloidosis (HCCA). Six asymptomatic...... individuals, who had the Alu 1 restriction fragment length polymorphism (RFLP) marker reported to cosegregate with the disease, also had cystatin C amyloid deposits in the skin. Three asymptomatic individuals (age 17-46) belonging to the HCCA families were without amyloid in the skin but had Alu 1 RFLP marker...

  12. Data on amyloid precursor protein accumulation, spontaneous physical activity, and motor learning after traumatic brain injury in the triple-transgenic mouse model of Alzheimer׳s disease.

    Science.gov (United States)

    Kishimoto, Yasushi; Shishido, Hajime; Sawanishi, Mayumi; Toyota, Yasunori; Ueno, Masaki; Kubota, Takashi; Kirino, Yutaka; Tamiya, Takashi; Kawai, Nobuyuki

    2016-12-01

    This data article contains supporting information regarding the research article entitled "Traumatic brain injury accelerates amyloiddeposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer׳s disease" (H. Shishido, Y. Kishimoto, N. Kawai, Y. Toyota, M. Ueno, T. Kubota, Y. Kirino, T. Tamiya, 2016) [1]. Triple-transgenic (3×Tg)-Alzheimer׳s disease (AD) model mice exhibited significantly poorer spatial learning than sham-treated 3×Tg-AD mice 28 days after traumatic brain injury (TBI). Correspondingly, amyloid-β (Aβ) deposition within the hippocampus was significantly greater in 3×Tg-AD mice 28 days after TBI. However, data regarding the short-term and long-term influences of TBI on amyloid precursor protein (APP) accumulation in AD model mice remain limited. Furthermore, there is little data showing whether physical activity and motor learning are affected by TBI in AD model mice. Here, we provide immunocytochemistry data confirming that TBI induces significant increases in APP accumulation in 3×Tg-AD mice at both 7 days and 28 days after TBI. Furthermore, 3×Tg-AD model mice exhibit a reduced ability to acquire conditioned responses (CRs) during delay eyeblink conditioning compared to sham-treated 3×Tg-AD model mice 28 days after TBI. However, physical activity and motor performance are not significantly changed in TBI-treated 3×Tg-AD model mice. PMID:27656663

  13. Data on amyloid precursor protein accumulation, spontaneous physical activity, and motor learning after traumatic brain injury in the triple-transgenic mouse model of Alzheimer׳s disease.

    Science.gov (United States)

    Kishimoto, Yasushi; Shishido, Hajime; Sawanishi, Mayumi; Toyota, Yasunori; Ueno, Masaki; Kubota, Takashi; Kirino, Yutaka; Tamiya, Takashi; Kawai, Nobuyuki

    2016-12-01

    This data article contains supporting information regarding the research article entitled "Traumatic brain injury accelerates amyloiddeposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer׳s disease" (H. Shishido, Y. Kishimoto, N. Kawai, Y. Toyota, M. Ueno, T. Kubota, Y. Kirino, T. Tamiya, 2016) [1]. Triple-transgenic (3×Tg)-Alzheimer׳s disease (AD) model mice exhibited significantly poorer spatial learning than sham-treated 3×Tg-AD mice 28 days after traumatic brain injury (TBI). Correspondingly, amyloid-β (Aβ) deposition within the hippocampus was significantly greater in 3×Tg-AD mice 28 days after TBI. However, data regarding the short-term and long-term influences of TBI on amyloid precursor protein (APP) accumulation in AD model mice remain limited. Furthermore, there is little data showing whether physical activity and motor learning are affected by TBI in AD model mice. Here, we provide immunocytochemistry data confirming that TBI induces significant increases in APP accumulation in 3×Tg-AD mice at both 7 days and 28 days after TBI. Furthermore, 3×Tg-AD model mice exhibit a reduced ability to acquire conditioned responses (CRs) during delay eyeblink conditioning compared to sham-treated 3×Tg-AD model mice 28 days after TBI. However, physical activity and motor performance are not significantly changed in TBI-treated 3×Tg-AD model mice.

  14. An overview on therapeutics attenuating amyloid β level in Alzheimer's disease: targeting neurotransmission, inflammation, oxidative stress and enhanced cholesterol levels.

    Science.gov (United States)

    Zhou, Xiaoling; Li, Yifei; Shi, Xiaozhe; Ma, Chun

    2016-01-01

    Alzheimer's disease (AD) is the most common underlying cause of dementia, and novel drugs for its treatment are needed. Of the different theories explaining the development and progression of AD, "amyloid hypothesis" is the most supported by experimental data. This hypothesis states that the cleavage of amyloid precursor protein (APP) leads to the formation of amyloid beta (Aβ) peptides that congregate with formation and deposition of Aβ plaques in the frontal cortex and hippocampus. Risk factors including neurotransmitter modulation, chronic inflammation, metal-induced oxidative stress and elevated cholesterol levels are key contributors to the disease progress. Current therapeutic strategies abating AD progression are primarily based on anti-acetylcholinesterase (AChE) inhibitors as cognitive enhancers. The AChE inhibitor, donepezil, is proven to strengthen cognitive functions and appears effective in treating moderate to severe AD patients. N-Methyl-D-aspartate receptor antagonist, memantine, is also useful, and its combination with donepezil demonstrated a strong stabilizing effect in clinical studies on AD. Nonsteroidal anti-inflammatory drugs delayed the onset and progression of AD and attenuated cognitive dysfunction. Based upon epidemiological evidence and animal studies, antioxidants emerged as potential AD preventive agents; however, clinical trials revealed inconsistencies. Pharmacokinetic and pharmacodynamic profiling demonstrated pleiotropic functions of the hypolipidemic class of drugs, statins, potentially contributing towards the prevention of AD. In addition, targeting the APP processing pathways, stimulating neuroprotective signaling mechanisms, using the amyloid anti-aggregants and Aβ immunotherapy surfaced as well-tested strategies in reducing the AD-like pathology. Overall, this review covers mechanism of inducing the Aβ formation, key risk factors and major therapeutics prevalent in the AD treatment nowadays. It also delineates the need

  15. 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.

  16. Cognitive functioning in relation to brain amyloid-β in healthy adults with Down syndrome.

    Science.gov (United States)

    Hartley, Sigan L; Handen, Benjamin L; Devenny, Darlynne A; Hardison, Regina; Mihaila, Iulia; Price, Julie C; Cohen, Annie D; Klunk, William E; Mailick, Marsha R; Johnson, Sterling C; Christian, Bradley T

    2014-09-01

    Nearly all adults with Down syndrome show neuropathology of Alzheimer's disease, including amyloiddeposition, by their fifth decade of life. In the current study, we examined the association between brain amyloiddeposition, assessed via in vivo assessments of neocortical Pittsburgh compound B, and scores on an extensive neuropsychological battery of measures of cognitive functioning in 63 adults (31 male, 32 female) with Down syndrome aged 30-53 years who did not exhibit symptoms of dementia. Twenty-two of the adults with Down syndrome were identified as having elevated neocortical Pittsburgh compound B retention levels. There was a significant positive correlation (r = 0.62, P Down syndrome who had elevated neocortical Pittsburgh compound B retention levels and those who did not on any of the neuropsychological measures. Similarly, when examining Pittsburgh compound B as a continuous variable, after controlling for mental age and chronological age, only the Rivermead Picture Recognition score was significantly negatively associated with neocortical Pittsburgh compound B retention. Our findings indicate that many adults with Down syndrome can tolerate amyloiddeposition without deleterious effects on cognitive functioning. However, we may have obscured true effects of amyloiddeposition by controlling for chronological age in our analyses. Moreover, our sample included adults with Down syndrome who were most 'resistant' to the effects of amyloiddeposition, as adults already exhibiting clinical symptoms of dementia symptoms were excluded from the study.

  17. Prediction of Peptide and Protein Propensity for Amyloid Formation.

    Science.gov (United States)

    Família, Carlos; Dennison, Sarah R; Quintas, Alexandre; Phoenix, David A

    2015-01-01

    Understanding which peptides and proteins have the potential to undergo amyloid formation and what driving forces are responsible for amyloid-like fiber formation and stabilization remains limited. This is mainly because proteins that can undergo structural changes, which lead to amyloid formation, are quite diverse and share no obvious sequence or structural homology, despite the structural similarity found in the fibrils. To address these issues, a novel approach based on recursive feature selection and feed-forward neural networks was undertaken to identify key features highly correlated with the self-assembly problem. This approach allowed the identification of seven physicochemical and biochemical properties of the amino acids highly associated with the self-assembly of peptides and proteins into amyloid-like fibrils (normalized frequency of β-sheet, normalized frequency of β-sheet from LG, weights for β-sheet at the window position of 1, isoelectric point, atom-based hydrophobic moment, helix termination parameter at position j+1 and ΔG° values for peptides extrapolated in 0 M urea). Moreover, these features enabled the development of a new predictor (available at http://cran.r-project.org/web/packages/appnn/index.html) capable of accurately and reliably predicting the amyloidogenic propensity from the polypeptide sequence alone with a prediction accuracy of 84.9 % against an external validation dataset of sequences with experimental in vitro, evidence of amyloid formation. PMID:26241652

  18. Prediction of Peptide and Protein Propensity for Amyloid Formation.

    Directory of Open Access Journals (Sweden)

    Carlos Família

    Full Text Available Understanding which peptides and proteins have the potential to undergo amyloid formation and what driving forces are responsible for amyloid-like fiber formation and stabilization remains limited. This is mainly because proteins that can undergo structural changes, which lead to amyloid formation, are quite diverse and share no obvious sequence or structural homology, despite the structural similarity found in the fibrils. To address these issues, a novel approach based on recursive feature selection and feed-forward neural networks was undertaken to identify key features highly correlated with the self-assembly problem. This approach allowed the identification of seven physicochemical and biochemical properties of the amino acids highly associated with the self-assembly of peptides and proteins into amyloid-like fibrils (normalized frequency of β-sheet, normalized frequency of β-sheet from LG, weights for β-sheet at the window position of 1, isoelectric point, atom-based hydrophobic moment, helix termination parameter at position j+1 and ΔG° values for peptides extrapolated in 0 M urea. Moreover, these features enabled the development of a new predictor (available at http://cran.r-project.org/web/packages/appnn/index.html capable of accurately and reliably predicting the amyloidogenic propensity from the polypeptide sequence alone with a prediction accuracy of 84.9 % against an external validation dataset of sequences with experimental in vitro, evidence of amyloid formation.

  19. Amyloid Structure and Assembly: Insights from Scanning Transmission Electron Microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Goldsbury, C.; Wall, J.; Baxa, U.; Simon, M. N.; Steven, A. C.; Engel, A.; Aebi, U.; Muller, S. A.

    2011-01-01

    Amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as Alzheimer's disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR).

  20. Amyloid polyneuropathy caused by wild-type transthyretin

    OpenAIRE

    Lam, L.; Margeta, M; Layzer, R

    2015-01-01

    © 2015 Wiley Periodicals, Inc. Introduction: Amyloidosis derived from transthyretin (TTR) molecules is typically caused by mutations of the TTR gene. Methods: We describe an elderly patient with a severe length-dependent polyneuropathy that unexpectedly proved to be caused by wild-type transthyretin amyloidosis. Results: The diagnosis was made by muscle biopsy, because no amyloid deposits were found in the biopsied nerve segment. Most cases of wild-type transthyretin amyloidosis occur in elde...

  1. 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

  2. In vitro fibrillization of Alzheimer's amyloid-β peptide (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.

  3. In vitro fibrillization of Alzheimer’s amyloid-β peptide (1-42

    Directory of Open Access Journals (Sweden)

    Ann Tiiman

    2015-09-01

    Full Text Available 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.

  4. Towards a Pharmacophore for Amyloid

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-09-16

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

  5. Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease.

    Science.gov (United States)

    Rockenstein, Edward; Torrance, Magdalena; Mante, Michael; Adame, Anthony; Paulino, Amy; Rose, John B; Crews, Leslie; Moessler, Herbert; Masliah, Eliezer

    2006-05-15

    Cerebrolysin is a peptide mixture with neurotrophic effects that might reduce the neurodegenerative pathology in Alzheimer's disease (AD). We have previously shown in an amyloid protein precursor (APP) transgenic (tg) mouse model of AD-like neuropathology that Cerebrolysin ameliorates behavioral deficits, is neuroprotective, and decreases amyloid burden; however, the mechanisms involved are not completely clear. Cerebrolysin might reduce amyloid deposition by regulating amyloid-beta (Abeta) degradation or by modulating APP expression, maturation, or processing. To investigate these possibilities, APP tg mice were treated for 6 months with Cerebrolysin and analyzed in the water maze, followed by RNA, immunoblot, and confocal microscopy analysis of full-length (FL) APP and its fragments, beta-secretase (BACE1), and Abeta-degrading enzymes [neprilysin (Nep) and insulin-degrading enzyme (IDE)]. Consistent with previous studies, Cerebrolysin ameliorated the performance deficits in the spatial learning portion of the water maze and reduced the synaptic pathology and amyloid burden in the brains of APP tg mice. These effects were associated with reduced levels of FL APP and APP C-terminal fragments, but levels of BACE1, Notch1, Nep, and IDE were unchanged. In contrast, levels of active cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3beta [GSK-3beta; but not stress-activated protein kinase-1 (SAPK1)], kinases that phosphorylate APP, were reduced. Furthermore, Cerebrolysin reduced the levels of phosphorylated APP and the accumulation of APP in the neuritic processes. Taken together, these results suggest that Cerebrolysin might reduce AD-like pathology in the APP tg mice by regulating APP maturation and transport to sites where Abeta protein is generated. This study clarifies the mechanisms through which Cerebrolysin might reduce Abeta production and deposition in AD and further supports the importance of this compound in the potential treatment of early AD.

  6. Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy

    Science.gov (United States)

    Reijmer, Yael D.; Fotiadis, Panagiotis; Martinez-Ramirez, Sergi; Salat, David H.; Schultz, Aaron; Shoamanesh, Ashkan; Ayres, Alison M.; Vashkevich, Anastasia; Rosas, Diana; Schwab, Kristin; Leemans, Alexander; Biessels, Geert-Jan; Rosand, Jonathan; Johnson, Keith A.; Viswanathan, Anand; Gurol, M. Edip

    2015-01-01

    Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = −0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging

  7. Protection of the blood-brain barrier by pentosan against amyloid-β-induced toxicity.

    Science.gov (United States)

    Deli, Mária A; Veszelka, Szilvia; Csiszár, Boglárka; Tóth, Andrea; Kittel, Agnes; Csete, Mária; Sipos, Aron; Szalai, Anikó; Fülöp, Lívia; Penke, Botond; Abrahám, Csongor S; Niwa, Masami

    2010-01-01

    Endothelial cells of brain capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer's disease. Amyloid-β (Aβ) peptides are key pathological elements in the development of the disease. A blood-brain barrier model, based on primary rat brain endothelial cells was used in which the barrier properties were induced by glial cells. The effects of amyloid peptides have been tested on cell viability and barrier functions. Aβ showed toxic effects on primary rat brain endothelial cells measured by MTT dye conversion and the lactate dehydrogenase release. Morphologically cytoplasmic vacuolization, disruption of the structure of cytoplasmic organelles and tight junctions could be observed in brain endothelial cells. Treatment with Aβ1-42 decreased the electrical resistance, and increased the permeability of brain endothelial cell monolayers for both fluorescein and albumin. Serum amyloid P component which stabilizes Aβ fibrils in cortical amyloid plaques and cerebrovascular amyloid deposits significantly potentiated the barrier-weakening effect of Aβ1-42. Sulfated polysaccharide pentosan could decrease the toxic effects of Aβ peptides in brain endothelial cells. It could also significantly protect the barrier integrity of monolayers from damaging actions of peptides. Pentosan modified the size, and significantly decreased the number of amyloid aggregates demonstrated by atomic force microscopy. The present data further support the toxic effects of amyloid peptides on brain endothelial cells, and can contribute to the development of molecules protecting the blood-brain barrier in Alzheimer's disease.

  8. Degeneration of beta-amyloid-associated cholinergic structures in transgenic APP SW mice.

    Science.gov (United States)

    Lüth, Hans-Joachim; Apelt, Jenny; Ihunwo, Amadi O; Arendt, Thomas; Schliebs, Reinhard

    2003-07-01

    Cholinergic dysfunction is a consistent feature of Alzheimer's disease, and the interrelationship between beta-amyloid deposits, inflammation and early cholinergic cell loss is still not fully understood. To characterize the mechanisms by which beta-amyloid and pro-inflammatory cytokines may exert specific degenerating actions on cholinergic cells ultrastructural investigations by electron microscopy were performed in brain sections from transgenic Tg2576 mice that express the Swedish double mutation of the human amyloid precursor protein and progressively develop beta-amyloid plaques during aging. Both light and electron microscopical investigations of the cerebral cortex of 19-month-old transgenic mice revealed a number of pathological tissue responses in close proximity of beta-amyloid plaques, such as activated microglia, astroglial proliferation, increased number of fibrous astrocytes, brain edema, degeneration of nerve cells, dendrites and axon terminals. Ultrastructural detection of choline acetyl transferase (ChAT)-immunostaining in cerebral cortical sections of transgenic mice clearly demonstrated degeneration of ChAT-immunoreactive fibres in the environment of beta-amyloid plaques and activated glial cells suggesting a role of beta-amyloid and/or inflammation in specific degeneration of cholinergic synaptic structures. PMID:12788508

  9. Visualization of microhemorrhages with optical histology in mouse model of cerebral amyloid angiopathy (Conference Presentation)

    Science.gov (United States)

    Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly; Choi, Bernard

    2016-03-01

    Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microhemorrhages. Conventional methods, such as magnetic resonance imaging (MRI), can detect microhemorrhages while positron emission tomography (PET) with Pittsburgh Compound B can detect amyloid deposits. MRI and PET can separately demonstrate the presence of microhemorrhages and CAA in affected brains in vivo; however, there is still a lack of strong evidence for the direct involvement of CAA in the presence of microhemorrhage formation. In this study, we use optical histology, a method which combines histochemical staining, chemical optical clearing, and optical imaging, in a Tg2576 mouse model of Alzheimer's disease to enable simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microhemorrhages, and amyloid deposits. Our data strongly suggest that microhemorrhages are localized within the brain regions affected by amyloid deposits. All but two observed microhemorrhages (n=18) were closely localized with vessels affected by CAA whereas no microhemorrhages or amyloid deposits were observed in wild type mouse brain sections. Our data also suggest that the predominant type of CAA-related microhemorrhage is associated with leaky or ruptured hemorrhagic microvasculature within the hippocampus and cerebral cortex rather than occluded ischemic microvasculature. The proposed optical histology method will allow future studies about the relationship between CAA and microhemorrhages during disease development and in response to treatment strategies.

  10. Histochemical Differential Diagnosis and Polarization Optical Analysis of Amyloid and Amyloidosis

    Directory of Open Access Journals (Sweden)

    M. Bély

    2006-01-01

    Full Text Available Amyloidosis is characterized by extracellular deposition of protein fibrils of chemically heterogeneous composition. Early recognition and identification of amyloid deposits allows an early start of therapy, which may entail a better prognosis. Congo red staining according to Romhányi (1971 is a highly specific and sensitive method for early microscopic recognition of amyloidosis. The main and most important types of amyloidosis may be distinguished by classic histochemical methods of performate pretreatment according to Romhányi (1979, or by KMnO4 oxidation according to Wright (1977 followed by Congo red staining and viewed under polarized light. Differences in the speed of breakdown (disintegration of amyloid deposits according to Bély and Apáthy allow a more precise distinction of various types of amyloid.

  11. The development of cerebral amyloid angiopathy in cerebral vessels. A review with illustrations based upon own investigated post mortem cases.

    Science.gov (United States)

    Mendel, T A; Wierzba-Bobrowicz, T; Lewandowska, E; Stępień, T; Szpak, G M

    2013-12-01

    The process of β-amyloid accumulation in cerebral vessels is presented. Cerebral amyloid angiopathy (CAA) was confirmed during an autopsy. It was diagnosed according to the Boston criteria. Cerebral amyloid angiopathy can involve all kinds of cerebral vessels (cortical and leptomeningeal arterioles, capillaries and veins). The development of CAA is a progressive process. β-amyloid appears first in the tunica media, surrounding smooth muscle cells, and in the adventitia. β-amyloid is progressively accumulated, causing a gradual loss of smooth muscle cells in the vessel wall and finally replacing them. Then, the detachment and delamination of the outer part of the tunica media results in the "double barrel" appearance, fibrinoid necrosis, and microaneurysm formation. Microbleeding with perivascular deposition of erythrocytes and blood breakdown products can also occur. β-amyloid can also be deposited in the surrounding of the affected vessels of the brain parenchyma, known as "dysphoric CAA". Ultrastructurally, when deposits of amyloid fibers were localized in or outside the arteriolar wall, the degenerating vascular smooth muscle cells were observed. In the Institute of Psychiatry and Neurology the study was carried out in a group of 48 patients who died due to intracerebral hemorrhage caused by sporadic CAA. PMID:24375040

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

    Science.gov (United States)

    Tosun, Duygu; Schuff, Norbert; Mathis, Chester A; Jagust, William; Weiner, Michael W

    2011-04-01

    Amyloid-β accumulation in the brain is thought to be one of the earliest events in Alzheimer's disease, possibly leading to synaptic dysfunction, neurodegeneration and cognitive/functional decline. The earliest detectable changes seen with neuroimaging appear to be amyloid-β accumulation detected by (11)C-labelled Pittsburgh compound B positron emission tomography imaging. However, some individuals tolerate high brain amyloid-β loads without developing symptoms, while others progressively decline, suggesting that events in the brain downstream from amyloiddeposition, such as regional brain atrophy rates, play an important role. The main purpose of this study was to understand the relationship between the regional distributions of increased amyloid-β and the regional distribution of increased brain atrophy rates in patients with mild cognitive impairment. To simultaneously capture the spatial distributions of amyloid-β and brain atrophy rates, we employed the statistical concept of parallel independent component analysis, an effective method for joint analysis of multimodal imaging data. Parallel independent component analysis identified significant relationships between two patterns of amyloiddeposition and atrophy rates: (i) increased amyloid-β burden in the left precuneus/cuneus and medial-temporal regions was associated with increased brain atrophy rates in the left medial-temporal and parietal regions; and (ii) in contrast, increased amyloid-β burden in bilateral precuneus/cuneus and parietal regions was associated with increased brain atrophy rates in the right medial temporal regions. The spatial distribution of increased amyloid-β and the associated spatial distribution of increased brain atrophy rates embrace a characteristic pattern of brain structures known for a high vulnerability to Alzheimer's disease pathology, encouraging for the use of (11)C-labelled Pittsburgh compound B positron emission tomography measures as early indicators of

  13. Immunotherapy against amyloid pathology in Alzheimer's disease.

    Science.gov (United States)

    Galimberti, Daniela; Ghezzi, Laura; Scarpini, Elio

    2013-10-15

    The first drugs developed for Alzheimer's disease (AD), anticholinesterase inhibitors (AchEI), increase acetylcholine levels, previously demonstrated to be reduced in AD. To date, four AchEI are approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine. These treatments are symptomatic, whereas drugs under development are supposed to modify pathological steps leading to AD, thus acting on the evolution of the disease. For this reason they are currently termed "disease modifying" drugs. To block the progression of the disease, they have to interfere with pathogenic steps at the basis of clinical symptoms, including the deposition of extracellular amyloid beta (Aβ) plaques and of intracellular neurofibrillary tangles. The most innovative approach is represented by the vaccination and passive immunization against Aβ peptide. In this article, current knowledge about concluded and ongoing clinical trials with both vaccination with different antigens and passive immunization will be reviewed and discussed.

  14. THE EOSINOPHILIC MATERIAL IN ADENOMATOID ODONTOGENIC TUMOR ASSOCIATED WITH AMYLOID PROTEIN COMPONENT

    Institute of Scientific and Technical Information of China (English)

    SONG Bao-ping; LI Yong-mei; Haruo Okabe

    1999-01-01

    Objective: To investigate the relation between eosinophilic materials and amyloid P (AP) component in adenomatoid odontogenic tumor (AOT). Methods: The expression of amyloid proteins and basement membrane proteins, including type Ⅳ collagen, laminin and heparin sulfate proteoglycan (HSPG), in AOT were analyzed by immunohistochemical method. Results:Most eosinophilic droplets among tumor cells and some epithelial cells showed positive stain for AP component.The immunoreactions of type Ⅳ collagen and laminin were only found in blood vessels of this tumor. The tumor cells and eosinophilic materials in duct-like structures were constantly unstained for both amyloid and basement membrane proteins. Present results suggest that the nature and composition of eosinophilic droplets may differ from the eosinophilic layer in ductlike structures. This study first demonstrated that the amyloid-like deposition in AOT is associated with AP component by immunohistochemical method. It supported that AP component may be epithelial origin since the AP immunolocalization was found in tumor cells.

  15. C1q binding and complement activation by prions and amyloids.

    Science.gov (United States)

    Sim, Robert B; Kishore, Uday; Villiers, Christian L; Marche, Patrice N; Mitchell, Daniel A

    2007-01-01

    C1q binds to many non-self and altered-self-materials. These include microorganisms, immune complexes, apoptotic and necrotic cells and their breakdown products, and amyloids. C1q binding to amyloid fibrils found as extracellular deposits in tissues, and subsequent complement activation are involved in the pathology of several amyloid diseases, such as Alzheimer's disease. Prion diseases, such as scrapie also involve formation of amyloid by polymerization of the host prion protein (PrP). Complement activation is likely to contribute to neuronal damage in the end stages of prion diseases, but is also thought to participate in the initial infection, dissemination and replication stages. Infectious prion particles are likely to bind C1q and activate the complement system. Bound complement proteins may then influence the uptake and transport of prion particles by dendritic cells (DCs) and their subsequent proliferation at sites such as follicular DCs. PMID:17544820

  16. Porcine prion protein amyloid.

    Science.gov (United States)

    Hammarström, Per; Nyström, Sofie

    2015-01-01

    Mammalian prions are composed of misfolded aggregated prion protein (PrP) with amyloid-like features. Prions are zoonotic disease agents that infect a wide variety of mammalian species including humans. Mammals and by-products thereof which are frequently encountered in daily life are most important for human health. It is established that bovine prions (BSE) can infect humans while there is no such evidence for any other prion susceptible species in the human food chain (sheep, goat, elk, deer) and largely prion resistant species (pig) or susceptible and resistant pets (cat and dogs, respectively). PrPs from these species have been characterized using biochemistry, biophysics and neurobiology. Recently we studied PrPs from several mammals in vitro and found evidence for generic amyloidogenicity as well as cross-seeding fibril formation activity of all PrPs on the human PrP sequence regardless if the original species was resistant or susceptible to prion disease. Porcine PrP amyloidogenicity was among the studied. Experimentally inoculated pigs as well as transgenic mouse lines overexpressing porcine PrP have, in the past, been used to investigate the possibility of prion transmission in pigs. The pig is a species with extraordinarily wide use within human daily life with over a billion pigs harvested for human consumption each year. Here we discuss the possibility that the largely prion disease resistant pig can be a clinically silent carrier of replicating prions.

  17. A is for Amylin and Amyloid in Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Hayden MR

    2001-07-01

    Full Text Available Amyloid deposits within the islet of the pancreas have been known for a century. In 1987, the islet amyloid precursor polypeptide (IAPP amylin (a 37 amino acid was discovered. Recently there has been an explosion of amylin's importance in the development of type 2 diabetes mellitus (T2DM. This review is intended to share what is understood about amylin derived amyloid and the role it plays in T2DM. Whether islet amyloid is an epiphenomenona, a tombstone, or a trigger it leaves an indelible footprint in greater that 70% of the patients with T2DM. There is current data supporting the damaging role of intermediate sized toxic amyloid particles to the beta cell resulting in a beta cell defect which contributes to a relative deficiency or loss of insulin secretion. Within the islet there is an intense redox stress which may be associated with the unfolding of amylin's native secondary structure compounding its amyloidogenic properties. In addition to the beta cell defect there may be an absorptive defect as a result of amyloid deposition in the basement membranes which form an envelope around the inta-islet capillary endothelium. We have an opportunity to change our current treatment modalities with newer medications and we should attempt to diagnose T2DM earlier and use these newer treatment strategies in combination to decrease glucotoxicity without elevating endogenous insulin and amylin. In the 21st century our goal should be to prevent remodeling, save the pancreatic islet, conquer islet amyloid, and amyloid diabetes.

  18. Beyond the obvious limits of ore deposits: The use of mineralogical, geochemical, and biological features for the remote detection of mineralization

    Science.gov (United States)

    Kelley, D.L.; Kelley, K.D.; Coker, W.B.; Caughlin, B.; Doherty, M.E.

    2006-01-01

    Far field features of ore deposits include mineralogical, geochemical, or biological attributes that can be recognized beyond the obvious limits of the deposits. They can be primary, if formed in association with mineralization or alteration processes, or secondary, if formed from the interaction of ore deposits with the hydrosphere and biosphere. This paper examines a variety of far field features of different ore deposit types and considers novel applications to exploration and discovery. Primary far field features include mineral and rock chemistry, isotopic or element halos, fluid pathways and thermal anomalies in host-rock sequences. Examples include the use of apatite chemistry to distinguish intrusive rocks permissive for iron oxide copper gold (IOCG) and porphyry deposits; resistate mineral (e.g., rutile, tourmaline) chemistry in exploration for volcanogenic massive sulfide (VMS), orogenic gold, and porphyry deposits; and pyrite chemistry to vector toward sedimentary exhalative (sedex) deposits. Distinctive whole-rock geochemical signatures also can be recognized as a far field feature of porphyry deposits. For example, unique Sr/Y ratios in whole-rock samples, used to distinguish barren versus fertile magmas for Cu mineralization, result from the differentiation of oxidized hydrous melts. Anomalous concentrations of halogen elements (Cl, Br, and I) have been found for distances of up to 200 m away from some mineralized centers. Variations in isotopic composition between ore-bearing and barren intrusions and/or systematic vertical and lateral zonation in sulfur, carbon, or oxygen isotope values have been documented for some deposit types. Owing to the thermal aureole that extends beyond the area of mineralization for some deposits, detection of paleothermal effects through methods such as conodont alteration indices, vitrinite or bitumen reflectance, illite crystallinity, and apatite or zircon thermochronology studies also can be valuable, particularly for

  19. Depositional ''cyclicity'' on carbonate platforms: Real-world limits on computer-model output

    Energy Technology Data Exchange (ETDEWEB)

    Boss, S.K.; Neumann, A.C. (Univ. of North Carolina, Chapel Hill, NC (United States)); Rasmussen, K.A. (Northern Virginia Community Coll., Annandale, VA (United States))

    1994-03-01

    Computer-models which attempt to define interactions among dynamic parameters believed to influence the development of ''cyclic'' carbonate platform sequences have been popularized over the past few years. These models typically utilize vectors for subsidence (constant) and cyclical (sinusoidal) eustatic sea-level to create accommodation space which is filled by sedimentation (depth-dependent rates) following an appropriate lag time (non-depositional episode during initial platform flooding). Since these models are intended to reflect general principles of cyclic carbonate deposition, it is instructive to test their predictive utility by comparing typical model outputs with an actively evolving depositional cycle on a modern carbonate platform where rates of subsidence, eustatic sea-level and sediment accumulation are known. Holocene carbonate deposits across northern Great Bahama Bank provide such an ideal test-platform for model-data comparisons. On Great Bahama Bank, formation of accommodation space depends on eustatic sea-level rise because tectonic subsidence is very slow. Contrary to typical model input parameters, however, the rate of formation of accommodation space varies irregularly across the bank-top because irregular bank-top topography (produced by subaerial erosion and karstification) results in differential flooding of the platform surface. Results of this comparison indicate that typical computer-model input variables (subsidence, sea-level, sedimentation, lag-time) and output depositional geometries are poorly correlated with real depositional patterns across Great Bahama Bank. Since other modern carbonate platforms and ancient carbonate sequences display similarly complex stratigraphies, it is suggested that present computer-modeling results have little predictive value for stratigraphic interpretation.

  20. A guide to the lower limit - combination of size and grade - of deposits of interest for uranium resources

    International Nuclear Information System (INIS)

    An attempt has been made to establish a method of classifying in broad terms low-tonnage/low-grade uranium resources in terms of size, recovery grade and gross sales revenue at various price levels. To arrive at a basis for discussion, the following assumptions are made: (i) An overall average U3O8 recovery grade of less than 50 g/t will never constitute a viable proposition; (ii) That no deposit, or cluster of deposits, containing less than 500,000 t ore will constitute a viable deposit; and (iii) Revenue requirements would vary according to the needs of the producer. It is, however, suggested that a gross sales revenue of US $50,000,000 over the life of the mine (10 years) is regarded as an absolute minimum requirement for viability. From these data a family of curves has been constructed using a tonnage/grade combination which gives a gross revenue of US $50,000,000 for various price categories in terms of $/kg U. These curves may then be used to categorize deposits and to ascertain whether they are likely to constitute a viable proposition within the constraints listed above. (author)

  1. Targeting amyloid-degrading enzymes as therapeutic strategies in neurodegeneration.

    Science.gov (United States)

    Turner, Anthony J; Fisk, Lilia; Nalivaeva, Natalia N

    2004-12-01

    The levels of amyloid beta-peptides (Abeta) in the brain represent a dynamic equilibrium state as a result of their biosynthesis from the amyloid precursor protein (APP) by beta- and gamma-secretases, their degradation by a team of amyloid-degrading enzymes, their subsequent oligomerization, and deposition into senile plaques. While most therapeutic attention has focused on developing inhibitors of secretases to prevent Abeta formation, enhancing the rate of Abeta degradation represents an alternative and viable strategy. Current evidence both in vivo and in vitro suggests that there are three major players in amyloid turnover: neprilysin, endothelin converting enzyme(s), and insulin-degrading enzyme, all of which are zinc metallopeptidases. Other proteases have also been implicated in amyloid metabolism, including angiotensin-converting enzyme, and plasmin but for these the evidence is less compelling. Neprilysin and endothelin converting enzyme(s) are homologous membrane proteins of the M13 peptidase family, which normally play roles in the biosynthesis and/or metabolism of regulatory peptides. Insulin-degrading enzyme is structurally and mechanistically distinct. The regional, cellular, and subcellular localizations of these enzymes differ, providing an efficient and diverse mechanism for protecting the brain against the normal accumulation of toxic Abeta peptides. Reduction in expression levels of some of these proteases following insults (e.g., hypoxia and ischemia) or aging might predispose to the development of Alzheimer's disease. Conversely, enhancement of their levels by gene delivery or pharmacological means could be neuroprotective. Even a relatively small enhancement of Abeta metabolism could slow the inexorable progression of the disease. The relative merits of targeting these enzymes for the treatment of Alzheimer's disease will be reviewed and possible side-effects of enhancing their activity evaluated.

  2. 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.

  3. Principal component analysis with pre-normalization improves the signal-to-noise ratio and image quality in positron emission tomography studies of amyloid deposits in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Razifar, Pasha [Molecular Imaging and CT Research, GE Healthcare, WI 53188, Waukesha (United States); Engler, Henry [Department of Medical Science, Uppsala University, SE-751 85 Uppsala (Sweden); Blomquist, Gunnar [Department of Oncology, Radiology and Clinical Immunology, Uppsala University, SE-751 85 Uppsala (Sweden); Ringheim, Anna; Estrada, Sergio [Uppsala Imanet AB, GE Healthcare, Box 967, SE-751 09, Uppsala (Sweden); Laangstroem, Bengt [Department of Biochemistry and Organic Chemistry, Uppsala University, SE-751 24 Uppsala (Sweden); Bergstroem, Mats [Department of Pharmaceutical Biosciences, Uppsala University, SE-751 24 Uppsala (Sweden)

    2009-06-07

    This study introduces a new approach for the application of principal component analysis (PCA) with pre-normalization on dynamic positron emission tomography (PET) images. These images are generated using the amyloid imaging agent N-methyl [{sup 11}C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole ([{sup 11}C]PIB) in patients with Alzheimer's disease (AD) and healthy volunteers (HVs). The aim was to introduce a method which, by using the whole dataset and without assuming a specific kinetic model, could generate images with improved signal-to-noise and detect, extract and illustrate changes in kinetic behavior between different regions in the brain. Eight AD patients and eight HVs from a previously published study with [{sup 11}C]PIB were used. The approach includes enhancement of brain regions where the kinetics of the radiotracer are different from what is seen in the reference region, pre-normalization for differences in noise levels and removal of negative values. This is followed by slice-wise application of PCA (SW-PCA) on the dynamic PET images. Results obtained using the new approach were compared with results obtained using reference Patlak and summed images. The new approach generated images with good quality in which cortical brain regions in AD patients showed high uptake, compared to cerebellum and white matter. Cortical structures in HVs showed low uptake as expected and in good agreement with data generated using kinetic modeling. The introduced approach generated images with enhanced contrast and improved signal-to-noise ratio (SNR) and discrimination power (DP) compared to summed images and parametric images. This method is expected to be an important clinical tool in the diagnosis and differential diagnosis of dementia.

  4. Analysis of the surface photoabsorption signal during self-limited submonolayer growth of InP in metalorganic chemical vapor deposition

    CERN Document Server

    Lee, T W; Moon, Y B; Yoon, E J; Kim, Y D

    1999-01-01

    In situ, real-time monitoring of InP atomic layer epitaxy (ALE) was performed in low-pressure metalorganic chemical vapor deposition (LP-MOCVD) by surface photoabsorption (SPA). A self-limiting adsorption condition was obtained from the trimethylindium (TMIn) decomposition experiment at various conditions. It was found that the growth rate was less than 1 monolayer (ML)/cycle. From the in situ, real-time SPA measurement during InP ALE, the incomplete PH sub 3 decomposition on the methyl-terminated In surface was attributed to the self-limiting submonolayer growth per cycle.

  5. Nanomechanical properties of single amyloid fibrils

    Science.gov (United States)

    Sweers, K. K. M.; Bennink, M. L.; Subramaniam, V.

    2012-06-01

    Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils.

  6. Functional Amyloid Formation within Mammalian Tissue.

    Directory of Open Access Journals (Sweden)

    2005-11-01

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

  7. SPECT imaging of peripheral amyloid in mice by targeting hyper-sulfated heparan sulfate proteoglycans with specific scFv antibodies

    International Nuclear Information System (INIS)

    Introduction: Amyloid deposits are associated with a broad spectrum of disorders including monoclonal gammopathies, chronic inflammation, and Alzheimer's disease. In all cases, the amyloid pathology contains, in addition to protein fibrils, a plethora of associated molecules, including high concentrations of heparan sulfate proteoglycans (HSPGs). Methods: We have evaluated radioiodinated scFvs that bind HS for their ability to image amyloid deposits in vivo. scFv's with different binding characteristics were isolated by phage display using HS extracted from bovine kidney or mouse and human skeletal muscle glycosaminoglycans (GAGs). Following purification and radioiodination, the biodistribution of 125I-scFv's was assessed in mice with inflammation-associated AA amyloidosis or in amyloid-free mice by using SPECT imaging, biodistribution measurements and tissue autoradiography. Results: Four different scFv's all showed binding in vivo to amyloid in the spleen, liver and kidney of diseased mice; however, three of the scFv's also bound to sites within these organs in disease free mice. One scFv specific for hypersulfated HSPGs preferentially bound amyloid and did not accumulate in healthy tissues. Conclusions: These data indicate that HS expressed in amyloid deposits has unique qualities that can be distinguished from HS in normal tissues. A scFv specific for rare hypersulfated HS was used to selectively image AA amyloid in mice with minimal retention in normal tissue.

  8. Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy.

    Science.gov (United States)

    Schmidt, Hartmut H-J; Barroso, Fabio; González-Duarte, Alejandra; Conceição, Isabel; Obici, Laura; Keohane, Denis; Amass, Leslie

    2016-09-01

    Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, severe, and irreversible, adult-onset, hereditary disorder caused by autosomal-dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR-FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease-modifying treatment options for a wider spectrum of patients with TTR-FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation-specific predictive genetic testing in first-degree relatives of index patients diagnosed with TTR-FAP and the structured clinical follow-up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353-360, 2016.

  9. Characteristics of Amyloid-Related Oligomers Revealed by Crystal Structures of Macrocyclic [beta]-Sheet Mimics

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Cong; Sawaya, Michael R.; Cheng, Pin-Nan; Zheng, Jing; Nowick, James S.; Eisenberg, David (UCI); (UCLA)

    2011-09-20

    Protein amyloid oligomers have been strongly linked to amyloid diseases and can be intermediates to amyloid fibers. {beta}-Sheets have been identified in amyloid oligomers. However, because of their transient and highly polymorphic properties, the details of their self-association remain elusive. Here we explore oligomer structure using a model system: macrocyclic peptides. Key amyloidogenic sequences from A{beta} and tau were incorporated into macrocycles, thereby restraining them to {beta}-strands, but limiting the growth of the oligomers so they may crystallize and cannot fibrillate. We determined the atomic structures for four such oligomers, and all four reveal tetrameric interfaces in which {beta}-sheet dimers pair together by highly complementary, dry interfaces, analogous to steric zippers found in fibers, suggesting a common structure for amyloid oligomers and fibers. In amyloid fibers, the axes of the paired sheets are either parallel or antiparallel, whereas the oligomeric interfaces display a variety of sheet-to-sheet pairing angles, offering a structural explanation for the heterogeneity of amyloid oligomers.

  10. Insights into the variability of nucleated amyloid polymerization by a minimalistic model of stochastic protein assembly

    Science.gov (United States)

    Eugène, Sarah; Xue, Wei-Feng; Robert, Philippe; Doumic, Marie

    2016-05-01

    Self-assembly of proteins into amyloid aggregates is an important biological phenomenon associated with human diseases such as Alzheimer's disease. Amyloid fibrils also have potential applications in nano-engineering of biomaterials. The kinetics of amyloid assembly show an exponential growth phase preceded by a lag phase, variable in duration as seen in bulk experiments and experiments that mimic the small volumes of cells. Here, to investigate the origins and the properties of the observed variability in the lag phase of amyloid assembly currently not accounted for by deterministic nucleation dependent mechanisms, we formulate a new stochastic minimal model that is capable of describing the characteristics of amyloid growth curves despite its simplicity. We then solve the stochastic differential equations of our model and give mathematical proof of a central limit theorem for the sample growth trajectories of the nucleated aggregation process. These results give an asymptotic description for our simple model, from which closed form analytical results capable of describing and predicting the variability of nucleated amyloid assembly were derived. We also demonstrate the application of our results to inform experiments in a conceptually friendly and clear fashion. Our model offers a new perspective and paves the way for a new and efficient approach on extracting vital information regarding the key initial events of amyloid formation.

  11. Depletion of Spleen Macrophages Delays AA Amyloid Development: A Study Performed in the Rapid Mouse Model of AA Amyloidosis

    OpenAIRE

    Katarzyna Lundmark; Aida Vahdat Shariatpanahi; Westermark, Gunilla T.

    2013-01-01

    AA amyloidosis is a systemic disease that develops secondary to chronic inflammatory diseases Macrophages are often found in the vicinity of amyloid deposits and considered to play a role in both formation and degradation of amyloid fibrils. In spleen reside at least three types of macrophages, red pulp macrophages (RPM), marginal zone macrophages (MZM), metallophilic marginal zone macrophages (MMZM). MMZM and MZM are located in the marginal zone and express a unique collection of scavenger r...

  12. 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...

  13. 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.

  14. Reduction and degradation of amyloid aggregates by a pulsed radio-frequency cold atmospheric plasma jet

    Energy Technology Data Exchange (ETDEWEB)

    Bayliss, D L; Walsh, J L; Iza, F; Kong, M G [Department of Electronic and Electrical Engineering, Loughborough University, Leicestershire LE11 3TU (United Kingdom); Shama, G [Department of Chemical Engineering, Loughborough University, Leicestershire LE11 3TU (United Kingdom)], E-mail: m.g.kong@lboro.ac.uk

    2009-11-15

    Surface-borne amyloid aggregates with mature fibrils are used as a non-infectious prion model to evaluate cold atmospheric plasmas (CAPs) as a prion inactivation strategy. Using a helium-oxygen CAP jet with pulsed radio-frequency (RF) excitation, amyloid aggregates deposited on freshly cleaved mica discs are reduced substantially leaving only a few spherical fragments of sub-micrometer sizes in areas directly treated by the CAP jet. Outside the light-emitting part of the CAP jet, plasma treatment results in a 'skeleton' of much reduced amyloid stacks with clear evidence of fibril fragmentation. Analysis of possible plasma species and the physical configuration of the jet-sample interaction suggests that the skeleton structures observed are unlikely to have arisen as a result of physical forces of detachment, but instead by progressive diffusion of oxidizing plasma species into porous amyloid aggregates. Composition of chemical bonds of this reduced amyloid sample is very different from that of intact amyloid aggregates. These suggest the possibility of on-site degradation by CAP treatment with little possibility of spreading contamination elsewhere , thus offering a new reaction chemistry route to protein infectivity control with desirable implications for the practical implementation of CAP-based sterilization systems.

  15. Reduction and degradation of amyloid aggregates by a pulsed radio-frequency cold atmospheric plasma jet

    Science.gov (United States)

    Bayliss, D. L.; Walsh, J. L.; Shama, G.; Iza, F.; Kong, M. G.

    2009-11-01

    Surface-borne amyloid aggregates with mature fibrils are used as a non-infectious prion model to evaluate cold atmospheric plasmas (CAPs) as a prion inactivation strategy. Using a helium-oxygen CAP jet with pulsed radio-frequency (RF) excitation, amyloid aggregates deposited on freshly cleaved mica discs are reduced substantially leaving only a few spherical fragments of sub-micrometer sizes in areas directly treated by the CAP jet. Outside the light-emitting part of the CAP jet, plasma treatment results in a 'skeleton' of much reduced amyloid stacks with clear evidence of fibril fragmentation. Analysis of possible plasma species and the physical configuration of the jet-sample interaction suggests that the skeleton structures observed are unlikely to have arisen as a result of physical forces of detachment, but instead by progressive diffusion of oxidizing plasma species into porous amyloid aggregates. Composition of chemical bonds of this reduced amyloid sample is very different from that of intact amyloid aggregates. These suggest the possibility of on-site degradation by CAP treatment with little possibility of spreading contamination elsewhere , thus offering a new reaction chemistry route to protein infectivity control with desirable implications for the practical implementation of CAP-based sterilization systems.

  16. Reduction and degradation of amyloid aggregates by a pulsed radio-frequency cold atmospheric plasma jet

    International Nuclear Information System (INIS)

    Surface-borne amyloid aggregates with mature fibrils are used as a non-infectious prion model to evaluate cold atmospheric plasmas (CAPs) as a prion inactivation strategy. Using a helium-oxygen CAP jet with pulsed radio-frequency (RF) excitation, amyloid aggregates deposited on freshly cleaved mica discs are reduced substantially leaving only a few spherical fragments of sub-micrometer sizes in areas directly treated by the CAP jet. Outside the light-emitting part of the CAP jet, plasma treatment results in a 'skeleton' of much reduced amyloid stacks with clear evidence of fibril fragmentation. Analysis of possible plasma species and the physical configuration of the jet-sample interaction suggests that the skeleton structures observed are unlikely to have arisen as a result of physical forces of detachment, but instead by progressive diffusion of oxidizing plasma species into porous amyloid aggregates. Composition of chemical bonds of this reduced amyloid sample is very different from that of intact amyloid aggregates. These suggest the possibility of on-site degradation by CAP treatment with little possibility of spreading contamination elsewhere , thus offering a new reaction chemistry route to protein infectivity control with desirable implications for the practical implementation of CAP-based sterilization systems.

  17. 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

  18. Inhibition of amyloid-beta-induced cell death in human brain pericytes in vitro.

    NARCIS (Netherlands)

    Rensink, A.A.M.; Verbeek, M.M.; Otte-Holler, I.; Donkelaar, H.J. ten; Waal, R.M.W. de; Kremer, H.P.H.

    2002-01-01

    Amyloid-beta protein (A beta) deposition in the cerebral vascular walls is one of the key features of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). A beta(1-40) carrying the 'Dutch' mutation (HCHWA-D A beta(1-40)) induces pronounced degeneration of cul

  19. TLR2 is a primary receptor for Alzheimer's amyloid beta peptide to trigger neuroinflammatory activation.

    NARCIS (Netherlands)

    Liu, S.; Liu, Y.; Hao, W.; Wolf, L.; Kiliaan, A.J.; Penke, B.; Rube, C.E.; Walter, J.; Heneka, M.T.; Hartmann, T.; Menger, M.D.; Fassbender, K.

    2012-01-01

    Microglia activated by extracellularly deposited amyloid beta peptide (Abeta) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering an

  20. Energetic deposition of metal ions: Observation of self-sputtering and limited sticking for off-normal angles of incidence

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Hongchen; Anders, Andre

    2009-09-15

    The deposition of films under normal and off-normal angle of incidence has been investigated to show the relevance of non-sticking of and self-sputtering by energetic ions, leading to the formation of neutral atoms. The flow of energetic ions was obtained using a filtered cathodic arc system in high vacuum and therefore the ion flux had a broad energy distribution of typically 50-100 eV per ion. The range of materials included Cu, Ag, Au, Ti, and Ni. Consistent with molecular dynamics simulations published in the literature, the experiments show, for all materials, that the combined effects of non-sticking and self-sputtering are very significant, especially for large off-normal angles. Modest heating and intentional introduction of oxygen background affect the results.

  1. Incorporation of homogeneous, nanoscale MnO2 within ultraporous carbon structures via self-limiting electroless deposition: implications for electrochemical capacitors.

    Science.gov (United States)

    Fischer, Anne E; Pettigrew, Katherine A; Rolison, Debra R; Stroud, Rhonda M; Long, Jeffrey W

    2007-02-01

    The self-limiting reaction of aqueous permanganate with carbon nanofoams produces conformal, nanoscopic deposits of birnessite ribbons and amorphous MnO2 throughout the ultraporous carbon structure. The MnO2 coating contributes additional capacitance to the carbon nanofoam while maintaining the favorable high-rate electrochemical performance inherent to the ultraporous carbon structure of the nanofoam. Such a three-dimensional design exploits the benefits of a nanoscopic MnO2-carbon interface to produce an exceptionally high area-normalized capacitance (1.5 F cm-2), as well as high volumetric capacitance (90 F cm-3). PMID:17297991

  2. DNA aptamers detecting generic amyloid epitopes

    OpenAIRE

    Mitkevich, Olga V.; Kochneva-Pervukhova, Natalia V; Surina, Elizaveta R.; Benevolensky, Sergei V.; Kushnirov, Vitaly V.; Ter-Avanesyan, Michael D.

    2012-01-01

    Amyloids are fibrillar protein aggregates resulting from non-covalent autocatalytic polymerization of various structurally and functionally unrelated proteins. Previously we have selected DNA aptamers, which bind specifically to the in vitro assembled amyloid fibrils of the yeast prionogenic protein Sup35. Here we show that such DNA aptamers can be used to detect SDS-insoluble amyloid aggregates of the Sup35 protein, and of some other amyloidogenic proteins, including mouse PrP, formed in yea...

  3. Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade

    Directory of Open Access Journals (Sweden)

    Huntington Potter

    2012-01-01

    Full Text Available The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE. Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.

  4. "Red-flag" symptom clusters in transthyretin familial amyloid polyneuropathy.

    Science.gov (United States)

    Conceição, Isabel; González-Duarte, Alejandra; Obici, Laura; Schmidt, Hartmut H-J; Simoneau, Damien; Ong, Moh-Lim; Amass, Leslie

    2016-03-01

    Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretin-derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR-FAP is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity. Based on published literature and expert opinion, symptom clusters suggesting TTR-FAP are reviewed, and practical guidance to facilitate earlier diagnosis is provided. TTR-FAP should be suspected if progressive peripheral sensory-motor neuropathy is observed in combination with one or more of the following: family history of a neuropathy, autonomic dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR-FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large- and small-fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed. PMID:26663427

  5. Amyloid myopathy: a diagnostic challenge

    Directory of Open Access Journals (Sweden)

    Heli Tuomaala

    2009-08-01

    Full Text Available Amyloid myopathy (AM is a rare manifestation of primary systemic amyloidosis (AL. Like inflammatory myopathies, it presents with proximal muscle weakness and an increased creatine kinase level. We describe a case of AL with severe, rapidly progressive myopathy as the initial symptom. The clinical manifestation and muscle biopsy were suggestive of inclusion body myositis. AM was not suspected until amyloidosis was seen in the gastric mucosal biopsy. The muscle biopsy was then re-examined more specifically, and Congo red staining eventually showed vascular and interstitial amyloid accumulation, which led to a diagnosis of AM. The present case illustrates the fact that the clinical picture of AM can mimic that of inclusion body myositis.

  6. Towards a Pharmacophore for Amyloid

    Science.gov (United States)

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

    2011-01-01

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of β-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. PMID:21695112

  7. Imaging β-amyloid using [{sup 18}F]flutemetamol positron emission tomography: from dosimetry to clinical diagnosis

    Energy Technology Data Exchange (ETDEWEB)

    Heurling, Kerstin; Lubberink, Mark [Uppsala University, Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala (Sweden); Leuzy, Antoine [Karolinska Institutet, Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Huddinge (Sweden); Zimmer, Eduardo R. [Pontifical Catholic University of Rio Grande do Sul (PUCRS), Brain Institute of Rio Grande do Sul (BraIns), Porto Alegre (Brazil); Federal University of Rio Grande do Sul (UFRGS), Department of Biochemistry, Porto Alegre (Brazil); Nordberg, Agneta [Karolinska Institutet, Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Huddinge (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden)

    2016-02-15

    In Alzheimer's disease (AD), the deposition of β-amyloid (Aβ) is hypothesized to result in a series of secondary neurodegenerative processes, leading ultimately to synaptic dysfunction and neuronal loss. Since the advent of the first Aβ-specific positron emission tomography (PET) ligand, {sup 11}C-Pittsburgh compound B ([{sup 11}C]PIB), several {sup 18}F ligands have been developed that circumvent the limitations of [{sup 11}C]PIB tied to its short half-life. To date, three such compounds have been approved for clinical use by the US and European regulatory bodies, including [{sup 18}F]AV-45 ([{sup 18}F]florbetapir; Amyvid trademark), [{sup 18}F]-BAY94-9172 ([{sup 18}F]florbetaben; Neuraceq trademark) and [{sup 18}F]3'-F-PIB ([{sup 18}F]flutemetamol; Vizamyl trademark). The present review aims to summarize and discuss the currently available knowledge on [{sup 18}F]flutemetamol PET. As the {sup 18}F analogue of [{sup 11}C]PIB, [{sup 18}F]flutemetamol may be of use in the differentiation of AD from related neurodegenerative disorders and may help with subject selection and measurement of target engagement in the context of clinical trials testing anti-amyloid therapeutics. We will also discuss its potential use in non-AD amyloidopathies. (orig.)

  8. Bryophytes as Climate Indicators: moss and liverwort photosynthetic limitations and carbon isotope signals in organic material and peat deposits

    Science.gov (United States)

    Griffiths, H.; Royles, J.; Horwath, A.; Hodell, D. A.; Convey, P.; Hodgson, D.; Wingate, L.; Ogeé, J.

    2011-12-01

    Bryophytes make a significant contribution to carbon sequestration and storage in polar, boreal, temperate and tropical biomes, and yet there is limited understanding of the determinants of carbon isotope composition. Bryophytes are poikilohydric and lack stomata in the vegetative (gametophyte) stage, and lack of roots and reliance on liquid water to maintain hydration status also imposes diffusional limitations on CO2 uptake and extent of carbon isotope discrimination. Real-time gas exchange and instantaneous discrimination studies can be used to quantify responses to liquid phase limitation. Thus, wetted tissues show less negative δ13C signals due to liquid phase conductance and, as the thallus surface dries, maximum CO2 assimilation and discrimination are attained when the limitation is primarily the internal (mesophyll) conductance. Continued desiccation then leads to additional biochemical limitation in drought tolerant species, and low discrimination, although the carbon gain is low at this time. In this paper we explore the extent of carbon isotope discrimination in bulk organic material and cellulose as a function of climatic and environmental conditions, in temperate, tropical and Antarctic bryophytes. Field studies have been used to investigate seasonal variations in precipitation and water vapour inputs for cloud forest formations as a function of bryophyte biomass, diversity and isotope composition in epiphytes (particularly leafy liverworts) along an altitudinal gradient in Peru. In the Antarctic, moss banks sampled on Signy Island consisted of only two species, primarily Chorisodontium aciphyllum and some Polytrichum strictum, allowing the collection of shallow and deep cores representative of growth over the past 200 to 2000 years. The well-preserved peat has provided data on growth (14C) and stable isotopic proxies (13C, 18O) for material contemporary with recent anthropogenic climate forcing (over the past 200 years), for comparison with longer

  9. Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function

    Directory of Open Access Journals (Sweden)

    Iwamoto Sean

    2006-11-01

    Full Text Available Abstract Background Neurodegeneration in Alzheimer's disease is associated with increased apoptosis and parallels increased levels of amyloid beta, which can induce neuronal apoptosis. Estrogen exposure prior to neurotoxic insult of hippocampal neurons promotes neuronal defence and survival against neurodegenerative insults including amyloid beta. Although all underlying molecular mechanisms of amyloid beta neurotoxicity remain undetermined, mitochondrial dysfunction, including altered calcium homeostasis and Bcl-2 expression, are involved in neurodegenerative vulnerability. Results In this study, we investigated the mechanism of 17β-estradiol-induced prevention of amyloid beta-induced apoptosis of rat hippocampal neuronal cultures. Estradiol treatment prior to amyloid beta exposure significantly reduced the number of apoptotic neurons and the associated rise in resting intracellular calcium levels. Amyloid beta exposure provoked down regulation of a key antiapoptotic protein, Bcl-2, and resulted in mitochondrial translocation of Bax, a protein known to promote cell death, and subsequent release of cytochrome c. E2 pretreatment inhibited the amyloid beta-induced decrease in Bcl-2 expression, translocation of Bax to the mitochondria and subsequent release of cytochrome c. Further implicating the mitochondria as a target of estradiol action, in vivo estradiol treatment enhanced the respiratory function of whole brain mitochondria. In addition, estradiol pretreatment protected isolated mitochondria against calcium-induced loss of respiratory function. Conclusion Therefore, we propose that estradiol pretreatment protects against amyloid beta neurotoxicity by limiting mitochondrial dysfunction via activation of antiapoptotic mechanisms.

  10. 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.

  11. What is limiting low-temperature atomic layer deposition of Al2O3? A vibrational sum-frequency generation study

    International Nuclear Information System (INIS)

    The surface reactions during atomic layer deposition (ALD) of Al2O3 from Al(CH3)3 and H2O have been studied with broadband sum-frequency generation to reveal what is limiting the growth at low temperatures. The –CH3 surface coverage was measured for temperatures between 100 and 300 °C and the absolute reaction cross sections, describing the reaction kinetics, were determined for both half-cycles. It was found that –CH3 groups persisted on the surface after saturation of the H2O half-cycle. From a direct correlation with the growth per cycle, it was established that the reduced reactivity of H2O towards –CH3 is the dominant factor limiting the ALD process at low temperatures

  12. What is limiting low-temperature atomic layer deposition of Al{sub 2}O{sub 3}? A vibrational sum-frequency generation study

    Energy Technology Data Exchange (ETDEWEB)

    Vandalon, V., E-mail: v.vandalon@tue.nl, E-mail: w.m.m.kessels@tue.nl; Kessels, W. M. M., E-mail: v.vandalon@tue.nl, E-mail: w.m.m.kessels@tue.nl [Department of Applied Physics, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven (Netherlands)

    2016-01-04

    The surface reactions during atomic layer deposition (ALD) of Al{sub 2}O{sub 3} from Al(CH{sub 3}){sub 3} and H{sub 2}O have been studied with broadband sum-frequency generation to reveal what is limiting the growth at low temperatures. The –CH{sub 3} surface coverage was measured for temperatures between 100 and 300 °C and the absolute reaction cross sections, describing the reaction kinetics, were determined for both half-cycles. It was found that –CH{sub 3} groups persisted on the surface after saturation of the H{sub 2}O half-cycle. From a direct correlation with the growth per cycle, it was established that the reduced reactivity of H{sub 2}O towards –CH{sub 3} is the dominant factor limiting the ALD process at low temperatures.

  13. Clinical, FDG and amyloid PET imaging in posterior cortical atrophy.

    Science.gov (United States)

    Singh, Tarun D; Josephs, Keith A; Machulda, Mary M; Drubach, Daniel A; Apostolova, Liana G; Lowe, Val J; Whitwell, Jennifer L

    2015-06-01

    The purpose of this study was to identify the clinical, [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and amyloid-PET findings in a large cohort of posterior cortical atrophy (PCA) patients, to examine the neural correlates of the classic features of PCA, and to better understand the features associated with early PCA. We prospectively recruited 25 patients who presented to the Mayo Clinic between March 2013 and August 2014 and met diagnostic criteria for PCA. All patients underwent a standardized set of tests and amyloid imaging with [(11)C] Pittsburg compound B (PiB). Seventeen (68 %) underwent FDG-PET scanning. We divided the cohort at the median disease duration of 4 years in order to assess clinical and FDG-PET correlates of early PCA (n = 13). The most common clinical features were simultanagnosia (92 %), dysgraphia (68 %), poly-mini-myoclonus (64 %) and oculomotor apraxia (56.5 %). On FDG-PET, hypometabolism was observed bilaterally in the lateral and medial parietal and occipital lobes. Simultanagnosia was associated with hypometabolism in the right occipital lobe and posterior cingulum, optic ataxia with hypometabolism in left occipital lobe, and oculomotor apraxia with hypometabolism in the left parietal lobe and posterior cingulate gyrus. All 25 PCA patients were amyloid positive. Simultanagnosia was the only feature present in 85 % of early PCA patients. The syndrome of PCA is associated with posterior hemisphere hypometabolism and with amyloid deposition. Many of the classic features of PCA show associated focal, but not widespread, areas of involvement of these posterior hemispheric regions. Simultanagnosia appears to be the most common and hence sensitive feature of early PCA. PMID:25862483

  14. The contrasting effect of macromolecular crowding on amyloid fibril formation.

    Directory of Open Access Journals (Sweden)

    Qian Ma

    Full Text Available BACKGROUND: Amyloid fibrils associated with neurodegenerative diseases can be considered biologically relevant failures of cellular quality control mechanisms. It is known that in vivo human Tau protein, human prion protein, and human copper, zinc superoxide dismutase (SOD1 have the tendency to form fibril deposits in a variety of tissues and they are associated with different neurodegenerative diseases, while rabbit prion protein and hen egg white lysozyme do not readily form fibrils and are unlikely to cause neurodegenerative diseases. In this study, we have investigated the contrasting effect of macromolecular crowding on fibril formation of different proteins. METHODOLOGY/PRINCIPAL FINDINGS: As revealed by assays based on thioflavin T binding and turbidity, human Tau fragments, when phosphorylated by glycogen synthase kinase-3β, do not form filaments in the absence of a crowding agent but do form fibrils in the presence of a crowding agent, and the presence of a strong crowding agent dramatically promotes amyloid fibril formation of human prion protein and its two pathogenic mutants E196K and D178N. Such an enhancing effect of macromolecular crowding on fibril formation is also observed for a pathological human SOD1 mutant A4V. On the other hand, rabbit prion protein and hen lysozyme do not form amyloid fibrils when a crowding agent at 300 g/l is used but do form fibrils in the absence of a crowding agent. Furthermore, aggregation of these two proteins is remarkably inhibited by Ficoll 70 and dextran 70 at 200 g/l. CONCLUSIONS/SIGNIFICANCE: We suggest that proteins associated with neurodegenerative diseases are more likely to form amyloid fibrils under crowded conditions than in dilute solutions. By contrast, some of the proteins that are not neurodegenerative disease-associated are unlikely to misfold in crowded physiological environments. A possible explanation for the contrasting effect of macromolecular crowding on these two sets of

  15. 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 ...

  16. Augmented Senile Plaque Load in Aged Female β-Amyloid Precursor Protein-Transgenic Mice

    OpenAIRE

    Callahan, Michael J.; Lipinski, William J.; Bian, Feng; Durham, Robert A.; Pack, Amy; Walker, Lary C.

    2001-01-01

    Transgenic mice (Tg2576) overexpressing human β-amyloid precursor protein with the Swedish mutation (APP695SWE) develop Alzheimer’s disease-like amyloid β protein (Aβ) deposits by 8 to 10 months of age. These mice show elevated levels of Aβ40 and Aβ42, as well as an age-related increase in diffuse and compact senile plaques in the brain. Senile plaque load was quantitated in the hippocampus and neocortex of 8- to 19-month-old male and female Tg2576 mice. In all mice, plaque burden increased m...

  17. Use of amyloid-PET to determine cutpoints for CSF markers

    DEFF Research Database (Denmark)

    Zwan, Marissa D; Rinne, Juha O; Hasselbalch, Steen G;

    2016-01-01

    , 99 with mild cognitive impairment, 195 with Alzheimer disease [AD] dementia, and 82 with non-AD dementia) from 5 European centers. We calculated for each center and for the pooled cohort CSF Aβ42 and Aβ42/tau ratio cutpoints for cortical amyloid deposition based on visual interpretation of [11C...... concordance was found when using a dichotomized Aβ42/tau ratio. Exploratory analysis showed that participants with a positive amyloid-PET and normal CSF Aβ42 levels had higher CSF tau and phosphorylated tau levels and more often had mild cognitive impairment or AD dementia compared with participants who had...

  18. 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.

  19. Amyloid beta1–42 and the phoshorylated tau threonine 231 in brains of aged cynomolgus monkeys (Macaca fascicularis)

    DEFF Research Database (Denmark)

    Darusman, Huda Shalahudin; Gjedde, Albert; Sajuthi, Dondin;

    2014-01-01

    Pathological hallmarks indicative of Alzheimer's disease (AD), which are the plaques of amyloid beta1-42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers...... indicative of AD, had brain lesions similar to human patients suffering from senile dementia. Generating immunohistochemistry technique to biomarkers of amyloid beta1-42 and the phosphorylated tau 231, our study assessed the amyloidopathy, such as indicative to the senile plaques and cerebral amyloid......, the amyloids were found to deposit in the small veins and capillaries. In one of the affected individuals, phosphorylated tau was positively stained intracellularly of the neurons, indicating a possibility of an early stage of the formation of tangles. These findings add to the body of evidence of the utility...

  20. Development of a Standardized Approach to Disclosing Amyloid Imaging Research Results in Mild Cognitive Impairment

    Science.gov (United States)

    Lingler, Jennifer H.; Butters, Meryl A.; Gentry, Amanda L.; Hu, Lu; Hunsaker, Amanda E.; Klunk, William E.; Mattos, Meghan K.; Parker, Lisa A.; Roberts, J. Scott; Schulz, Richard

    2016-01-01

    The increased use of PET amyloid imaging in clinical research has sparked numerous concerns about whether and how to return such research test results to study participants. Chief among these is the question of how best to disclose amyloid imaging research results to individuals who have cognitive symptoms that could impede comprehension of the information conveyed. We systematically developed and evaluated informational materials for use in pre-test counseling and post-test disclosures of amyloid imaging research results in mild cognitive impairment (MCI). Using simulated sessions, persons with MCI and their family care partners (N=10 dyads) received fictitious but realistic information regarding brain amyloid status, followed by an explanation of how results impact Alzheimer’s disease risk. Satisfaction surveys, comprehension assessments, and focus group data were analyzed to evaluate the materials developed. The majority of persons with MCI and their care partners comprehended and were highly satisfied with the information presented. Focus group data reinforced findings of high satisfaction and included 6 recommendations for practice: 1) offer pre-test counseling, 2) use clear graphics, 3) review participants’ own brain images during disclosures, 4) offer take-home materials, 5) call participants post-disclosure to address emerging questions, and 6) communicate seamlessly with primary care providers. Further analysis of focus group data revealed that participants understood the limitations of amyloid imaging, but nevertheless viewed the prospect of learning one’s amyloid status as valuable and empowering. PMID:27060950

  1. Acetylcholinesterase, a senile plaque component, affects the fibrillogenesis of amyloid-beta-peptides.

    Science.gov (United States)

    Alvarez, A; Bronfman, F; Pérez, C A; Vicente, M; Garrido, J; Inestrosa, N C

    1995-12-01

    Acetylcholinesterase (AChE) colocalizes with amyloid-beta peptide (A beta) deposits present in the brain of Alzheimer's patients. Recent studies showed that A beta 1-40 can adopt two different conformational states in solution (an amyloidogenic conformer, A beta ac, and a non-amyloidogenic conformer, A beta nac) which have distinct abilities to form amyloid fibrils. We report here that AChE binds A beta nac and accelerates amyloid formation by the same peptide. No such effect was observed with A beta ac, the amyloidogenic conformer, suggesting that AChE acts as a 'pathological chaperone' inducing a conformational transition from A beta nac into A beta ac in vitro.

  2. Characterization of Amyloid Cores in Prion Domains

    Science.gov (United States)

    Sant’Anna, Ricardo; Fernández, Maria Rosario; Batlle, Cristina; Navarro, Susanna; de Groot, Natalia S.; Serpell, Louise; Ventura, Salvador

    2016-01-01

    Amyloids consist of repetitions of a specific polypeptide chain in a regular cross-β-sheet conformation. Amyloid propensity is largely determined by the protein sequence, the aggregation process being nucleated by specific and short segments. Prions are special amyloids that become self-perpetuating after aggregation. Prions are responsible for neuropathology in mammals, but they can also be functional, as in yeast prions. The conversion of these last proteins to the prion state is driven by prion forming domains (PFDs), which are generally large, intrinsically disordered, enriched in glutamines/asparagines and depleted in hydrophobic residues. The self-assembly of PFDs has been thought to rely mostly on their particular amino acid composition, rather than on their sequence. Instead, we have recently proposed that specific amyloid-prone sequences within PFDs might be key to their prion behaviour. Here, we demonstrate experimentally the existence of these amyloid stretches inside the PFDs of the canonical Sup35, Swi1, Mot3 and Ure2 prions. These sequences self-assemble efficiently into highly ordered amyloid fibrils, that are functionally competent, being able to promote the PFD amyloid conversion in vitro and in vivo. Computational analyses indicate that these kind of amyloid stretches may act as typical nucleating signals in a number of different prion domains. PMID:27686217

  3. Amyloid fibrils compared to peptide nanotubes.

    Science.gov (United States)

    Zganec, Matjaž; Zerovnik, Eva

    2014-09-01

    Prefibrillar oligomeric states and amyloid fibrils of amyloid-forming proteins qualify as nanoparticles. We aim to predict what biophysical and biochemical properties they could share in common with better researched peptide nanotubes. We first describe what is known of amyloid fibrils and prefibrillar aggregates (oligomers and protofibrils): their structure, mechanisms of formation and putative mechanism of cytotoxicity. In distinction from other neuronal fibrillar constituents, amyloid fibrils are believed to cause pathology, however, some can also be functional. Second, we give a review of known biophysical properties of peptide nanotubes. Finally, we compare properties of these two macromolecular states side by side and discuss which measurements that have already been done with peptide nanotubes could be done with amyloid fibrils as well.

  4. The proteome response to amyloid protein expression in vivo.

    Directory of Open Access Journals (Sweden)

    Ricardo A Gomes

    Full Text Available Protein misfolding disorders such as Alzheimer, Parkinson and transthyretin amyloidosis are characterized by the formation of protein amyloid deposits. Although the nature and location of the aggregated proteins varies between different diseases, they all share similar molecular pathways of protein unfolding, aggregation and amyloid deposition. Most effects of these proteins are likely to occur at the proteome level, a virtually unexplored reality. To investigate the effects of an amyloid protein expression on the cellular proteome, we created a yeast expression system using human transthyretin (TTR as a model amyloidogenic protein. We used Saccharomyces cerevisiae, a living test tube, to express native TTR (non-amyloidogenic and the amyloidogenic TTR variant L55P, the later forming aggregates when expressed in yeast. Differential proteome changes were quantitatively analyzed by 2D-differential in gel electrophoresis (2D-DIGE. We show that the expression of the amyloidogenic TTR-L55P causes a metabolic shift towards energy production, increased superoxide dismutase expression as well as of several molecular chaperones involved in protein refolding. Among these chaperones, members of the HSP70 family and the peptidyl-prolyl-cis-trans isomerase (PPIase were identified. The latter is highly relevant considering that it was previously found to be a TTR interacting partner in the plasma of ATTR patients but not in healthy or asymptomatic subjects. The small ubiquitin-like modifier (SUMO expression is also increased. Our findings suggest that refolding and degradation pathways are activated, causing an increased demand of energetic resources, thus the metabolic shift. Additionally, oxidative stress appears to be a consequence of the amyloidogenic process, posing an enhanced threat to cell survival.

  5. Depolymerization of insulin amyloid fibrils by albumin-modified magnetic fluid

    Science.gov (United States)

    Siposova, Katarina; Kubovcikova, Martina; Bednarikova, Zuzana; Koneracka, Martina; Zavisova, Vlasta; Antosova, Andrea; Kopcansky, Peter; Daxnerova, Zuzana; Gazova, Zuzana

    2012-02-01

    Pathogenesis of amyloid-related diseases is associated with the presence of protein amyloid deposits. Insulin amyloids have been reported in a patient with diabetes undergoing treatment by injection of insulin and causes problems in the production and storage of this drug and in application of insulin pumps. We have studied the interference of insulin amyloid fibrils with a series of 18 albumin magnetic fluids (MFBSAs) consisting of magnetite nanoparticles modified by different amounts of bovine serum albumin (w/w BSA/Fe3O4 from 0.005 up to 15). We have found that MFBSAs are able to destroy amyloid fibrils in vitro. The extent of fibril depolymerization was affected by nanoparticle physical-chemical properties (hydrodynamic diameter, zeta potential and isoelectric point) determined by the BSA amount present in MFBSAs. The most effective were MFBSAs with lower BSA/Fe3O4 ratios (from 0.005 to 0.1) characteristic of about 90% depolymerizing activity. For the most active magnetic fluids (ratios 0.01 and 0.02) the DC50 values were determined in the range of low concentrations, indicating their ability to interfere with insulin fibrils at stoichiometric concentrations. We assume that the present findings represent a starting point for the application of the active MFBSAs as therapeutic agents targeting insulin amyloidosis.

  6. Depolymerization of insulin amyloid fibrils by albumin-modified magnetic fluid

    International Nuclear Information System (INIS)

    Pathogenesis of amyloid-related diseases is associated with the presence of protein amyloid deposits. Insulin amyloids have been reported in a patient with diabetes undergoing treatment by injection of insulin and causes problems in the production and storage of this drug and in application of insulin pumps. We have studied the interference of insulin amyloid fibrils with a series of 18 albumin magnetic fluids (MFBSAs) consisting of magnetite nanoparticles modified by different amounts of bovine serum albumin (w/w BSA/Fe3O4 from 0.005 up to 15). We have found that MFBSAs are able to destroy amyloid fibrils in vitro. The extent of fibril depolymerization was affected by nanoparticle physical–chemical properties (hydrodynamic diameter, zeta potential and isoelectric point) determined by the BSA amount present in MFBSAs. The most effective were MFBSAs with lower BSA/Fe3O4 ratios (from 0.005 to 0.1) characteristic of about 90% depolymerizing activity. For the most active magnetic fluids (ratios 0.01 and 0.02) the DC50 values were determined in the range of low concentrations, indicating their ability to interfere with insulin fibrils at stoichiometric concentrations. We assume that the present findings represent a starting point for the application of the active MFBSAs as therapeutic agents targeting insulin amyloidosis. (paper)

  7. 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.

  8. Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy.

    Science.gov (United States)

    Carr, A S; Pelayo-Negro, A L; Jaunmuktane, Z; Scalco, R S; Hutt, D; Evans, M R B; Heally, E; Brandner, S; Holton, J; Blake, J; Whelan, C J; Wechalekar, A D; Gillmore, J D; Hawkins, P N; Reilly, M M

    2015-06-01

    Hereditary transthyretin amyloidosis (ATTR) is a genetically and clinically heterogeneous disease manifesting with predominant peripheral and autonomic neuropathy; cardiomyopathy, or both. ATTR V122I is the most common variant associated with non-neuropathic familial amyloid cardiomyopathy. We present an unusual case of V122I amyloidosis with features of amyloid neuropathy and myopathy, supported by histological confirmation in both sites and diffuse tracer uptake on (99m)Tc-3,3-Diphosphono-1,2-Propanodicarboxylic acid (DPD) scintigraphy throughout skeletal and cardiac muscle. A 64 year old Jamaican man presented with cardiac failure. Cardiac MR revealed infiltrative cardiomyopathy; abdominal fat aspirate confirmed the presence of amyloid, and he was homozygous for the V122I variant of transthyretin. He also described general weakness and EMG demonstrated myopathic features. Sural nerve and vastus lateralis biopsy showed TTR amyloid. The patient is being treated with diflunisal, an oral TTR stabilising agent. Symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition has not previously been described. Extracardiac amyloidosis has implications for diagnosis and treatment. PMID:25819286

  9. The polyphenol Oleuropein aglycone hinders the growth of toxic transthyretin amyloid assemblies.

    Science.gov (United States)

    Leri, Manuela; Nosi, Daniele; Natalello, Antonino; Porcari, Riccardo; Ramazzotti, Matteo; Chiti, Fabrizio; Bellotti, Vittorio; Doglia, Silvia Maria; Stefani, Massimo; Bucciantini, Monica

    2016-04-01

    Transthyretin (TTR) is involved in a subset of familial or sporadic amyloid diseases including senile systemic amyloidosis (SSA), familial amyloid polyneuropathy and cardiomyopathy (FAP/FAC) for which no effective therapy has been found yet. These conditions are characterized by extracellular deposits primarily found in the heart parenchyma and in peripheral nerves whose main component are amyloid fibrils, presently considered the main culprits of cell sufferance. The latter are polymeric assemblies grown from misfolded TTR, either wt or carrying one out of many identified mutations. The recent introduction in the clinical practice of synthetic TTR-stabilizing molecules that reduce protein aggregation provides the rationale to search natural effective molecules able to interfere with TTR amyloid aggregation by hindering the appearance of toxic species or by favoring the growth of harmless aggregates. Here we carried out an in depth biophysical and morphological study on the molecular features of the aggregation of wt- and L55P-TTR involved in SSA or FAP/FAC, respectively, and on the interference with fibril aggregation, stability and toxicity to cardiac HL-1 cells to demonstrate the ability of Oleuropein aglycone (OleA), the main phenolic component of the extra virgin olive oil. We describe the molecular basis of such interference and the resulting reduction of TTR amyloid aggregate cytotoxicity. Our data offer the possibility to validate and optimize the use of OleA or its molecular scaffold to rationally design promising drugs against TTR-related pathologies that could enter a clinical experimental phase. PMID:27012632

  10. TiO 2 chemical vapor deposition on Si(111) in ultrahigh vacuum: Transition from interfacial phase to crystalline phase in the reaction limited regime

    Science.gov (United States)

    Karlsson, P. G.; Richter, J. H.; Andersson, M. P.; Johansson, M. K.-J.; Blomquist, J.; Uvdal, P.; Sandell, A.

    2011-07-01

    The interaction between the metal organic precursor molecule titanium(IV) isopropoxide (TTIP) and three different surfaces has been studied: Si(111)-(7 × 7), SiOx/Si(111) and TiO2. These surfaces represent the different surface compositions encountered during TTIP mediated TiO2 chemical vapor deposition on Si(111). The surface chemistry of the titanium(IV) isopropoxide precursor and the film growth have been explored by core level photoelectron spectroscopy and x-ray absorption spectroscopy using synchrotron radiation. The resulting film morphology has been imaged with scanning tunneling microscopy. The growth rate depends on both surface temperature and surface composition. The behavior can be rationalized in terms of the surface stability of isopropoxy and isopropyl groups, confirming that growth at 573 K is a reaction limited process.

  11. Distribution of beta-amyloid in the canine brain.

    Science.gov (United States)

    Hou, Y; White, R G; Bobik, M; Marks, J S; Russell, M J

    1997-03-01

    The distribution of amyloid-beta protein (A beta) in the canine brain was demonstrated by immunochemistry on serially sectioned tissues from 10 aged mixed breed dogs. Summation of quantitative data and relegation to anatomical sites for the 10 dogs showed A beta to be widely distributed in the cortex and hippocampus while completely absent in the brain stem and cerebellum. The highest density of A beta was in the dentate gyrus of the hippocampus. Cortical areas exhibiting the greatest A beta deposition were the posterior and medial suprasylvius gyrus and the proreus gyrus of the frontal lobe. Unlike humans the canine entorhinal cortex, amygdala, basal ganglia and olfactory bulbs were rarely affected. This suggested that the highly developed olfactory pathways of the canine are generally spared from A beta deposition. PMID:9141082

  12. Amyloid-associated nucleic acid hybridisation.

    Directory of Open Access Journals (Sweden)

    Sebastian Braun

    Full Text Available Nucleic acids promote amyloid formation in diseases including Alzheimer's and Creutzfeldt-Jakob disease. However, it remains unclear whether the close interactions between amyloid and nucleic acid allow nucleic acid secondary structure to play a role in modulating amyloid structure and function. Here we have used a simplified system of short basic peptides with alternating hydrophobic and hydrophilic amino acid residues to study nucleic acid - amyloid interactions. Employing biophysical techniques including X-ray fibre diffraction, circular dichroism spectroscopy and electron microscopy we show that the polymerized charges of nucleic acids concentrate and enhance the formation of amyloid from short basic peptides, many of which would not otherwise form fibres. In turn, the amyloid component binds nucleic acids and promotes their hybridisation at concentrations below their solution K(d, as shown by time-resolved FRET studies. The self-reinforcing interactions between peptides and nucleic acids lead to the formation of amyloid nucleic acid (ANA fibres whose properties are distinct from their component polymers. In addition to their importance in disease and potential in engineering, ANA fibres formed from prebiotically-produced peptides and nucleic acids may have played a role in early evolution, constituting the first entities subject to Darwinian evolution.

  13. Hacking the Code of Amyloid Formation

    Science.gov (United States)

    Pastor, M Teresa; Esteras-Chopo, Alexandra

    2007-01-01

    Many research efforts in the last years have been directed towards understanding the factors determining protein misfolding and amyloid formation. Protein stability and amino acid composition have been identified as the two major factors in vitro. The research of our group has been focused on understanding the relationship between amino acid sequence and amyloid formation. Our approach has been the design of simple model systems that reproduce the biophysical properties of natural amyloids. An amyloid sequence pattern was extracted that can be used to detect amyloidogenic hexapeptide stretches in proteins. We have added evidence supporting that these amyloidogenic stretches can trigger amyloid formation by nonamyloidogenic proteins. Some experimental results in other amyloid proteins will be analyzed under the conclusions obtained in these studies. Our conclusions together with evidences from other groups suggest that amyloid formation is the result of the interplay between a decrease of protein stability, and the presence of highly amyloidogenic regions in proteins. As many of these results have been obtained in vitro, the challenge for the next years will be to demonstrate their validity in in vivo systems. PMID:19164912

  14. Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of Amyloid-β in Th1- and Th17-Versions of Experimental Autoimmune Encephalomyelitis

    OpenAIRE

    Grant, Jacqueline L.; Ghosn, Eliver Eid Bou; Axtell, Robert C.; Herges, Katja; Kuipers, Hedwich F.; Woodling, Nathan S.; Andreasson, Katrin; Herzenberg, Leonard A.; Herzenberg, Leonore A.; Steinman, Lawrence

    2012-01-01

    β-amyloid-42 (Aβ42) and β-amyloid-40 (Aβ40), major components of senile plaque deposits in Alzheimer’s disease (AD), are considered neurotoxic and pro-inflammatory. In multiple sclerosis (MS), Aβ42 is upregulated in brain lesions and damaged axons. Here we found, unexpectedly, that treatment with either Aβ42 or Aβ40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction ...

  15. Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: A multimodal imaging investigation

    Science.gov (United States)

    Racine, Annie M.; Adluru, Nagesh; Alexander, Andrew L.; Christian, Bradley T.; Okonkwo, Ozioma C.; Oh, Jennifer; Cleary, Caitlin A.; Birdsill, Alex; Hillmer, Ansel T.; Murali, Dhanabalan; Barnhart, Todd E.; Gallagher, Catherine L.; Carlsson, Cynthia M.; Rowley, Howard A.; Dowling, N. Maritza; Asthana, Sanjay; Sager, Mark A.; Bendlin, Barbara B.; Johnson, Sterling C.

    2014-01-01

    Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (Aβ+), amyloid indeterminate (Aβi), or amyloid negative (Aβ−) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ− in all three ROIs and in Aβi compared to Aβ− in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses

  16. Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: A multimodal imaging investigation

    Directory of Open Access Journals (Sweden)

    Annie M. Racine

    2014-01-01

    Full Text Available Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD, but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI, in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71 from the Wisconsin Registry for Alzheimer's Prevention (WRAP, a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB positron emission tomography (PET. Participants were grouped as amyloid positive (Aβ+, amyloid indeterminate (Aβi, or amyloid negative (Aβ− based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA, mean diffusivity (MD, axial diffusivity (Da, and radial diffusivity (Dr, were performed based on amyloid grouping. Three regions of interest (ROIs, the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ− in all three ROIs and in Aβi compared to Aβ− in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with

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

    Directory of Open Access Journals (Sweden)

    Johan F Paulsson

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

  18. Pitfalls of voxel-based amyloid PET analyses for diagnosis of Alzheimer's disease. Artifacts due to non-specific uptake in the white matter and the skull

    International Nuclear Information System (INIS)

    Two methods are commonly used in brain image voxel-based analyses widely used for dementia work-ups: 3-dimensional stereotactic surface projections (3D-SSP) and statistical parametric mapping (SPM). The methods calculate the Z-scores of the cortical voxels that represent the significance of differences compared to a database of brain images with normal findings, and visualize them as surface brain maps. The methods are considered useful in amyloid positron emission tomography (PET) analyses to detect small amounts of amyloiddeposits in early-stage Alzheimer's disease (AD), but are not fully validated. We analyzed the 11C-labeled 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227) amyloid PET imaging of 56 subjects (20 individuals with mild cognitive impairment [MCl], 19 AD patients, and 17 non-demented [ND] volunteers) with 3D-SSP and the easy Z-score imaging system (eZIS) that is an SPM-based method. To clarify these methods' limitations, we visually compared Z-score maps output from the two methods and investigated the causes of discrepancies between them. Discrepancies were found in 27 subjects (9 MCl, 13 AD, and 5 ND). Relatively high white matter uptake was considered to cause higher Z-scores on 3D-SSP in 4 subjects (1 MCl and 3 ND). Meanwhile, in 17 subjects (6 MCl, 9 AD, and 2 ND), Z-score overestimation on eZIS corresponded with high skull uptake and disappeared after removing the skull uptake ('scalping'). Our results suggest that non-specific uptakes in the white matter and skull account for errors in voxel-based amyloid PET analyses. Thus, diagnoses based on 3D-SSP data require checking white matter uptake, and 'scalping' is recommended before eZIS analysis. (author)

  19. Rapid Growth of Crystalline Mn5O8 by Self-Limited Multilayer Deposition using Mn(EtCp)2 and O3.

    Science.gov (United States)

    Young, Matthias J; Hare, Christopher D; Cavanagh, Andrew S; Musgrave, Charles B; George, Steven M

    2016-07-20

    This work investigates the use of ozone as a post-treatment of ALD-grown MnO and as a coreactant with bis(ethylcyclopentadienyl)manganese (Mn(EtCp)2) in ALD-like film growth. In situ quartz crystal microbalance measurements are used to monitor the mass changes during growth, which are coupled with ex situ materials characterization following deposition to evaluate the resulting film composition and structure. We determined that during O3 post-treatment of ALD-grown MnO, O3 oxidizes the near-surface region corresponding to a conversion of 22 Å of the MnO film to MnO2. Following oxidation by O3, exposure of Mn(EtCp)2 results in mass gains of over 300 ng/cm(2), which exceeds the expected mass gain for reaction of the Mn(EtCp)2 precursor with surface hydroxyls by over four times. We attribute this high mass gain to adsorbed Mn(EtCp)2 shedding its EtCp ligands at the surface and releasing Mn(II) ions which subsequently diffuse into the bulk film and partially reduce the oxidized film back to MnO. These Mn(EtCp)2 and O3 reactions are combined in sequential steps with (a) Mn(EtCp)2 reacting at the surface of an O-rich layer, shedding its two EtCp ligands and freeing Mn(II) to diffuse into the film followed by (b) O3 oxidizing the film surface and withdrawing Mn from the subsurface to create an O-rich layer. This deposition process results in self-limiting multilayer deposition of crystalline Mn5O8 films with a density of 4.7 g/cm(3) and an anomalously high growth rate of 5.7 Å/cycle. Mn5O8 is a metastable phase of manganese oxide which possesses an intermediate composition between the alternating MnO and MnO2 compositions of the near-surface during the Mn(EtCp)2 and O3 exposures. PMID:27351207

  20. Amyloids in solid-state nuclear magnetic resonance: potential causes of the usually low resolution

    Directory of Open Access Journals (Sweden)

    Espargaró A

    2015-11-01

    Full Text Available Alba Espargaró, Maria Antònia Busquets, Joan Estelrich, Raimon Sabate Department of Physical Chemistry, School of Pharmacy, Institute of Nanoscience and Nanotechnology (IN2UB, University of Barcelona, Barcelona, Spain Abstract: Amyloids are non-crystalline and insoluble, which imply that the classical structural biology tools, ie, X-ray crystallography and solution nuclear magnetic resonance (NMR, are not suitable for their analysis. In the last years, solid-state NMR (ssNMR has emerged as an alternative tool to decrypt the structural signatures of amyloid fibrils, providing major contributions to our understanding of molecular structures of amyloids such as β-amyloid peptide associated with Alzheimer’s disease or fungal prions, among others. Despite this, the wide majority of amyloid fibrils display low resolution by ssNMR. Usually, this low resolution has been attributed to a high disorder or polymorphism of the fibrils, suggesting the existence of diverse elementary β-sheet structures. Here, we propose that a single β-sheet structure could be responsible for the broadening of the line widths in the ssNMR spectra. Although the fibrils and fibers consist of a single elementary structure, the angle of twist of each individual fibril in the mature fiber depends on the number of individual fibrils as well as the fibril arrangement in the final mature fiber. Thus, a wide range of angles of twist could be observed in the same amyloid sample. These twist variations involve changes in amino acid alignments that could be enough to limit the ssNMR resolution. Keywords: amyloid, fibril, misfolding, β-structure, ssNMR, NMR, β-sheet

  1. Genetics Home Reference: hereditary cerebral amyloid angiopathy

    Science.gov (United States)

    ... prognosis of a genetic condition? Genetic and Rare Diseases Information Center Frequency The prevalence of hereditary cerebral amyloid angiopathy is unknown. The Dutch type is the most common, with over 200 ...

  2. Association between memory and amyloid deposition–synaptic dysfunction in people with EMCI, LMCI and Alzheimer’s disease

    DEFF Research Database (Denmark)

    Dauar, Marina; Rowley, Jared; Mohades, Sara;

    Background: Deficits in list of words or history recall performance is associated with regional declines in brain metabolism, neurodegeneration and amyloid deposition. However, little is known regarding the neurocorrelates of these tests in early stages of AD. Here we aimed to investigate the ass...

  3. Islet amyloid polypeptide inserts into phospholipid monolayers as monomer.

    Science.gov (United States)

    Engel, Maarten F M; Yigittop, HaciAli; Elgersma, Ronald C; Rijkers, Dirk T S; Liskamp, Rob M J; de Kruijff, Ben; Höppener, Jo W M; Antoinette Killian, J

    2006-02-24

    Amyloid deposits in the pancreatic islets of Langerhans are thought to be a main factor responsible for death of the insulin-producing islet beta-cells in type 2 diabetes. It is hypothesized that beta-cell death is related to interaction of the 37 amino acid residue human islet amyloid polypeptide (hIAPP), the major constituent of islet amyloid, with cellular membranes. However, the mechanism of hIAPP-membrane interactions is largely unknown. Here, we study the nature and the molecular details of the initial step of hIAPP-membrane interactions by using the monolayer technique. It is shown that both freshly dissolved hIAPP and the non-amyloidogenic mouse IAPP (mIAPP) have a pronounced ability to insert into phospholipid monolayers, even at lipid packing conditions that exceed the conditions that occur in biological membranes. In contrast, the fibrillar form of hIAPP has lost the ability to insert. These results, combined with the observations that both the insertion kinetics and the dependence of insertion on the initial surface pressure are similar for freshly dissolved hIAPP and mIAPP, indicate that hIAPP inserts into phospholipid monolayers most likely as a monomer. In addition, our results suggest that the N-terminal part of hIAPP, which is nearly identical with that of mIAPP, is largely responsible for insertion. This is supported by experiments with hIAPP fragments, which show that a peptide consisting of the 19 N-terminal residues of hIAPP efficiently inserts into phospholipid monolayers, whereas an amyloidogenic decapeptide, consisting of residues 20-29 of hIAPP, inserts much less efficiently. The results obtained here suggest that hIAPP monomers might insert with high efficiency in biological membranes in vivo. This process could play an important role as a first step in hIAPP-induced membrane damage in type 2 diabetes. PMID:16403520

  4. Amyloid Burden Is Associated With Self-Reported Sleep In Non-Demented Late Middle-Aged Adults

    Science.gov (United States)

    Sprecher, Kate E.; Bendlin, Barbara B.; Racine, Annie M.; Okonkwo, Ozioma C.; Christian, Bradley T.; Koscik, Rebecca L.; Sager, Mark A.; Asthana, Sanjay; Johnson, Sterling C.; Benca, Ruth M.

    2015-01-01

    Midlife may be an ideal window for intervention in Alzheimer’s disease (AD). To determine whether sleep is associated with early signs of AD neuropathology (amyloid deposition) in late midlife, we imaged brain amyloid deposits using Positron Emission Tomography (PET) with [C-11]Pittsburgh Compound B (PiB), and assessed sleep with the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study (MOS) Sleep Scale in 98 cognitively healthy adults (aged 62.4 ± 5.7 years) from the Wisconsin Registry for Alzheimer’s Prevention. We used multiple regression to test the extent to which sleep scores predicted regional amyloid burden. Participants reporting less adequate sleep, more sleep problems and greater somnolence on the MOS had greater amyloid burden in AD-sensitive brain regions (angular gyrus, frontal medial orbital cortex, cingulate gyrus and precuneus). Amyloid was not associated with reported sleep amount, symptoms of sleep disordered breathing, trouble falling asleep or ESS. Poor sleep may be a risk factor for AD and a potential early marker of AD or target for preventative interventions in mid-life. PMID:26059712

  5. Amyloid myopathy presenting with respiratory failure.

    OpenAIRE

    Ashe, J.; Borel, C O; Hart, G.; Humphrey, R L; Derrick, D A; Kuncl, R W

    1992-01-01

    Amyloidosis is a rare cause of myopathy. Its prominent or presenting feature may be respiratory failure. Physiological measurement of transdiaphragmatic pressure and biopsy specimens of muscle show the pathological mechanism to be diaphragm weakness due to amyloid infiltration of the diaphragm rather than parenchymal lung involvement. Thus amyloid myopathy even without the typical macroglossia and muscle pseudohypertrophy should be considered as one of the neurological causes of respiratory f...

  6. Characteristics of glucose metabolism and amyloid deposition by positron emission tomography images in Alzheimer's disease%阿尔茨海默病葡萄糖代谢与淀粉样蛋白正电子发射断层显像成像特点

    Institute of Scientific and Technical Information of China (English)

    纪勇; 石志鸿; 蔡莉; 刘帅; 韩彤; 王颖; 刘淑玲; 韩景献; 周玉颖

    2013-01-01

    目的 利用18F-脱氧葡萄糖(FDG)及11C匹兹堡化合物B(PIB)显像探讨阿尔茨海默病(AD)的正电子发射断层显像(PET)影像学特点. 方法 轻度、中度AD各6例患者行神经心理学量表评定及头颅核磁共振(MRI)扫描.12例患者及6例健康对照行FDG-PET和PIB-PET脑显像.通过目测和计算机成像系统对结果进行分析. 结果 轻度和中度AD患者目测分析颞叶内侧萎缩、皮层萎缩、侧脑室扩大无明显差别.轻度AD患者葡萄糖代谢率减低主要部位为颞顶联合区皮层、顶下小叶、颞上回、楔前叶、后扣带回、尾状核等;中度AD患者出现额叶上中回、额下回、颞中回、前扣带回等部位代谢减低;AD患者淀粉样蛋白沉积主要部位为额叶、顶叶皮层、后扣带回、楔前叶、颞叶外侧.AD患者45 min额叶、颞叶外侧、顶叶PIB放射性活性清除率较对照组明显减低,但轻度和中度AD患者PIB清除率没有明显差别. 结论 FDG PET功能成像反应脑部葡萄糖代谢的改变,与痴呆的程度相关,PET PIB成像能反映AD特有的病理改变,与痴呆的程度不相关,FDG PET结合PIB PET对AD的诊断具有重要的意义.%Objective To investigate positron emission tomography (PET) image characteristics of glucose metabolism and amyloid deposition as demonstrated by fluorodeoxyglucose (18 F-FDG) and Pittsburgh Compound B (PiB) in Alzheimer's disease (AD).Methods Patients with mild AD and moderate AD (n=6,each) were included in this study.6 healthy subjects were selected as normal controls.Cognitive function was assessed by the mini-mental state examination,montreal cognitive assessment and Clinical Dementia Rating.Ventricular dilation,cortical and hippocampal atrophy were detected by brain magnetic resonance imaging.18 F FDG and PIB PET cerebral images were performed in patients and normal controls.PET images were analyzed by visual ization and computer imaging system.Results There were no significant

  7. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Rehana Akter

    2016-01-01

    Full Text Available The hormone islet amyloid polypeptide (IAPP, or amylin plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.

  8. Hybrid Amyloid Membranes for Continuous Flow Catalysis.

    Science.gov (United States)

    Bolisetty, Sreenath; Arcari, Mario; Adamcik, Jozef; Mezzenga, Raffaele

    2015-12-29

    Amyloid fibrils are promising nanomaterials for technological applications such as biosensors, tissue engineering, drug delivery, and optoelectronics. Here we show that amyloid-metal nanoparticle hybrids can be used both as efficient active materials for wet catalysis and as membranes for continuous flow catalysis applications. Initially, amyloid fibrils generated in vitro from the nontoxic β-lactoglobulin protein act as templates for the synthesis of gold and palladium metal nanoparticles from salt precursors. The resulting hybrids possess catalytic features as demonstrated by evaluating their activity in a model catalytic reaction in water, e.g., the reduction of 4-nitrophenol into 4-aminophenol, with the rate constant of the reduction increasing with the concentration of amyloid-nanoparticle hybrids. Importantly, the same nanoparticles adsorbed onto fibrils surface show improved catalytic efficiency compared to the same unattached particles, pointing at the important role played by the amyloid fibril templates. Then, filter membranes are prepared from the metal nanoparticle-decorated amyloid fibrils by vacuum filtration. The resulting membranes serve as efficient flow catalysis active materials, with a complete catalytic conversion achieved within a single flow passage of a feeding solution through the membrane.

  9. Relevance of amyloid precursor-like protein 2 C-terminal fragments in pancreatic cancer cells

    OpenAIRE

    PETERS, HALEY L.; Tuli, Amit; Wang, Xiaojian; Liu, Cuiling; Pan, Zenggang; Ouellette, Michel M.; Hollingsworth, Michael A.; MacDonald, Richard G.; Solheim, Joyce C.

    2012-01-01

    In some cellular systems, particularly neurons, amyloid precursor-like protein 2 (APLP2), and its highly homologous family member amyloid precursor protein (APP), have been linked to cellular growth. APLP2 and APP undergo regulated intramembrane proteolysis to produce C-terminal fragments. In this study, we found comprehensive expression of APLP2 C-terminal fragments in a panel of pancreatic cancer cell lines; however, APP C-terminal fragments were notably limited to the BxPC3 cell line. Exte...

  10. AMYLOID BETA ACCUMULATION IN HIV-1-INFECTED BRAIN: THE ROLE OF THE BLOOD BRAIN BARRIER

    OpenAIRE

    András, Ibolya E.; Toborek, Michal

    2012-01-01

    In recent years we face an increase in the aging of the HIV-1-infected population, which is not only due to effective antiretroviral therapy but also to new infections among older people. Even with the use of the antiretroviral therapy, HIV-associated neurocognitive disorders represent an increasing problem as the HIV-1-infected population ages. Increased amyloid beta (Aβ) deposition is characteristic of HIV-1-infected brains, and it has been hypothesized that brain vascular dysfunction contr...

  11. Historical and Current Concepts of Fibrillogenesis and In Vivo Amyloidogenesis: Implications of Amyloid Tissue Targeting

    Directory of Open Access Journals (Sweden)

    Robert eKisilevsky

    2016-05-01

    Full Text Available Historical and current concepts of in vitro fibrillogenesis are considered in the light of disorders in which amyloid is deposited at anatomic sites remote from the site of synthesis of the corresponding precursor protein. These clinical conditions set constraints on the interpretation of information derived from in vitro fibrillogenesis studies. They suggest that in addition to kinetic and thermodynamic factors identified in vitro, fibrillogenesis in vivo is determined by site specific factors most of which have yet to be identified.

  12. Historical and Current Concepts of Fibrillogenesis and In vivo Amyloidogenesis: Implications of Amyloid Tissue Targeting.

    Science.gov (United States)

    Kisilevsky, Robert; Raimondi, Sara; Bellotti, Vittorio

    2016-01-01

    Historical and current concepts of in vitro fibrillogenesis are considered in the light of disorders in which amyloid is deposited at anatomic sites remote from the site of synthesis of the corresponding precursor protein. These clinical conditions set constraints on the interpretation of information derived from in vitro fibrillogenesis studies. They suggest that in addition to kinetic and thermodynamic factors identified in vitro, fibrillogenesis in vivo is determined by site specific factors most of which have yet to be identified. PMID:27243018

  13. 4′-Iodo-4′-Deoxydoxorubicin Disrupts the Fibrillar Structure of Transthyretin Amyloid

    OpenAIRE

    Palha, Joana Almeida; Ballinari, Dario; Amboldi, Nadia; Cardoso, Isabel; Fernandes, Rui; Bellotti, Vittorio; Merlini, Giampaolo; Saraiva, Maria João

    2000-01-01

    Transthyretin (TTR) is a tetrameric protein synthesized mainly by the liver and the choroid plexus, from where it is secreted into the plasma and the cerebrospinal fluid, respectively. Some forms of polyneuropathy, vitreopathy, and cardiomyopathy are caused by the deposition of normal and/or mutant TTR molecules in the form of amyloid fibrils. Familial amyloidotic polyneuropathy is the most common form of TTR amyloidosis related to the V30M variant. It is still unclear the process by which so...

  14. The Effect of Milk Constituents and Crowding Agents on Amyloid Fibril Formation by κ-Casein.

    Science.gov (United States)

    Liu, Jihua; Dehle, Francis C; Liu, Yanqin; Bahraminejad, Elmira; Ecroyd, Heath; Thorn, David C; Carver, John A

    2016-02-17

    When not incorporated into the casein micelle, κ-casein, a major milk protein, rapidly forms amyloid fibrils at physiological pH and temperature. In this study, the effects of milk components (calcium, lactose, lipids, and heparan sulfate) and crowding agents on reduced and carboxymethylated (RCM) κ-casein fibril formation was investigated using far-UV circular dichroism spectroscopy, thioflavin T binding assays, and transmission electron microscopy. Longer-chain phosphatidylcholine lipids, which form the lining of milk ducts and milk fat globules, enhanced RCM κ-casein fibril formation irrespective of whether the lipids were in a monomeric or micellar state, whereas shorter-chain phospholipids and triglycerides had little effect. Heparan sulfate, a component of the milk fat globule membrane and catalyst of amyloid deposition in extracellular tissue, had little effect on the kinetics of RCM κ-casein fibril formation. Major nutritional components such as calcium and lactose also had no significant effect. Macromolecular crowding enhances protein-protein interactions, but in contrast to other fibril-forming species, the extent of RCM κ-casein fibril formation was reduced by the presence of a variety of crowding agents. These data are consistent with a mechanism of κ-casein fibril formation in which the rate-determining step is dissociation from the oligomer to give the highly amyloidogenic monomer. We conclude that the interaction of κ-casein with membrane-associated phospholipids along its secretory pathway may contribute to the development of amyloid deposits in mammary tissue. However, the formation of spherical oligomers such as casein micelles is favored over amyloid fibrils in the crowded environment of milk, within which the occurrence of amyloid fibrils is low. PMID:26807595

  15. 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 amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

  16. Amyloid-linked cellular toxicity triggered by bacterial inclusion bodies

    International Nuclear Information System (INIS)

    The aggregation of proteins in the form of amyloid fibrils and plaques is the characteristic feature of some pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. The mechanisms by which the aggregation processes result in cell damage are under intense investigation but recent data indicate that prefibrillar aggregates are the most proximate mediators of toxicity rather than mature fibrils. Since it has been shown that prefibrillar forms of the nondisease-related misfolded proteins are highly toxic to cultured mammalian cells we have studied the cytoxicity associated to bacterial inclusion bodies that have been recently described as protein deposits presenting amyloid-like structures. We have proved that bacterial inclusion bodies composed by a misfolding-prone β-galactosidase fusion protein are clearly toxic for mammalian cells but the β-galactosidase wild type enzyme forming more structured thermal aggregates does not impair cell viability, despite it also binds and enter into the cells. These results are in the line that the most cytotoxic aggregates are early prefibrilar assemblies but discard the hypothesis that the membrane destabilization is Key event to subsequent disruption of cellular processes, such as ion balance, oxidative state and the eventually cell death

  17. Yeast prions form infectious amyloid inclusion bodies in bacteria

    Directory of Open Access Journals (Sweden)

    Espargaró Alba

    2012-06-01

    Full Text Available Abstract Background Prions were first identified as infectious proteins associated with fatal brain diseases in mammals. However, fungal prions behave as epigenetic regulators that can alter a range of cellular processes. These proteins propagate as self-perpetuating amyloid aggregates being an example of structural inheritance. The best-characterized examples are the Sup35 and Ure2 yeast proteins, corresponding to [PSI+] and [URE3] phenotypes, respectively. Results Here we show that both the prion domain of Sup35 (Sup35-NM and the Ure2 protein (Ure2p form inclusion bodies (IBs displaying amyloid-like properties when expressed in bacteria. These intracellular aggregates template the conformational change and promote the aggregation of homologous, but not heterologous, soluble prionogenic molecules. Moreover, in the case of Sup35-NM, purified IBs are able to induce different [PSI+] phenotypes in yeast, indicating that at least a fraction of the protein embedded in these deposits adopts an infectious prion fold. Conclusions An important feature of prion inheritance is the existence of strains, which are phenotypic variants encoded by different conformations of the same polypeptide. We show here that the proportion of infected yeast cells displaying strong and weak [PSI+] phenotypes depends on the conditions under which the prionogenic aggregates are formed in E. coli, suggesting that bacterial systems might become useful tools to generate prion strain diversity.

  18. Gelsolin amyloid angiopathy causes severe disruption of the arterial wall.

    Science.gov (United States)

    Koskelainen, Susanna; Pihlamaa, Tiia; Suominen, Sinikka; Zhao, Fang; Salo, Tuula; Risteli, Juha; Baumann, Marc; Kalimo, Hannu; Kiuru-Enari, Sari

    2016-08-01

    Hereditary gelsolin amyloidosis (HGA) is a dominantly inherited systemic disease reported worldwide. HGA is characterized by ophthalmological, neurological, and dermatological manifestations. AGel amyloid accumulates at basal lamina of epithelial and muscle cells, thus amyloid angiopathy is encountered in nearly every organ. HGA patients have cardiovascular, hemorrhagic, and potentially vascularly induced neurological problems. To clarify pathomechanisms of AGel angiopathy, we performed histological, immunohistochemical, and electron microscopic analyses on facial temporal artery branches from 8 HGA patients and 13 control subjects. We demonstrate major pathological changes in arteries: disruption of the tunica media, disorganization of vascular smooth muscle cells, and accumulation of AGel fibrils in arterial walls, where they associate with the lamina elastica interna, which becomes fragmented and diminished. We also provide evidence of abnormal accumulation and localization of collagen types I and III and an increase of collagen type I degradation product in the tunica media. Vascular smooth muscle cells appear to be morphologically and semi-quantitatively normal, only their basal lamina is often thickened. In conclusion, angiopathy in HGA results in severe disruption of arterial walls, characterized by prominent AGel deposition, collagen derangement and severe elastolysis, and it may be responsible for several, particularly hemorrhagic, disease manifestations in HGA. PMID:27198069

  19. Amyloid-β Associated Cortical Thinning in Clinically Normal Elderly

    Science.gov (United States)

    Becker, J Alex; Hedden, Trey; Carmasin, Jeremy; Maye, Jacqueline; Rentz, Dorene M; Putcha, Deepti; Fischl, Bruce; Greve, Douglas N; Marshall, Gad A; Salloway, Stephen; Marks, Donald; Buckner, Randy L; Sperling, Reisa A; Johnson, Keith A

    2011-01-01

    Objective Both amyloid-β (Aβ) deposition and brain atrophy are associated with Alzheimer's disease (AD) and the disease process likely begins many years before symptoms appear. We sought to determine whether clinically normal (CN) older individuals with Aβ deposition revealed by positron emission tomography (PET) imaging using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume reductions in a pattern similar to that seen in AD. Methods A total of 119 older individuals (87 CN subjects and 32 patients with mild AD) underwent PiB PET and high-resolution structural magnetic resonance imaging (MRI). Regression models were used to relate PiB retention to cortical thickness and hippocampal volume. Results We found that PiB retention in CN subjects was (1) age-related and (2) associated with cortical thickness reductions, particularly in parietal and posterior cingulate regions extending into the precuneus, in a pattern similar to that observed in mild AD. Hippocampal volume reduction was variably related to Aβ deposition. Interpretation We conclude that Aβ deposition is associated with a pattern of cortical thickness reduction consistent with AD prior to the development of cognitive impairment. ANN NEUROL 2010; PMID:21437929

  20. The Role of the 14–20 Domain of the Islet Amyloid Polypeptide in Amyloid Formation

    Directory of Open Access Journals (Sweden)

    Sharon Gilead

    2008-01-01

    Full Text Available The molecular mechanism of amyloid formation by the islet amyloid polypeptide (IAPP has been intensively studied since its identification in the late 1980s. The IAPP(20–29 region is considered to be the central amyloidogenic module of the polypeptide. This assumption is mainly based on the amyloidogenic properties of the region and on the large sequence diversity within this region between the human and mouse IAPP, as the mouse IAPP does not form amyloids. A few years ago, another region within IAPP was identified that seems to be at least as important as IAPP(20–29 in facilitation of molecular recognition that leads to amyloid formation. Here, we reinforce our and others' previous findings by analyzing supporting evidence from the recent literature. Moreover, we provide new proofs to our hypothesis by comparing between the amyloidogenic properties of the two regions derived from the IAPP of cats, which is also known to form amyloid fibrils.

  1. 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.

  2. Advances in the pathogenesis of Alzheimer’s disease: a re-evaluation of amyloid cascade hypothesis

    Directory of Open Access Journals (Sweden)

    Dong Suzhen

    2012-09-01

    Full Text Available Abstract Alzheimer’s disease (AD is a common neurodegenerative disease characterized clinically by progressive deterioration of memory, and pathologically by histopathological changes including extracellular deposits of amyloid-beta (A-beta peptides forming senile plaques (SP and the intracellular neurofibrillary tangles (NFT of hyperphosphorylated tau in the brain. This review focused on the new developments of amyloid cascade hypothesis with details on the production, metabolism and clearance of A-beta, and the key roles of some important A-beta-related genes in the pathological processes of AD. The most recent research advances in genetics, neuropathology and pathogenesis of the disease were also discussed.

  3. The pentraxins, C-reactive protein and serum amyloid P component, are cleared and catabolized by hepatocytes in vivo.

    OpenAIRE

    Hutchinson, W L; Noble, G. E.; Hawkins, P N; Pepys, M B

    1994-01-01

    The cellular sites of clearance and degradation of the pentraxin plasma proteins, C-reactive protein, the classical acute phase reactant, and serum amyloid P component (SAP), a universal constituent of amyloid deposits, were sought using the ligand 125I-tyramine cellobiose (TC) which is substantially retained within the cells in which catabolism takes place. Pentraxins labeled with 125I-TC showed the same in vitro and in vivo ligand binding and the same in vivo plasma t1/2 as the directly iod...

  4. Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology.

    Science.gov (United States)

    Spangenberg, Elizabeth E; Lee, Rafael J; Najafi, Allison R; Rice, Rachel A; Elmore, Monica R P; Blurton-Jones, Mathew; West, Brian L; Green, Kim N

    2016-04-01

    In addition to amyloid-β plaque and tau neurofibrillary tangle deposition, neuroinflammation is considered a key feature of Alzheimer's disease pathology. Inflammation in Alzheimer's disease is characterized by the presence of reactive astrocytes and activated microglia surrounding amyloid plaques, implicating their role in disease pathogenesis. Microglia in the healthy adult mouse depend on colony-stimulating factor 1 receptor (CSF1R) signalling for survival, and pharmacological inhibition of this receptor results in rapid elimination of nearly all of the microglia in the central nervous system. In this study, we set out to determine if chronically activated microglia in the Alzheimer's disease brain are also dependent on CSF1R signalling, and if so, how these cells contribute to disease pathogenesis. Ten-month-old 5xfAD mice were treated with a selective CSF1R inhibitor for 1 month, resulting in the elimination of ∼80% of microglia. Chronic microglial elimination does not alter amyloid-β levels or plaque load; however, it does rescue dendritic spine loss and prevent neuronal loss in 5xfAD mice, as well as reduce overall neuroinflammation. Importantly, behavioural testing revealed improvements in contextual memory. Collectively, these results demonstrate that microglia contribute to neuronal loss, as well as memory impairments in 5xfAD mice, but do not mediate or protect from amyloid pathology.

  5. 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

  6. 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

  7. Amyloid goiter presented as a subacute thyroiditis-like symptom in a patient with hypersensitivity vasculitis.

    Science.gov (United States)

    Nagai, Y; Ohta, M; Yokoyama, H; Takamura, T; Kobayashi, K I

    1998-06-01

    We present a 25-year-old woman with amyloid goiter due to hypersensitivity vasculitis, who developed transient thyrotoxicosis resembling subacute thyroiditis. She received prednisolone (20 mg/ day) for three years for hypersensitivity vasculitis, and was diagnosed as having secondary amyloidosis by biopsies of the stomach, rectum and kidneys. She noticed neck swelling with severe right neck tenderness, palpitation, hyperhidrosis and weight loss. An elastic firm diffuse goiter was palpable, and the upper pole of the right lobe was extremely tender. Her serum free T4 and T3 levels were high, and the serum TSH was suppressed to subnormal. She was positive for serum C-reactive protein. Anti-thyroidal autoantibodies were all negative. Her thyrotoxicosis subsided spontaneously within one week. Serum titers of antibodies to various viruses were unchanged during the clinical course for two weeks, but she was positive for HLA B35. Examination of a needle-biopsy specimen of the thyroid gland showed extensive amyloid deposition and no evidence of subacute thyroiditis. We considered her transient thyrotoxicosis to be associated with amyloid goiter. The clinical course of this case was similar to the subacute thyroiditis-like syndrome, first described by Ikenoue et al. When patients with primary or secondary amyloidosis have symptoms and signs of subacute thyroiditis, but develop an unusual course, amyloid goiter should be considered. PMID:9790279

  8. Tackling amyloidogenesis in Alzheimer’s disease with A2V variants of Amyloid

    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

  9. 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.

  10. Systemic Amyloid A Amyloidosis in Island Foxes (Urocyon littoralis): Severity and Risk Factors.

    Science.gov (United States)

    Gaffney, P M; Witte, C; Clifford, D L; Imai, D M; O'Brien, T D; Trejo, M; Liberta, F; Annamalai, K; Fändrich, M; Masliah, E; Munson, L; Sigurdson, C J

    2016-05-01

    Systemic amyloid A (AA) amyloidosis is highly prevalent (34%) in endangered island foxes (Urocyon littoralis) and poses a risk to species recovery. Although elevated serum AA (SAA) from prolonged or recurrent inflammation predisposes to AA amyloidosis, additional risk factors are poorly understood. Here we define the severity of glomerular and medullary renal amyloid and identify risk factors for AA amyloidosis in 321 island foxes necropsied from 1987 through 2010. In affected kidneys, amyloid more commonly accumulated in the medullary interstitium than in the glomeruli (98% [n= 78 of 80] vs 56% [n= 45], respectively;P< .0001), and medullary deposition was more commonly severe (19% [n= 20 of 105]) as compared with glomeruli (7% [n= 7];P= .01). Univariate odds ratios (ORs) of severe renal AA amyloidosis were greater for short- and long-term captive foxes as compared with free-ranging foxes (ORs = 3.2, 3.7, respectively; overall P= .05) and for females as compared with males (OR = 2.9;P= .05). Multivariable logistic regression revealed that independent risk factors for amyloid development were increasing age class (OR = 3.8;P< .0001), San Clemente Island subspecies versus San Nicolas Island subspecies (OR = 5.3;P= .0003), captivity (OR = 5.1;P= .0001), and nephritis (OR = 2.3;P= .01). The increased risk associated with the San Clemente subspecies or captivity suggests roles for genetic as well as exogenous risk factors in the development of AA amyloidosis. PMID:26419399

  11. Scintigraphic imaging and turnover studies with iodine-131 labelled serum amyloid P component in systemic amyloidosis

    International Nuclear Information System (INIS)

    Radiolabelled serum amyloid P component (SAP) is a specific tracer for amyloid. Iodine-123 has ideal physical characteristics for scintigraphy but is expensive and not widely available. Here we report serial imaging and turnover studies in which we labelled SAP with iodine-131, a cheap alternative isotope which would be expected to yield poorer images but permit more prolonged turnover measurements. Imaging and plasma clearance and whole body retention (WBR) of tracer were studied for up to 7 days in ten patients with proven systemic AL amyloidosis and two patients in whom the diagnosis was suspected, after i.v. administration of about 37 MBq of 131I-SAP. Normal blood pool images were obtained in the latter two subjects and amyloidosis was subsequently refuted histologically. WBR at 48 h was 65% of the injected dose (i.d.). Among the other ten patients, amyloid deposits were identified in the spleen in eight cases, liver in five and kidneys in four; other sites that gave positive results included bone, joints and soft tissues, and the myocardium in one case. Up to 95% of the tracer localised into amyloid within 6-h, and the values for WBR became progressively more discriminating during the study period, exceeding the normal reference value (131I-SAP produced diagnostic scans in every patient in this series and, coupled with the detailed turnover information, is adequate for monitoring disease progress. (orig.)

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

    Directory of Open Access Journals (Sweden)

    Francesca Crosta

    2015-01-01

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

  13. 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

    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 underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear

  14. Appropriate Use Criteria for Amyloid PET

    Science.gov (United States)

    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 potentially be appropriately used. Peer-reviewed, published literature was searched to ascertain available evidence relevant to these scenarios, and the AIT developed a consensus of expert opinion. While empirical evidence of impact on clinical outcomes is not yet available, a set of specific Appropriate Use Criteria (AUC) were agreed upon that define the types of patients and clinical circumstances in which amyloid PET could be used. Both appropriate and inappropriate uses were considered and formulated, and are reported and discussed here. Because both dementia care and amyloid PET technology are in active development, these AUC will require periodic reassessment. Future research directions are also outlined, including diagnostic utility and patient-centered outcomes. PMID:23360977

  15. 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.

  16. 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....

  17. Protective effects of ferulic acid in amyloid precursor protein plus presenilin-1 transgenic mouse model of Alzheimer disease.

    Science.gov (United States)

    Yan, Ji-Jing; Jung, Jun-Sub; Kim, Taek-Keun; Hasan, Ashraful; Hong, Chang-Won; Nam, Ju-Suk; Song, Dong-Keun

    2013-01-01

    We previously reported the protective effects of long-term administration of ferulic acid against the in vivo toxicity of β-amyloid peptide administered intracerebroventricularly in mice. In the present study, we investigated the effects of ferulic acid in transgenic amyloid precursor protein (APP)swe/presenilin 1 (PS1)dE9 (APP/PS1) mouse model of Alzheimer disease (AD). Chronic (for 6 months from the age of 6 to 12 months) oral administration of ferulic acid at a dose of 5.3 mg/kg/day significantly enhanced the performance in novel-object recognition task, and reduced amyloid deposition and interleukin-1 beta (IL-1β) levels in the frontal cortex. These results suggest that ferulic acid at a certain dosage could be useful for prevention and treatment of AD.

  18. S100A12 suppresses pro-inflammatory, but not pro-thrombotic functions of serum amyloid A.

    Directory of Open Access Journals (Sweden)

    Yuen Ming Chung

    Full Text Available S100A12 is elevated in the circulation in patients with chronic inflammatory diseases and recent studies indicate pleiotropic functions. Serum amyloid A induces monocyte cytokines and tissue factor. S100A12 did not stimulate IL-6, IL-8, IL-1β or TNF-α production by human peripheral blood mononuclear cells but low amounts consistently reduced cytokine mRNA and protein levels induced by serum amyloid A, by ∼49% and ∼46%, respectively. However, S100A12 did not affect serum amyloid A-induced monocyte tissue factor. In marked contrast, LPS-induced cytokines or tissue factor were not suppressed by S100A12. S100A12 did not alter cytokine mRNA stability or the cytokine secretory pathway. S100A12 and serum amyloid A did not appear to form complexes and although they may have common receptors, suppression was unlikely via receptor competition. Serum amyloid A induces cytokines via activation of NF-κB and the MAPK pathways. S100A12 reduced serum amyloid A-, but not LPS-induced ERK1/2 phosphorylation to baseline. It did not affect JNK or p38 phosphorylation or the NF-κB pathway. Reduction in ERK1/2 phosphorylation by S100A12 was unlikely due to changes in intracellular reactive oxygen species, Ca(2+ flux or to recruitment of phosphatases. We suggest that S100A12 may modulate sterile inflammation by blunting pro-inflammatory properties of lipid-poor serum amyloid A deposited in chronic lesions where both proteins are elevated as a consequence of macrophage activation.

  19. 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

    -implicated proteins can induce antigen-specific anti-inflammatory immune responses in mucosal lymphoid tissue which then act systemically. We hypothesized that chronic mucosal administration of Abeta peptide might induce an anti-inflammatory process in AD brain tissue that could beneficially affect......Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease......-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...

  20. Microglial responses to amyloid β peptide opsonization and indomethacin treatment

    Directory of Open Access Journals (Sweden)

    Leonard Brian

    2005-08-01

    Full Text Available Abstract Background Recent studies have suggested that passive or active immunization with anti-amyloid β peptide (Aβ antibodies may enhance microglial clearance of Aβ deposits from the brain. However, in a human clinical trial, several patients developed secondary inflammatory responses in brain that were sufficient to halt the study. Methods We have used an in vitro culture system to model the responses of microglia, derived from rapid autopsies of Alzheimer's disease patients, to Aβ deposits. Results Opsonization of the deposits with anti-Aβ IgG 6E10 enhanced microglial chemotaxis to and phagocytosis of Aβ, as well as exacerbated microglial secretion of the pro-inflammatory cytokines TNF-α and IL-6. Indomethacin, a common nonsteroidal anti-inflammatory drug (NSAID, had no effect on microglial chemotaxis or phagocytosis, but did significantly inhibit the enhanced production of IL-6 after Aβ opsonization. Conclusion These results are consistent with well known, differential NSAID actions on immune cell functions, and suggest that concurrent NSAID administration might serve as a useful adjunct to Aβ immunization, permitting unfettered clearance of Aβ while dampening secondary, inflammation-related adverse events.

  1. 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.)

  2. Compressive deformation of ultralong amyloid fibrils

    Science.gov (United States)

    Paparcone, Raffaella; Cranford, Steven; Buehler, Markus J.

    2010-12-01

    Involved in various neurodegenerative diseases, amyloid fibrils and plaques feature a hierarchical structure, ranging from the atomistic to the micrometer scale. At the atomistic level, a dense and organized hydrogen bond network is resembled in a beta-sheet rich secondary structure, which drives a remarkable stiffness in the range of 10-20GPa, larger than many other biological nanofibrils, a result confirmed by both experiment and theory. However, the understanding of how these exceptional mechanical properties transfer from the atomistic to the nanoscale remains unknown. Here we report a multiscale analysis that, from the atomistic-level structure of a single fibril, extends to the mesoscale level, reaching size scales of hundreds of nanometers. We use parameters directly derived from full atomistic simulations of A β (1-40) amyloid fibrils to parameterize a mesoscopic coarse-grained model, which is used to reproduce the elastic properties of amyloid fibrils. We then apply our mesoscopic model in an analysis of the buckling behavior of amyloid fibrils with different lengths and report a comparison with predictions from continuum beam theory. An important implication of our results is a severe reduction of the effective modulus due to buckling, an effect that could be important to interpret experimental results of ultra-long amyloid fibrils. Our model represents a powerful tool to mechanically characterize molecular structures on the order of hundreds of nanometers to micrometers on the basis of the underlying atomistic behavior. The work provides insight into structural and mechanical properties of amyloid fibrils and may enable further analysis of larger-scale assemblies such as amyloidogenic bundles or plaques as found in disease states.

  3. 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

  4. Amyloids or prions? That is the question.

    Science.gov (United States)

    Sabate, Raimon; Rousseau, Frederic; Schymkowitz, Joost; Batlle, Cristina; Ventura, Salvador

    2015-01-01

    Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation.

  5. Quenched Hydrogen Exchange NMR of Amyloid Fibrils.

    Science.gov (United States)

    Alexandrescu, Andrei T

    2016-01-01

    Amyloid fibrils are associated with a number of human diseases. These aggregatively misfolded intermolecular β-sheet assemblies constitute some of the most challenging targets in structural biology because to their complexity, size, and insolubility. Here, protocols and controls are described for experiments designed to study hydrogen-bonding in amyloid fibrils indirectly, by transferring information about amide proton occupancy in the fibrils to the dimethyl sulfoxide-denatured state. Since the denatured state is amenable to solution NMR spectroscopy, the method can provide residue-level-resolution data on hydrogen exchange for the monomers that make up the fibrils.

  6. White matter hyperintensities are associated with amyloid burden in APOE4 non-carriers.

    Science.gov (United States)

    Noh, Young; Seo, Sang Won; Jeon, Seun; Lee, Jong Min; Kim, Jung-Hyun; Kim, Geon Ha; Cho, Hanna; Yoon, Cindy W; Kim, Hee Jin; Ye, Byoung Seok; Kim, Sung Tae; Choe, Yearn Seong; Lee, Kyung-Han; Kim, Jae Seung; Ewers, Michael; Weiner, Michael W; Lee, Jae-Hong; Werring, David J; Kang, Dae Ryong; Kim, Chang Soo; Na, Duk L

    2014-01-01

    Previous preclinical studies have suggested a close relationship between cerebrovascular disease (CVD) and Alzheimer's disease. However, a direct correlation between CVD and amyloid burden has not yet been shown in humans. If there is a relationship between CVD and amyloid burden, it is possible that the apolipoprotein E4 (APOE4) genotype may have an effect on this relationship because APOE4 is a risk factor for the development of AD. We therefore evaluated the effects of APOE4 on the relationship between white matter hyperintensities (WMH), a marker of CVD, and amyloid burden, measured by 11C-Pittsburgh compound B (PiB) PET. We recruited 53 patients with subcortical vascular cognitive impairments, who had both WMH on MRI and amyloid deposition assessed by PiB PET. Twenty-two of these patients were APOE4 carriers (41.5%). In the APOE4 non-carriers, a significant positive correlation was shown between the volume of WMH and PiB retention (β = 7.0 × 10-3, p = 0.034) while no significant correlation was found in APOE4 carriers (β = -9.0 × 10-3, p = 0.085). Statistical parametric mapping analyses in APOE4 non-carriers showed that WMH were associated with PiB retention in the bilateral medial occipitotemporal gyrus, cuneus, and superior cerebellum. Our results suggested that WMH are correlated with amyloid burden especially in the posterior brain regions in APOE4 non-carriers. However, this correlation was not observed in APOE4 carriers, perhaps because in these subjects the influence of APOE4 overrides the effect of CVD.

  7. Effect of amyloid peptides on serum withdrawal-induced cell differentiation and cell viability

    Institute of Scientific and Technical Information of China (English)

    Yi Peng WANG; Ze Fen WANG; Ying Chun ZHANG; Qing TIAN; Jian Zhi WANG

    2004-01-01

    Abnormal deposition of amyloid-β(Aβ) peptides and formation of neuritic plaques are recognized as pathological processes in Alzheimer's disease (AD) brain. By using amyloid precursor protein (APP) transfected cells, this study aims to investigate the effect of overproduction of Aβ on cell differentiation and cell viability. It was shown that after serum withdrawal, untransfected cell (N2a/Wt) and vector transfected cells (N2a/vector) extended long and branched cell processes, whereas no neurites was induced in wild type APP (N2a/APP695) and Swedish mutant APP (N2a/APPswe) transfected N2a cells. After differentiation by serum withdrawal, the localization of APP/Aβ and neurofilament was extended to neurites, whereas those of APP-transfected cells were still restricted within the cell body. Levels of both APP and Aβ were significantly higher in N2a/APP695 and N2a/APPswe than in N2a/Wt, as determined by Western blot and Sandwich ELISA, respectively. To further investigate the effect of Aβ on the inhibition of cell differentiation,we added exogenously the similar level or about 10-times of the Aβ level produced by N2a/APP695 and N2a/APPswe to the culture medium and co-cultured with N2a/Wt for 12 h, and we found that the inhibition of serum withdrawalinduced differentiation observed in N2a/APP695 and N2a/APPswe could not be reproduced by exogenous administration of Aβ into N2a/Wt. We also observed that neither endogenous production nor exogenous addition of Aβ1-40 or Aβ1-42, even to hundreds fold of the physiological concentration, affected obviously the cell viability. These results suggest that the overproduction of Aβ could not arrest cell differentiation induced by serum deprivation and that, at least to a certain degree and in a limited time period, is not toxic to cell viability.

  8. Designed amyloid fibers as materials for selective carbon dioxide capture.

    Science.gov (United States)

    Li, Dan; Furukawa, Hiroyasu; Deng, Hexiang; Liu, Cong; Yaghi, Omar M; Eisenberg, David S

    2014-01-01

    New materials capable of binding carbon dioxide are essential for addressing climate change. Here, we demonstrate that amyloids, self-assembling protein fibers, are effective for selective carbon dioxide capture. Solid-state NMR proves that amyloid fibers containing alkylamine groups reversibly bind carbon dioxide via carbamate formation. Thermodynamic and kinetic capture-and-release tests show the carbamate formation rate is fast enough to capture carbon dioxide by dynamic separation, undiminished by the presence of water, in both a natural amyloid and designed amyloids having increased carbon dioxide capacity. Heating to 100 °C regenerates the material. These results demonstrate the potential of amyloid fibers for environmental carbon dioxide capture.

  9. Instrumental Activities of Daily Living Impairment Is Associated with Increased Amyloid Burden

    Science.gov (United States)

    Marshall, Gad A.; Olson, Lauren E.; Frey, Meghan T.; Maye, Jacqueline; Becker, J. Alex; Rentz, Dorene M.; Sperling, Reisa A.; Johnson, Keith A.

    2011-01-01

    Background/Aims Instrumental activities of daily living (IADL) impairment in Alzheimer's disease has been associated with global amyloid deposition in postmortem studies. We sought to determine whether IADL impairment is associated with increased cortical Pittsburgh Compound B (PiB) retention. Methods Fifty-five subjects (19 normal older controls, NC, and 36 with mild cognitive impairment, MCI) underwent clinical assessments and dynamic PiB positron emission tomography imaging. Results A linear multiple regression model showed that greater IADL impairment was associated with greater global PiB retention in all subjects (R2 = 0.40; unstandardized partial regression coefficient, β = 5.8; p = 0.0002) and in MCI subjects only (R2 = 0.28; β = 6.1; p = 0.003), but not in NC subjects only. Conclusion These results suggest that daily functional impairment is related to greater amyloid burden in MCI. PMID:21778725

  10. Effects of propofol and sevoflurane anesthesia on cognitive function and amyloid beta protein deposition in hippocampi of aged mice%异丙酚和七氟醚麻醉对老龄小鼠认知功能和海马β淀粉样蛋白沉积的影响

    Institute of Scientific and Technical Information of China (English)

    张军; 杨红梅; 谢淑华; 王雷; 耿立成

    2015-01-01

    Objective To evaluate the effects of propofol and sevoflurane anesthesia on cognitive function and amyloid beta protein ( Aβ) deposition in hippocampi of aged mice. Methods Thirty⁃six SAMP8 mice, aged 6 months, weighing 29-32 g, were randomly assigned into 4 groups ( n=9 each) using a random number table: control group ( group C ) , propofol anesthesia group ( group P ) , sevoflurane anesthesia group (group S) and propofol plus sevoflurane anesthesia group (group PS). In group P, propofol 140 mg∕kg was injected intraperitoneally, when righting reflex occurred, additional propofol 70 mg∕kg was given, and when it occurred again, additional propofol 40 mg∕kg was given. Group S continuously inhaled 1% sevoflurane for 120 min. Group PS continuously inhaled 2% sevoflurane for 120 min, and when righting reflex occurred, additional propofol 40 mg∕kg was given. Anesthesia was maintained for 120 min in P, S and PS groups. Before anesthesia and at 7, 14 and 28 days after anesthesia, Morris water maze test was performed, and the escape latency was recorded. Hippocampi were obtained to determine the expression of Aβ using immuno⁃histochemistry. Results Compared with group C, the escape latency was significantly prolonged at 7 days after anesthesia, and the expression of Aβwas up⁃regulated at 7, 14 and 28 days after anesthesia in group S, and no significant change was found in the parameters mentioned above in P and PS groups. Compared with the value at 7 days after anesthesia, the expression of Aβ was significantly down⁃regulated at 14 and 28 days after anesthesia in group S, and no significant change was found in the expression of Aβ at 14 and 28 days after anesthesia in C, P and PS groups. Conclusion Although sevoflurane anesthesia promotes Aβ deposition in hippocampi, it only causes short⁃term cognitive dysfunction, however, anesthesia with propofol or with propofol in combination with sevoflurane produces no influence in aged mice.%目的:评价

  11. Aspects of structural landscape of human islet amyloid polypeptide

    International Nuclear Information System (INIS)

    The human islet amyloid polypeptide (hIAPP) co-operates with insulin to maintain glycemic balance. It also constitutes the amyloid plaques that aggregate in the pancreas of type-II diabetic patients. We have performed extensive in silico investigations to analyse the structural landscape of monomeric hIAPP, which is presumed to be intrinsically disordered. For this, we construct from first principles a highly predictive energy function that describes a monomeric hIAPP observed in a nuclear magnetic resonance experiment, as a local energy minimum. We subject our theoretical model of hIAPP to repeated heating and cooling simulations, back and forth between a high temperature regime where the conformation resembles a random walker and a low temperature limit where no thermal motions prevail. We find that the final low temperature conformations display a high level of degeneracy, in a manner which is fully in line with the presumed intrinsically disordered character of hIAPP. In particular, we identify an isolated family of α-helical conformations that might cause the transition to amyloidosis, by nucleation

  12. Aspects of structural landscape of human islet amyloid polypeptide

    Energy Technology Data Exchange (ETDEWEB)

    He, Jianfeng, E-mail: hjf@bit.edu.cn; Dai, Jin, E-mail: daijing491@gmail.com [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Li, Jing, E-mail: jinglichina@139.com [Institute of Biopharmaceutical Research, Yangtze River Pharmaceutical Group Beijing Haiyan Pharmaceutical Co., Ltd, Beijing 102206 (China); Peng, Xubiao, E-mail: xubiaopeng@gmail.com [Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Niemi, Antti J., E-mail: Antti.Niemi@physics.uu.se [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Laboratoire de Mathematiques et Physique Theorique CNRS UMR 6083, Fédération Denis Poisson, Université de Tours, Parc de Grandmont, F37200 Tours (France)

    2015-01-28

    The human islet amyloid polypeptide (hIAPP) co-operates with insulin to maintain glycemic balance. It also constitutes the amyloid plaques that aggregate in the pancreas of type-II diabetic patients. We have performed extensive in silico investigations to analyse the structural landscape of monomeric hIAPP, which is presumed to be intrinsically disordered. For this, we construct from first principles a highly predictive energy function that describes a monomeric hIAPP observed in a nuclear magnetic resonance experiment, as a local energy minimum. We subject our theoretical model of hIAPP to repeated heating and cooling simulations, back and forth between a high temperature regime where the conformation resembles a random walker and a low temperature limit where no thermal motions prevail. We find that the final low temperature conformations display a high level of degeneracy, in a manner which is fully in line with the presumed intrinsically disordered character of hIAPP. In particular, we identify an isolated family of α-helical conformations that might cause the transition to amyloidosis, by nucleation.

  13. Fatal transmissible amyloid encephalopathy: a new type of prion disease associated with lack of prion protein membrane anchoring.

    Directory of Open Access Journals (Sweden)

    Bruce Chesebro

    2010-03-01

    Full Text Available Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres. PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen, a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI. Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease.

  14. Bap: A New Type of Functional Amyloid.

    Science.gov (United States)

    Di Martino, Patrick

    2016-09-01

    Bacteria can build a biofilm matrix scaffold from exopolysaccharides or proteins, and DNA. In a recent report, Taglialegna and colleagues show that pathogenic Staphylococcus aureus produces a protein scaffold based on amyloid assembly of fragments from the biofilm-associated protein. Amyloidogenesis occurs in response to environmental signals.

  15. Calumenin interacts with serum amyloid P component

    DEFF Research Database (Denmark)

    Vorum, H; Jacobsen, Christian; Honoré, Bent

    2000-01-01

    with calumenin in the presence of Ca(2+). Amino acid sequencing identified this protein as serum amyloid P component (SAP). Furthermore, we verified and characterized the calumenin-SAP interaction by the surface plasmon resonance technique. The findings indicate that calumenin may participate...

  16. Bap: A New Type of Functional Amyloid.

    Science.gov (United States)

    Di Martino, Patrick

    2016-09-01

    Bacteria can build a biofilm matrix scaffold from exopolysaccharides or proteins, and DNA. In a recent report, Taglialegna and colleagues show that pathogenic Staphylococcus aureus produces a protein scaffold based on amyloid assembly of fragments from the biofilm-associated protein. Amyloidogenesis occurs in response to environmental signals. PMID:27451288

  17. Humanized Tau Mice with Regionalized Amyloid Exhibit Behavioral Deficits but No Pathological Interaction

    Science.gov (United States)

    Yetman, Michael J.; Fowler, Stephanie W.; Jankowsky, Joanna L.

    2016-01-01

    Alzheimer’s disease (AD) researchers have struggled for decades to draw a causal link between extracellular Aβ aggregation and intraneuronal accumulation of microtubule-associated protein tau. The amyloid cascade hypothesis posits that Aβ deposition promotes tau hyperphosphorylation, tangle formation, cell loss, vascular damage, and dementia. While the genetics of familial AD and the pathological staging of sporadic disease support this sequence of events, attempts to examine the molecular mechanism in transgenic animal models have largely relied on models of other inherited tauopathies as the basis for testing the interaction with Aβ. In an effort to more accurately model the relationship between Aβ and wild-type tau in AD, we intercrossed mice that overproduce human Aβ with a tau substitution model in which all 6 isoforms of the human protein are expressed in animals lacking murine tau. We selected an amyloid model in which pathology was biased towards the entorhinal region so that we could further examine whether the anticipated changes in tau phosphorylation occurred at the site of Aβ deposition or in synaptically connected regions. We found that Aβ and tau had independent effects on locomotion, learning, and memory, but found no behavioral evidence for an interaction between the two transgenes. Moreover, we saw no indication of amyloid-induced changes in the phosphorylation or aggregation of human tau either within the entorhinal area or elsewhere. These findings suggest that robust amyloid pathology within the medial temporal lobe has little effect on the metabolism of wild type human tau in this model. PMID:27070146

  18. Herpes simplex virus interferes with amyloid precursor protein processing

    Directory of Open Access Journals (Sweden)

    Itzhaki Ruth F

    2005-08-01

    Full Text Available Abstract Background The early events underlying Alzheimer's disease (AD remain uncertain, although environmental factors may be involved. Work in this laboratory has shown that the combination of herpes simplex virus type 1 (HSV1 in brain and carriage of the APOE-ε4 allele of the APOE gene strongly increases the risk of developing AD. The development of AD is thought to involve abnormal aggregation or deposition of a 39–43 amino acid protein – β amyloid (Aβ – within the brain. This is cleaved from the much larger transmembranal protein 'amyloid precursor protein' (APP. Any agent able to interfere directly with Aβ or APP metabolism may therefore have the capacity to contribute towards AD. One recent report showed that certain HSV1 glycoprotein peptides may aggregate like Aβ; a second study described a role for APP in transport of virus in squid axons. However to date the effects of acute herpesvirus infection on metabolism of APP in human neuronal-type cells have not been investigated. In order to find if HSV1 directly affects APP and its degradation, we have examined this protein from human neuroblastoma cells (normal and transfected with APP 695 infected with the virus, using Western blotting. Results We have found that acute HSV1 (and also HSV2 infection rapidly reduces full length APP levels – as might be expected – yet surprisingly markedly increases levels of a novel C-terminal fragment of APP of about 55 kDa. This band was not increased in cells treated with the protein synthesis inhibitor cycloheximide Conclusion Herpes virus infection leads to rapid loss of full length APP from cells, yet also causes increased levels of a novel 55 kDa C-terminal APP fragment. These data suggest that infection can directly alter the processing of a transmembranal protein intimately linked to the aetiology of AD.

  19. Serum amyloid A inhibits osteoclast differentiation to maintain macrophage function.

    Science.gov (United States)

    Kim, Jiseon; Yang, Jihyun; Park, Ok-Jin; Kang, Seok-Seong; Yun, Cheol-Heui; Han, Seung Hyun

    2016-04-01

    Serum amyloid A is an acute phase protein that is elevated under inflammatory conditions. Additionally, the serum levels of serum amyloid A are associated with the progression of inflammatory arthritis; thus, serum amyloid A might be involved in the regulation of osteoclast differentiation. In the present study, we examined the effects of serum amyloid A on osteoclast differentiation and function. When bone marrow-derived macrophages, as osteoclast precursors, were stimulated with serum amyloid A in the presence of M-CSF and receptor activator of nuclear factor-κB ligand, osteoclast differentiation and its bone-resorption activity were substantially inhibited. TLR2 was important in the inhibitory effect of serum amyloid A on osteoclast differentiation, because serum amyloid A stimulated TLR2. The inhibitory effect was absent in bone marrow-derived macrophages obtained from TLR2-deficient mice. Furthermore, serum amyloid A inhibited the expression of c-Fos and nuclear factor of activated T cells c1, which are crucial transcription factors for osteoclast differentiation, but prevented downregulation of IFN regulatory factor-8, a negative regulator of osteoclast differentiation. In contrast, serum amyloid A sustained the endocytic capacity of bone marrow-derived macrophages and their ability to induce the proinflammatory cytokines, IL-6, IL-1β, and TNF-α. Taken together, these results suggest that serum amyloid A, when increased by inflammatory conditions, inhibits differentiation of macrophages to osteoclasts, likely to maintain macrophage function for host defense.

  20. A role for amyloid in cell aggregation and biofilm formation.

    Directory of Open Access Journals (Sweden)

    Melissa C Garcia

    Full Text Available Cell adhesion molecules in Saccharomyces cerevisiae and Candida albicans contain amyloid-forming sequences that are highly conserved. We have now used site-specific mutagenesis and specific peptide perturbants to explore amyloid-dependent activity in the Candida albicans adhesin Als5p. A V326N substitution in the amyloid-forming region conserved secondary structure and ligand binding, but abrogated formation of amyloid fibrils in soluble Als5p and reduced cell surface thioflavin T fluorescence. When displayed on the cell surface, Als5p with this substitution prevented formation of adhesion nanodomains and formation of large cellular aggregates and model biofilms. In addition, amyloid nanodomains were regulated by exogenous peptides. An amyloid-forming homologous peptide rescued aggregation and biofilm activity of Als5p(V326N cells, and V326N substitution peptide inhibited aggregation and biofilm activity in Als5p(WT cells. Therefore, specific site mutation, inhibition by anti-amyloid peturbants, and sequence-specificity of pro-amyloid and anti-amyloid peptides showed that amyloid formation is essential for nanodomain formation and activation.

  1. Amyloid-β peptides act as allosteric modulators of cholinergic signalling through formation of soluble BAβACs.

    Science.gov (United States)

    Kumar, Rajnish; Nordberg, Agneta; Darreh-Shori, Taher

    2016-01-01

    Amyloid-β peptides, through highly sophisticated enzymatic machinery, are universally produced and released in an action potential synchronized manner into the interstitial fluids in the brain. Yet no native functions are attributed to amyloid-β. The amyloid-β hypothesis ascribes just neurotoxicity properties through build-up of soluble homomeric amyloid-β oligomers or fibrillar deposits. Apolipoprotein-ε4 (APOE4) allele is the only confirmed genetic risk factor of sporadic Alzheimer's disease; once more it is unclear how it increases the risk of Alzheimer's disease. Similarly, central cholinergic signalling is affected selectively and early in the Alzheimer's disease brain, again why cholinergic neurons show this sensitivity is still unclear. However, the three main known Alzheimer's disease risk factors, advancing age, female gender and APOE4, have been linked to a high apolipoprotein-E and accumulation of the acetylcholine degrading enzyme, butyrylcholinesterase in cerebrospinal fluids of patients. Furthermore, numerous reports indicate that amyloid-β interacts with butyrylcholinesterase and apolipoprotein-E. We have proposed that this interaction leads to formation of soluble ultrareactive acetylcholine-hydrolyzing complexes termed BAβACs, to adjust at demand both synaptic and extracellular acetylcholine signalling. This hypothesis predicted presence of acetylcholine-synthesizing enzyme, choline acetyltransferase in extracellular fluids to allow maintenance of equilibrium between breakdown and synthesis of acetylcholine through continuous in situ syntheses. A recent proof-of-concept study led to the discovery of this enzyme in the human extracellular fluids. We report here that apolipoprotein-E, in particular ε4 isoprotein acts as one of the strongest endogenous anti-amyloid-β fibrillization agents reported in the literature. At biological concentrations, apolipoprotein-E prevented amyloid-β fibrillization for at least 65 h. We show that amyloid

  2. Fertility defects in mice expressing the L68Q variant of human cystatin C: a role for amyloid in male infertility.

    Science.gov (United States)

    Whelly, Sandra; Serobian, Gaiane; Borchardt, Clinton; Powell, Jonathan; Johnson, Seethal; Hakansson, Katarina; Lindstrom, Veronica; Abrahamson, Magnus; Grubb, Anders; Cornwall, Gail A

    2014-03-14

    Hereditary cystatin C amyloid angiopathy is an autosomal dominant disorder in which a variant form of cystatin C (L68Q) readily forms amyloid deposits in cerebral arteries in affected individuals resulting in early death. L68Q protein deposits in human cystatin C amyloid angiopathy patients have also been found in tissues outside of the brain including the testis, suggesting possible effects on fertility. Heterozygous transgenic mice (L68Q) that express the human L68Q variant of cystatin C under the control of the mouse cystatin C promoter were unable to generate offspring, suggesting the presence of L68Q cystatin C amyloid affected sperm function. In vitro studies showed that epididymal spermatozoa from L68Q mice were unable to fertilize oocytes and exhibited poor sperm motility. Furthermore, spermatozoa from L68Q mice exhibited reduced cell viability compared with wild type (WT) spermatozoa and often were detected in large agglutinated clumps. Examination of the epididymal fluid and spermatozoa from L68Q mice showed increased levels and distinct forms of cystatin C amyloid that were not present in WT mice. The addition of epididymal fluid from L68Q mice to WT spermatozoa resulted in a recapitulation of the L68Q phenotype in that WT spermatozoa showed reduced cell viability and motility compared with WT spermatozoa incubated in epididymal fluid from WT mice. L68Q epididymal fluid that was depleted of cystatin C amyloids, however, did not impair the motility of WT spermatozoa. Taken together these studies suggest that amyloids in the epididymal fluid can be cytotoxic to the maturing spermatozoa resulting in male infertility.

  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. 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.

  5. Site-directed mutations in the C-terminal extension of human alphaB-crystallin affect chaperone function and block amyloid fibril formation.

    Directory of Open Access Journals (Sweden)

    Teresa M Treweek

    Full Text Available BACKGROUND: Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease are associated with inappropriate protein deposition and ordered amyloid fibril assembly. Molecular chaperones, including alphaB-crystallin, play a role in the prevention of protein deposition. METHODOLOGY/PRINCIPAL FINDINGS: A series of site-directed mutants of the human molecular chaperone, alphaB-crystallin, were constructed which focused on the flexible C-terminal extension of the protein. We investigated the structural role of this region as well as its role in the chaperone function of alphaB-crystallin under different types of protein aggregation, i.e. disordered amorphous aggregation and ordered amyloid fibril assembly. It was found that mutation of lysine and glutamic acid residues in the C-terminal extension of alphaB-crystallin resulted in proteins that had improved chaperone activity against amyloid fibril forming target proteins compared to the wild-type protein. CONCLUSIONS/SIGNIFICANCE: Together, our results highlight the important role of the C-terminal region of alphaB-crystallin in regulating its secondary, tertiary and quaternary structure and conferring thermostability to the protein. The capacity to genetically modify alphaB-crystallin for improved ability to block amyloid fibril formation provides a platform for the future use of such engineered molecules in treatment of diseases caused by amyloid fibril formation.

  6. LASER APPLICATIONS AND OTHER TOPICS IN QUANTUM ELECTRONICS: Self-limiting of the thickness of diamond-like films deposited in the laser pyrolysis of liquid aromatic hydrocarbons

    Science.gov (United States)

    Simakin, Aleksandr V.; Lubnin, Evgenii N.; Shafeev, Georgii A.

    2000-03-01

    The process involving the self-regulation of the thickness of a diamond-like film, deposited on the interface between a transparent dielectric substrate (glass, sapphire, quartz) when a liquid aromatic hydrocarbon is heated by the radiation of a copper vapour laser, was observed and investigated. The film thickness reaches 100 nm and ceases to depend on the number of laser pulses, whereas the depth of the ablated region of the substrate, in which the film is deposited, increases monotonically. The self-regulation effect, observed over a wide range of pressures (from 0.08 to 10 bar), is caused both by the heating of the deposited film by the laser radiation to the graphitisation temperature and by its mechanical damage as a consequence of the difference between the coefficients of thermal expansion of the film and the substrate. The latter has been confirmed with the aid of x-ray Auger spectroscopy, the results of which indicate the formation in the liquid of a nanodisperse suspension of carbon particles with the diamond type of bonding.

  7. 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...

  8. Molecular Dynamics Simulation of Amyloid Beta Dimer Formation

    CERN Document Server

    Urbanc, B; Ding, F; Sammond, D; Khare, S; Buldyrev, S V; Stanley, H E; Dokholyan, N V

    2004-01-01

    Recent experiments with amyloid-beta (Abeta) peptide suggest that formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Abeta oligomers depends on their structure, which is governed by assembly dynamics. Due to limitations of current experimental techniques, a detailed knowledge of oligomer structure at the atomic level is missing. We introduce a molecular dynamics approach to study Abeta dimer formation: (1) we use discrete molecular dynamics simulations of a coarse-grained model to identify a variety of dimer conformations, and (2) we employ all-atom molecular mechanics simulations to estimate the thermodynamic stability of all dimer conformations. Our simulations of a coarse-grained Abeta peptide model predicts ten different planar beta-strand dimer conformations. We then estimate the free energies of all dimer conformations in all-atom molecular mechanics simulations with explicit water. We compare the free energies of Abeta(1-42) and Abeta(1-40...

  9. Fold modulating function: Bacterial toxins to functional amyloids

    Directory of Open Access Journals (Sweden)

    Adnan Khawaja Syed

    2014-08-01

    Full Text Available Many bacteria produce cytolytic toxins that target host cells or other competing microbes. It is well known that environmental factors control toxin expression, however recent work suggests that some bacteria manipulate the fold of these protein toxins to control their function. The β-sheet rich amyloid fold is a highly stable ordered aggregate that many toxins form in response to specific environmental conditions. When in the amyloid state, toxins become inert, losing the cytolytic activity they display in the soluble form. Emerging evidence suggest that some amyloids function as toxin storage systems until they are again needed, while other bacteria utilize amyloids as a structural matrix component of biofilms. This amyloid matrix component facilitates resistance to biofilm disruptive challenges. The bacterial amyloids discussed in this review reveal an elegant system where changes in protein fold and solubility dictate the function of proteins in response to the environment.

  10. Inhibition of insulin amyloid fibril formation by cyclodextrins.

    Science.gov (United States)

    Kitagawa, Keisuke; Misumi, Yohei; Ueda, Mitsuharu; Hayashi, Yuya; Tasaki, Masayoshi; Obayashi, Konen; Yamashita, Taro; Jono, Hirofumi; Arima, Hidetoshi; Ando, Yukio

    2015-01-01

    Localized insulin-derived amyloid masses occasionally form at the site of repeated insulin injections in patients with insulin-dependent diabetes and cause subcutaneous insulin resistance. Various kinds of insulin including porcine insulin, human insulin, and insulin analogues reportedly formed amyloid fibrils in vitro and in vivo, but the impact of the amino acid replacement in insulin molecules on amyloidogenicity is largely unknown. In the present study, we demonstrated the difference in amyloid fibril formation kinetics of human insulin and insulin analogues, which suggests an important role of the C-terminal domain of the insulin B chain in nuclear formation of amyloid fibrils. Furthermore, we determined that cyclodextrins, which are widely used as drug carriers in the pharmaceutical field, had an inhibitory effect on the nuclear formation of insulin amyloid fibrils. These findings have significant implications for the mechanism underlying insulin amyloid fibril formation and for developing optimal additives to prevent this subcutaneous adverse effect.

  11. Atomic View of a Toxic Amyloid Small Oligomer

    Energy Technology Data Exchange (ETDEWEB)

    Laganowsky, Arthur; Liu, Cong; Sawaya, Michael R.; Whitelegge, Julian P.; Park, Jiyong; Zhao, Minglei; Pensalfini, Anna; Soriaga, Angela B.; Landau, Meytal; Teng, Poh K.; Cascio, Duilio; Glabe, Charles; Eisenberg, David (UCI); (UCLA)

    2012-04-30

    Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here, we identify a segment of the amyloid-forming protein {alpha}{beta} crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: {beta}-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the {beta}-amyloid protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.

  12. Amyloid-Beta Peptide, Oxidative Stress and Inflammation in Alzheimer's Disease: Potential Neuroprotective Effects of Omega-3 Polyunsaturated Fatty Acids

    OpenAIRE

    S. C. Dyall

    2010-01-01

    Alzheimer's disease is the most common form of dementia in the elderly and is a progressive neurodegenerative disorder characterised by a decline in cognitive function and also profound alterations in mood and behaviour. The pathology of the disease is characterised by the presence of extracellular amyloid peptide deposits and intracellular neurofibrillary tangles in the brain. Although many hypotheses have been put forward for the aetiology of the disease, increased inflammation and oxidativ...

  13. Structure-Based Analysis of A19D, a Variant of Transthyretin Involved in Familial Amyloid Cardiomyopathy

    OpenAIRE

    Priscila Ferreira; Ricardo Sant'Anna; Nathalia Varejão; Cinthia Lima; Shenia Novis; Barbosa, Renata V.; Caldeira, Concy M.; Franklin D. Rumjanek; Salvador Ventura; Cruz, Marcia W.; Debora Foguel

    2013-01-01

    Transthyretin (TTR) is a tetrameric beta-sheet-rich protein. Its deposits have been implicated in four different amyloid diseases. Although aggregation of the wild-type sequence is responsible for the senile form of the disease, more than one hundred variants have been described thus far, most of which confer a more amyloidogenic character to TTR, mainly because they compromise the stability of the protein in relation to monomer formation, which upon misfolding is intrinsically aggregation-pr...

  14. 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...

  15. TDP-43 inclusion bodies formed in bacteria are structurally amorphous, non-amyloid and inherently toxic to neuroblastoma cells.

    Directory of Open Access Journals (Sweden)

    Claudia Capitini

    Full Text Available Accumulation of ubiquitin-positive, tau- and α-synuclein-negative intracellular inclusions of TDP-43 in the central nervous system represents the major hallmark correlated to amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Such inclusions have variably been described as amorphous aggregates or more structured deposits having an amyloid structure. Following the observations that bacterial inclusion bodies generally consist of amyloid aggregates, we have overexpressed full-length TDP-43 and C-terminal TDP-43 in E. coli, purified the resulting full-length and C-terminal TDP-43 containing inclusion bodies (FL and Ct TDP-43 IBs and subjected them to biophysical analyses to assess their structure/morphology. We show that both FL and Ct TDP-43 aggregates contained in the bacterial IBs do not bind amyloid dyes such as thioflavin T and Congo red, possess a disordered secondary structure, as inferred using circular dichroism and infrared spectroscopies, and are susceptible to proteinase K digestion, thus possessing none of the hallmarks for amyloid. Moreover, atomic force microscopy revealed an irregular structure for both types of TDP-43 IBs and confirmed the absence of amyloid-like species after proteinase K treatment. Cell biology experiments showed that FL TDP-43 IBs were able to impair the viability of cultured neuroblastoma cells when added to their extracellular medium and, more markedly, when transfected into their cytosol, where they are at least in part ubiquitinated and phosphorylated. These data reveal an inherently high propensity of TDP-43 to form amorphous aggregates, which possess, however, an inherently high ability to cause cell dysfunction. This indicates that a gain of toxic function caused by TDP-43 deposits is effective in TDP-43 pathologies, in addition to possible loss of function mechanisms originating from the cellular mistrafficking of the protein.

  16. TDP-43 inclusion bodies formed in bacteria are structurally amorphous, non-amyloid and inherently toxic to neuroblastoma cells.

    Science.gov (United States)

    Capitini, Claudia; Conti, Simona; Perni, Michele; Guidi, Francesca; Cascella, Roberta; De Poli, Angela; Penco, Amanda; Relini, Annalisa; Cecchi, Cristina; Chiti, Fabrizio

    2014-01-01

    Accumulation of ubiquitin-positive, tau- and α-synuclein-negative intracellular inclusions of TDP-43 in the central nervous system represents the major hallmark correlated to amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Such inclusions have variably been described as amorphous aggregates or more structured deposits having an amyloid structure. Following the observations that bacterial inclusion bodies generally consist of amyloid aggregates, we have overexpressed full-length TDP-43 and C-terminal TDP-43 in E. coli, purified the resulting full-length and C-terminal TDP-43 containing inclusion bodies (FL and Ct TDP-43 IBs) and subjected them to biophysical analyses to assess their structure/morphology. We show that both FL and Ct TDP-43 aggregates contained in the bacterial IBs do not bind amyloid dyes such as thioflavin T and Congo red, possess a disordered secondary structure, as inferred using circular dichroism and infrared spectroscopies, and are susceptible to proteinase K digestion, thus possessing none of the hallmarks for amyloid. Moreover, atomic force microscopy revealed an irregular structure for both types of TDP-43 IBs and confirmed the absence of amyloid-like species after proteinase K treatment. Cell biology experiments showed that FL TDP-43 IBs were able to impair the viability of cultured neuroblastoma cells when added to their extracellular medium and, more markedly, when transfected into their cytosol, where they are at least in part ubiquitinated and phosphorylated. These data reveal an inherently high propensity of TDP-43 to form amorphous aggregates, which possess, however, an inherently high ability to cause cell dysfunction. This indicates that a gain of toxic function caused by TDP-43 deposits is effective in TDP-43 pathologies, in addition to possible loss of function mechanisms originating from the cellular mistrafficking of the protein.

  17. Simulations of nucleation and elongation of amyloid fibrils

    OpenAIRE

    Zhang, Jianing; Muthukumar, M.

    2009-01-01

    We present a coarse-grained model for the growth kinetics of amyloid fibrils from solutions of peptides and address the fundamental mechanism of nucleation and elongation by using a lattice Monte Carlo procedure. We reproduce the three main characteristics of nucleation of amyloid fibrils: (1) existence of lag time, (2) occurrence of a critical concentration, and (3) seeding. We find the nucleation of amyloid fibrils to require a quasi-two-dimensional configuration, where a second layer of β ...

  18. Physical and structural basis for polymorphism in amyloid fibrils

    OpenAIRE

    Tycko, Robert

    2014-01-01

    As our understanding of the molecular structures of amyloid fibrils has matured over the past 15 years, it has become clear that, while amyloid fibrils do have well-defined molecular structures, their molecular structures are not uniquely determined by the amino acid sequences of their constituent peptides and proteins. Self-propagating molecular-level polymorphism is a common phenomenon. This article reviews current information about amyloid fibril structures, variations in molecular structu...

  19. New Insights in the Amyloid-Beta Interaction with Mitochondria

    OpenAIRE

    Carlos Spuch; Saida Ortolano; Carmen Navarro

    2012-01-01

    Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD). Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP) has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both...

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

    Directory of Open Access Journals (Sweden)

    Létitia Jean

    for observations that implicate hAChE in the extent of Abeta deposition in the brain. Furthermore, this process of heterologous amyloid seeding by a proteolytic fragment from another protein may represent a previously underestimated pathological trigger, implying that the abundance of the major amyloidogenic species (Abeta in AD, for example may not be the only important factor in neurodegeneration.

  1. 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

  2. Label-free detection of ApoE4-mediated β-amyloid aggregation on single nanoparticle uncovering Alzheimer's disease.

    Science.gov (United States)

    Kang, Min Kyung; Lee, Jeewon; Nguyen, Anh H; Sim, Sang Jun

    2015-10-15

    Beta amyloid (Aβ) deposition is a pathological milestone of Alzheimer's disease (AD). This is facilitated by an isoform of Apolipoprotein E4 (ApoE4), which is a dominant risk factor for AD. However, current in vitro Aβ aggregation assays were performed in extreme conditions not linked to physiological conditions, to understand the mechanism of Aβ induced neurotoxicity. Here, we present a simple method for the ApoE4-mediated Aβ aggregation at physiological conditions using single gold nanoparticle based on localized surface plasmon resonance (LSPR). It can be directly observed by dark-field microscope or even by the naked eye. Following LSPR principles, we used ApoE4 inducing Aβ42 self-assemblies on gold nanoparticles (AuNPs) surface via their surface charge interaction. Using physiologically mimic cerebrospinal fluid, we determined a detection limit of 1.5 pM for Aβ42 corresponding to the ~2.9 nm LSPR-peak shift under ApoE4. Interestingly, the result also shows that ApoE4 induces the aggregation of Aβ42 more specifically and rapidly than that of Aβ40. This is the first biomimetic platform for real-time detection of Aβ aggregation, mimicking biological conditions, which can be used to investigate AD directly.

  3. Amyloid-precursor-protein-lowering small molecules for disease modifying therapy of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Sina Cathérine Rosenkranz

    Full Text Available Alzheimer's disease (AD is the most common form of dementia in the elderly with progressive cognitive decline and memory loss. According to the amyloid-hypothesis, AD is caused by generation and subsequent cerebral deposition of β-amyloid (Aβ. Aβ is generated through sequential cleavage of the transmembrane Amyloid-Precursor-Protein (APP by two endoproteinases termed beta- and gamma-secretase. Increased APP-expression caused by APP gene dosage effects is a risk factor for the development of AD. Here we carried out a large scale screen for novel compounds aimed at decreasing APP-expression. For this we developed a screening system employing a cell culture model of AD. A total of 10,000 substances selected for their ability of drug-likeness and chemical diversity were tested for their potential to decrease APP-expression resulting in reduced Aβ-levels. Positive compounds were further evaluated for their effect at lower concentrations, absence of cytotoxicity and specificity. The six most promising compounds were characterized and structure function relationships were established. The novel compounds presented here provide valuable information for the development of causal therapies for AD.

  4. Interaction of serum amyloid P component with hexanoyl bis(d-proline) (CPHPC)

    Energy Technology Data Exchange (ETDEWEB)

    Kolstoe, Simon E. [University College London, Rowland Hill Street, London NW3 2PF (United Kingdom); Jenvey, Michelle C. [University of Southampton, Southampton SO17 1BJ (United Kingdom); Purvis, Alan [Imperial College London, London SW7 2AZ (United Kingdom); Light, Mark E. [University of Southampton, Southampton SO17 1BJ (United Kingdom); Thompson, Darren [University of Sussex, Falmer, Brighton BN1 9RQ (United Kingdom); Hughes, Peter; Pepys, Mark B.; Wood, Stephen P., E-mail: s.wood@ucl.ac.uk [University College London, Rowland Hill Street, London NW3 2PF (United Kingdom)

    2014-08-01

    Serum amyloid P component is a pentameric plasma glycoprotein that recognizes and binds to amyloid fibres in a calcium-dependent fashion and is likely to contribute to their deposition and persistence in vivo. Five molecules of the drug CPHPC avidly cross-link pairs of protein pentamers and the decameric complex is rapidly cleared in vivo. Crystal structures of the protein in complex with a bivalent drug and cadmium ions, which improve crystal quality, allow the definition of the preferred bound drug isomers. Under physiological conditions, the pentameric human plasma protein serum amyloid P component (SAP) binds hexanoyl bis(d-proline) (R-1-(6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl) pyrrolidine-2-carboxylic acid; CPHPC) through its d-proline head groups in a calcium-dependent interaction. Cooperative effects in binding lead to a substantial enhancement of affinity. Five molecules of the bivalent ligand cross-link and stabilize pairs of SAP molecules, forming a decameric complex that is rapidly cleared from the circulation by the liver. Here, it is reported that X-ray analysis of the SAP complex with CPHPC and cadmium ions provides higher resolution detail of the interaction than is observed with calcium ions. Conformational isomers of CPHPC observed in solution by HPLC and by X-ray analysis are compared with the protein-bound form. These are discussed in relation to the development of CPHPC to provide SAP depletion for the treatment of amyloidosis and other indications.

  5. Effects of diet-induced hypercholesterolemia on amyloid accumulation in ovariectomized mice

    Indian Academy of Sciences (India)

    V Kaliyamurthi; V Thanigavelan; G Victor Rajamanickam

    2012-12-01

    A central hypothesis in the study of Alzheimer’s disease (AD) is the accumulation and aggregation of -amyloid peptide (A). Recent epidemiological studies suggest that patients with elevated cholesterol and decreased estrogen levels are more susceptible to AD through A accumulation. To test the above hypothesis, we used ovariectomized with diet-induced hypercholesterolemia (OVX) and hypercholesterolemia (HCL) diet alone mouse models. HPLC analysis reveals the presence of beta amyloid in the OVX and HCL mice brain. Congo red staining analysis revealed the extent of amyloid deposition in OVX and hypercholesterolemia mice brain. Overall, A levels were higher in OVX mice than in HCL. Secondly, estrogen receptors (ER) were assessed by immunohistochemistry and this suggested that there was a decreased expression of ER in OVX animals when compared to hypercholesterolemic animals. A was quantified by Western blot and ELISA analysis. Overall, Aβ levels were higher in OVX mice than in HCL mice. Our experimental results suggested that OVX animals were more susceptible to AD with significant increase in A peptide.

  6. Characterization of in vivo MRI detectable thalamic amyloid plaques from APP/PS1 mice

    Energy Technology Data Exchange (ETDEWEB)

    Dhenain, M. [URA CEA CNRS 2210, I2BM, SHFJ, 4 Place du General Leclerc, 91401 Orsay Cedex (France); Dhenain, M.; El Tannir El Tayara, N.; Wu, T.D.; Volk, A.; Quintana, C. [U759 INSERM, Centre Universitaire, Laboratoire 112, 91405 Orsay Cedex (France); Dhenain, M.; El Tannir El Tayara, N.; Wu, T.D.; Volk, A.; Quintana, C. [Institut Curie, Centre Universitaire, Laboratoire 112, 91405 Orsay Cedex (France); Guegan, M.; Delatour, B. [Instituto de Microelectronica de Madrid-CSIC, 8, Isaac Newton, 28760 Tres Cantos, Madrid (Spain)

    2009-07-01

    Amyloid deposits are one of the hallmarks of Alzheimer's disease. Recent studies, in transgenic mice modeling Alzheimer's disease showed that, using in vivo, contrast agent-free, MRI, thalamic amyloid plaques are more easily detected than other plaques of the brain. Our study evaluated the characteristics of these thalamic plaques in a large population of APP/PS1, PS1 and C57BL/6 mice. Thalamic spots were detected in all mice but with different frequency and magnitude. Hence, the prevalence and size of the lesions were higher in APP/PS1 mice. However, even in APP/PS1 mice, thalamic spots did not occur in all the old animals. In APP/PS1 mice, spots detection was related to high iron and calcium load within amyloid plaques and thus reflects the ability of such plaque to capture large amounts of minerals. Interestingly, calcium and iron was also detected in extra-thalamic plaques but with a lower intensity. Hypointense lesions in the thalamus were not associated with the iron load in the tissue surrounding the plaques, nor with micro-hemorrhages, inflammation, or a neuro-degenerative context. (authors)

  7. Amyloid β-Protein as a Substrate Interacts with Extracellular Matrix to Promote Neurite Outgrowth

    Science.gov (United States)

    Koo, Edward H.; Park, Lisa; Selkoe, Dennis J.

    1993-05-01

    Progressive deposition of amyloid β-protein (Aβ) in brain parenchyma and blood vessels is a characteristic feature of Alzheimer disease. Recent evidence suggests that addition of solubilized synthetic Aβ to medium may produce toxic or trophic effects on cultured hippocampal neurons. Because soluble Aβ may not accumulate in significant quantities in brain, we asked whether immobilized Aβ peptide as a substrate alters neurite outgrowth from cultured rat peripheral sensory neurons. This paradigm may closely mimic the conditions in Alzheimer disease brain tissue, in which neurites contact insoluble, extracellular aggregates of β-amyloid. We detected no detrimental effects of Aβ substrate on neurite outgrowth. Rather, Aβ in combination with low doses of laminin or fibronectin enhanced neurite out-growth from these neuronal explants. Our results suggest that insoluble Aβ in the cerebral neuropil may serve as a neurite-promoting matrix, perhaps explaining the apparent regenerative response of neurites observed around amyloid plaques in Alzheimer disease. Moreover, in concert with the recent discovery of Aβ production by cultured neurons, our data suggest that Aβ plays a normal physiological role in brain by complexing with the extracellular matrix.

  8. Amyloid Beta-peptide (25-35) changes (Ca2+) in hippocampal neurons

    DEFF Research Database (Denmark)

    Mogensen, Helle Smidt; Beatty, Diane; Morris, Stephen;

    1998-01-01

    neuroscience, Alzheimer, calcium ion, hippocampal neurons, amyloid-beta-peptide, hydrogen ion, rat......neuroscience, Alzheimer, calcium ion, hippocampal neurons, amyloid-beta-peptide, hydrogen ion, rat...

  9. 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. PMID:27505013

  10. 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

  11. Formation of Toxic Amyloid Fibrils by Amyloid β-Protein on Ganglioside Clusters

    Directory of Open Access Journals (Sweden)

    Katsumi Matsuzaki

    2011-01-01

    Full Text Available It is widely accepted that the conversion of the soluble, nontoxic amyloid β-protein (Aβ monomer to aggregated toxic Aβ rich in β-sheet structures is central to the development of Alzheimer’s disease. However, the mechanism of the abnormal aggregation of Aβ in vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβ aggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβ amyloids formed in solution. Furthermore, differences between Aβ-(1–40 and Aβ-(1–42 in membrane interaction and amyloidogenesis are also emphasized.

  12. Design and Construction of Large Amyloid Fibers

    Directory of Open Access Journals (Sweden)

    Devin M. Ridgley

    2015-04-01

    Full Text Available Mixtures of “template” and “adder” proteins self-assemble into large amyloid fibers of varying morphology and modulus. Fibers range from low modulus, rectangular cross-sectioned tapes to high modulus, circular cross-sectioned cylinders. Varying the proteins in the mixture can elicit “in-between” morphologies, such as elliptical cross-sectioned fibers and twisted tapes, both of which have moduli in-between rectangular tapes and cylindrical fibers. Experiments on mixtures of proteins of known amino acid sequence show that control of the large amyloid fiber morphology is dependent on the amount of glutamine repeats or “Q-blocks” relative to hydrophobic side chained amino acids such as alanine, isoleucine, leucine, and valine in the adder protein. Adder proteins with only hydrophobic groups form low modulus rectangular cross-sections and increasing the Q-block content allows excess hydrogen bonding on amide groups that results in twist and higher modulus. The experimental results show that large amyloid fibers of specific shape and modulus can be designed and controlled at the molecular level.

  13. Amyloid β oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.

    Science.gov (United States)

    Viola, Kirsten L; Klein, William L

    2015-02-01

    Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson's and Alzheimer's. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca(2+) overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they

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

    Directory of Open Access Journals (Sweden)

    LI Jia-lin

    2012-06-01

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

  15. Effects of age and beta-amyloid on cognitive changes in normal elderly people

    OpenAIRE

    Oh, Hwamee; Madison, Cindee,; Haight, Thaddeus J.; Markley, Candace; Jagust, William J.

    2012-01-01

    Age-related decline is common in multiple cognitive domains. β-amyloid (Aβ) deposition, a pathological hallmark of Alzheimer’s disease, is also associated with cognitive changes in many older people. In this study, we examined a wide range of cognitive function in order to differentiate the effect of age and Aβ on cognition during aging. Using PET imaging with the radiotracer Pittsburgh compound B (PIB), we classified normal older subjects as High PIB-Old and Low PIB-Old and applied sequentia...

  16. In vivo detection of prion amyloid plaques using [11C]BF-227 PET

    International Nuclear Information System (INIS)

    In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain. The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Straeussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [11C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer's disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention. Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain. Although [11C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs. (orig.)

  17. In vivo detection of prion amyloid plaques using [{sup 11}C]BF-227 PET

    Energy Technology Data Exchange (ETDEWEB)

    Okamura, Nobuyuki; Yanai, Kazuhiko [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Shiga, Yusei; Itoyama, Yasuhito [Tohoku University School of Medicine, Department of Neurology, 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); Tashiro, Manabu [Tohoku University, Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Sendai (Japan); Tsuboi, Yoshio [Fukuoka University School of Medicine, Department of Neurology, Fukuoka (Japan); Furukawa, Katsutoshi; Arai, Hiroyuki [Institute of Development, Aging, and Cancer, Tohoku University, Department of Geriatrics and Gerontology, Division of Brain Sciences, Sendai (Japan); Iwata, Ren [Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Kudo, Yukitsuka [Tohoku University, Innovation of New Biomedical Engineering Center, Sendai (Japan); Doh-ura, Katsumi [Tohoku University School of Medicine, Department of Prion Research, 2-1 Seiryo-machi, Aoba-ku, Sendai (Japan)

    2010-05-15

    In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain. The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Straeussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [{sup 11}C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer's disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention. Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain. Although [{sup 11}C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs. (orig.)

  18. Stearic acids at sn-1, 3 positions of TAG are more efficient at limiting fat deposition than palmitic and oleic acids in C57BL/6 mice.

    Science.gov (United States)

    Gouk, Shiou-Wah; Cheng, Sit-Foon; Ong, Augustine Soon-Hock; Chuah, Cheng-Hock

    2014-04-14

    In the present study, we investigated the effect of long-acyl chain SFA, namely palmitic acid (16:0) and stearic acid (18:0), at sn-1, 3 positions of TAG on obesity. Throughout the 15 weeks of the experimental period, C57BL/6 mice were fed diets fortified with cocoa butter, sal stearin (SAL), palm mid fraction (PMF) and high-oleic sunflower oil (HOS). The sn-1, 3 positions were varied by 16:0, 18:0 and 18:1, whilst the sn-2 position was preserved with 18:1. The HOS-enriched diet was found to lead to the highest fat deposition. This was in accordance with our previous postulation. Upon normalisation of total fat deposited with food intake to obtain the fat:feed ratio, interestingly, mice fed the SAL-enriched diet exhibited significantly lower visceral fat/feed and total fat/feed compared with those fed the PMF-enriched diet, despite their similarity in SFA-unsaturated fatty acid-SFA profile. That long-chain SFA at sn-1, 3 positions concomitantly with an unsaturated FA at the sn-2 position exert an obesity-reducing effect was further validated. The present study is the first of its kind to demonstrate that SFA of different chain lengths at sn-1, 3 positions exert profound effects on fat accretion.

  19. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders.

    Science.gov (United States)

    Batarseh, Yazan S; Duong, Quoc-Viet; Mousa, Youssef M; Al Rihani, Sweilem B; Elfakhri, Khaled; Kaddoumi, Amal

    2016-01-01

    Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer's disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia. PMID:26959008

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-04-15

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

  1. Stepwise organization of the β-structure identifies key regions essential for the propagation and cytotoxicity of insulin amyloid fibrils.

    Science.gov (United States)

    Chatani, Eri; Imamura, Hiroshi; Yamamoto, Naoki; Kato, Minoru

    2014-04-11

    Amyloid fibrils are supramolecular assemblies, the deposition of which is associated with many serious diseases including Alzheimer, prion, and Huntington diseases. Several smaller aggregates such as oligomers and protofibrils have been proposed to play a role in early stages of the fibrillation process; however, little is known about how these species contribute to the formation of mature amyloid fibrils with a rigid cross-β structure. Here, we identified a new pathway for the formation of insulin amyloid fibrils at a high concentration of salt in which mature fibrils were formed in a stepwise manner via a prefibrillar intermediate: minute prefibrillar species initially accumulated, followed by the subsequent formation of thicker amyloid fibrils. Fourier transform infrared spectra suggested the sequential formation of two types of β-sheets with different strength hydrogen bonds, one of which was developed concomitantly with the mutual assembly of the prefibrillar intermediate to form mature fibrils. Interestingly, fibril propagation and cellular toxicity appeared only after the later step of structural organization, and a comparison of β-sheet regions between the prefibrillar intermediate and mature fibrils using proteolysis led to the proposal of specific regions essential for manifestation of these properties.

  2. Palmitoylethanolamide protects against the amyloid-β25-35-induced learning and memory impairment in mice, an experimental model of Alzheimer disease.

    Science.gov (United States)

    D'Agostino, Giuseppe; Russo, Roberto; Avagliano, Carmen; Cristiano, Claudia; Meli, Rosaria; Calignano, Antonio

    2012-06-01

    Alzheimer disease (AD) is the most common form of neurodegenerative dementia. Amyloiddeposition, neurofibrillary tangle formation, and neuro-inflammation are the major pathogenic mechanisms that in concert lead to memory dysfunction and decline of cognition. Palmitoylethanolamide (PEA) is the naturally occurring lipid amide between palmitic acid and ethanolamine. Despite its clear role in inflammation and pain control, only limited in vitro evidence exist about a role for PEA in neurodegenerative diseases. Here we describe the neuroprotective activities of PEA in mice injected intracerebroventricularly with amyloid-β 25-35 (Ab25-35) peptide (9 nmol). We used spatial and non-spatial memory tasks to evaluate learning and memory dysfunctions. Ab25-35 injection significantly impaired spontaneous alternation performances, water maze spatial reference and working-like memory, and novel object recognition test. PEA was administered once a day (3-30 mg/kg, subcutaneously), starting 3 h after Ab25-35, for 1 or 2 weeks. PEA reduced (10 mg/kg) or prevented (30 mg/kg) behavioral impairments induced by Ab25-35 injection. PEA failed to rescue memory deficits induced by Ab25-35 injection in peroxisome proliferator-activated receptor-α (PPAR-α) null mice. GW7647 (2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid; 5 mg/kg per day), a synthetic PPAR-α agonist, mimicked the effect of PEA. Acute treatment with PEA was ineffective. According with the neuroprotective profile of PEA observed during behavioral studies, experimental molecular and biochemical markers induced by Ab25-35 injection, such as lipid peroxidation, protein nytrosylation, inducible nitric oxide synthase induction, and caspase3 activation, were reduced by PEA treatment. These data disclose novel findings about the therapeutic potential of PEA, unrevealing a previously unknown therapeutic possibility to treat memory deficits associated with AD.

  3. Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy

    NARCIS (Netherlands)

    Reijmer, Yael D.; Fotiadis, Panagiotis; Martinez-Ramirez, Sergi; Salat, David H.; Schultz, Aaron; Shoamanesh, Ashkan; Ayres, Alison M.; Vashkevich, Anastasia; Rosas, Diana; Schwab, Kristin; Leemans, Alexander; Biessels, Geert Jan; Rosand, Jonathan; Johnson, Keith A.; Viswanathan, Anand; Gurol, M. Edip; Greenberg, Steven M.

    2015-01-01

    Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small s

  4. Computational Modelling of the Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Skeby, Katrine Kirkeby

    2014-01-01

    When proteins do not fold correctly, it can lead to very serious diseases. One such group of diseases is the amyloid diseases, of which Alzheimer’s disease (AD), Parkinson’s disease, and type 2 diabetes mellitus (T2DM) are members. The amyloid diseases are characterized by the aggregation...

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

    DEFF Research Database (Denmark)

    Heegaard, N.H.H.; Heegaard, Peter M. H.; Roepstorff, P.;

    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...

  6. Native human serum amyloid P component is a single pentamer

    DEFF Research Database (Denmark)

    Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH;

    1995-01-01

    Serum amyloid P component (SAP) and C-reactive protein (CRP) are members of the pentraxin protein family. SAP is the precursor protein to amyloid P component present in all forms of amyloidosis. The prevailing notion is that SAP in circulation has the form of a double pentameric molecule (decamer...

  7. The Tubular Sheaths Encasing Methanosaeta thermophila Filaments Are Functional Amyloids.

    Science.gov (United States)

    Dueholm, Morten S; Larsen, Poul; Finster, Kai; Stenvang, Marcel R; Christiansen, Gunna; Vad, Brian S; Bøggild, Andreas; Otzen, Daniel E; Nielsen, Per Halkjær

    2015-08-14

    Archaea are renowned for their ability to thrive in extreme environments, although they can be found in virtually all habitats. Their adaptive success is linked to their unique cell envelopes that are extremely resistant to chemical and thermal denaturation and that resist proteolysis by common proteases. Here we employ amyloid-specific conformation antibodies and biophysical techniques to show that the extracellular cell wall sheaths encasing the methanogenic archaea Methanosaeta thermophila PT are functional amyloids. Depolymerization of sheaths and subsequent MS/MS analyses revealed that the sheaths are composed of a single major sheath protein (MspA). The amyloidogenic nature of MspA was confirmed by in vitro amyloid formation of recombinant MspA under a wide range of environmental conditions. This is the first report of a functional amyloid from the archaeal domain of life. The amyloid nature explains the extreme resistance of the sheath, the elastic properties that allow diffusible substrates to penetrate through expandable hoop boundaries, and how the sheaths are able to split and elongate outside the cell. The archaeal sheath amyloids do not share homology with any of the currently known functional amyloids and clearly represent a new function of the amyloid protein fold. PMID:26109065

  8. 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 amyloid-β peptide 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 amyloid-β peptide 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

  9. Development of (F-18)-Labeled Amyloid Imaging Agents for PET

    International Nuclear Information System (INIS)

    The applicant proposes to design and synthesize a series of fluorine-18-labeled radiopharmaceuticals to be used as amyloid imaging agents for positron emission tomography (PET). The investigators will conduct comprehensive iterative in vitro and in vivo studies based upon well defined acceptance criteria in order to identify lead agents suitable for human studies. The long term goals are to apply the selected radiotracers as potential diagnostic agents of Alzheimer's disease (AD), as surrogate markers of amyloid in the brain to determine the efficacy of anti-amyloid therapeutic drugs, and as tools to help address basic scientific questions regarding the progression of the neuropathology of AD, such as testing the 'amyloid cascade hypothesis' which holds that amyloid accumulation is the primary cause of AD.

  10. Prevalence of cerebral amyloid pathology in persons without dementia

    DEFF Research Database (Denmark)

    Jansen, Willemijn J; Ossenkoppele, Rik; Knol, Dirk L;

    2015-01-01

    IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies....... OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified...... for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography...

  11. Development of [F-18]-Labeled Amyloid Imaging Agents for PET

    Energy Technology Data Exchange (ETDEWEB)

    Mathis, CA

    2007-05-09

    The applicant proposes to design and synthesize a series of fluorine-18-labeled radiopharmaceuticals to be used as amyloid imaging agents for positron emission tomography (PET). The investigators will conduct comprehensive iterative in vitro and in vivo studies based upon well defined acceptance criteria in order to identify lead agents suitable for human studies. The long term goals are to apply the selected radiotracers as potential diagnostic agents of Alzheimer's disease (AD), as surrogate markers of amyloid in the brain to determine the efficacy of anti-amyloid therapeutic drugs, and as tools to help address basic scientific questions regarding the progression of the neuropathology of AD, such as testing the "amyloid cascade hypothesis" which holds that amyloid accumulation is the primary cause of AD.

  12. Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle.

    Science.gov (United States)

    Schmidt, Jens; Barthel, Konstanze; Wrede, Arne; Salajegheh, Mohammad; Bähr, Mathias; Dalakas, Marinos C

    2008-05-01

    Distinct interrelationships between inflammation and beta-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN-gamma, TNF-alpha and IL-1 beta in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor protein (APP) significantly and consistently correlated with inflammation in the muscle and mRNA-levels of chemokines and IFN-gamma. Only in sIBM, immunohistochemical analysis revealed that inflammatory mediators including IL-1 beta co-localized to beta-amyloid depositions within myofibres. In human myotubes, exposure to IL-1 beta caused upregulation of APP with subsequent intracellular aggregation of beta-amyloid. Our data suggest that, in sIBM muscle, production of high amounts of pro-inflammatory mediators specifically induces beta-amyloid-associated degeneration. The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle.

  13. A catalytic surface for amyloid fibril formation

    Energy Technology Data Exchange (ETDEWEB)

    Hammarstroem, P; Ali, M M; Mishra, R; Tengvall, P; Lundstroem, I [Department of Physics, Biology and Chemistry, Linkoeping University, SE-581 83 Linkoeping (Sweden); Svensson, S [Astra Zeneca R and D, SE-151 85 Soedertaelje (Sweden)], E-mail: ingemar@ifm.liu.se

    2008-03-15

    A hydrophobic surface incubated in a solution of protein molecules (insulin monomers) was made into a catalytic surface for amyloid fibril formation by repeatedly incubate, rinse and dry the surface. The present contribution describes how this unexpected transformation occurred and its relation to rapid fibrillation of insulin solutions in contact with the surface. A tentative model of the properties of the catalytic surface is given, corroborated by ellipsometric measurements of the thickness of the organic layer on the surface and by atomic force microscopy. The surfaces used were spontaneously oxidized silicon made hydrophobic through treatment in dichlorodimethylsilane.

  14. Stability and cytotoxicity of crystallin amyloid nanofibrils

    Science.gov (United States)

    Kaur, Manmeet; Healy, Jackie; Vasudevamurthy, Madhusudan; Lassé, Moritz; Puskar, Ljiljana; Tobin, Mark J.; Valery, Celine; Gerrard, Juliet A.; Sasso, Luigi

    2014-10-01

    Previous work has identified crystallin proteins extracted from fish eye lenses as a cheap and readily available source for the self-assembly of amyloid nanofibrils. However, before exploring potential applications, the biophysical aspects and safety of this bionanomaterial need to be assessed so as to ensure that it can be effectively and safely used. In this study, crude crystallin amyloid fibrils are shown to be stable across a wide pH range, in a number of industrially relevant solvents, at both low and high temperatures, and in the presence of proteases. Crystallin nanofibrils were compared to well characterised insulin and whey protein fibrils using Thioflavin T assays and TEM imaging. Cell cytotoxicity assays suggest no adverse impact of both mature and fragmented crystallin fibrils on cell viability of Hec-1a endometrial cells. An IR microspectroscopy study supports long-term structural integrity of crystallin nanofibrils.Previous work has identified crystallin proteins extracted from fish eye lenses as a cheap and readily available source for the self-assembly of amyloid nanofibrils. However, before exploring potential applications, the biophysical aspects and safety of this bionanomaterial need to be assessed so as to ensure that it can be effectively and safely used. In this study, crude crystallin amyloid fibrils are shown to be stable across a wide pH range, in a number of industrially relevant solvents, at both low and high temperatures, and in the presence of proteases. Crystallin nanofibrils were compared to well characterised insulin and whey protein fibrils using Thioflavin T assays and TEM imaging. Cell cytotoxicity assays suggest no adverse impact of both mature and fragmented crystallin fibrils on cell viability of Hec-1a endometrial cells. An IR microspectroscopy study supports long-term structural integrity of crystallin nanofibrils. Electronic supplementary information (ESI) available: ThT fluorescence graphs of buffers and solvents used for

  15. The β-amyloid protein induces S100β expression in rat hippocampus through a mechanism that involves IL-1

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective To explore the effect of β-amyloid protein (Aβ) on S100β expression in rat hippocampus and its mechanisms. Methods At 7 days after bilateral stereotaxis injection of different dose of fibrillar Aβ 25-35 and interluekin-1 receptor antagonist (IL-1ra) into the rat CA1 region, the learning and memory abilities of rats were tested with passive avoidance task. Amyloid deposition was detected by using Congo red staining technique. Nissl staining and immunohistochemical techniques were used to analyze the number of neurons, and GFAP and the S100β expression in hippocampal CA1 region , respectively. Results After fibrillar Aβ injection, the step-through latency of rats was significantly shortened compared to that of the control group. The GFAP positive astrocytes were found surrounding amyloid deposition. Neuronal loss occurred in the pyramidal cell layer of CA1 region. The number of S100β positive cells in Aβ-treated group was significantly increased compared with that in the control group. After IL-1ra injection, the number of S100β positive cells was significantly decreased. Conclusion Intrahippocampal injection of Aβ 25-35 could cause similar pathologic changes of Alzheimer's disease. Aβ 25-35 was capable of up-regulating S100β expression in a dose-dependent manner. The injection of IL-1ra could attenuate the effect of Aβ on S100β expression.

  16. Limitations in the use of archived vent mussel samples to assess genetic connectivity among seafloor massive sulfide deposits: a case study with implications for environmental management

    Directory of Open Access Journals (Sweden)

    Rachel Elizabeth Boschen

    2015-12-01

    Full Text Available Genetic connectivity studies can inform the design of mitigation strategies used in environmental management. However, the expense of developing species-specific molecular markers and collecting samples at appropriate spatial and temporal scales can be prohibitive. Using archived material and existing molecular markers may provide a cost-effective way to assess population connectivity. Genetic connectivity studies are increasingly in demand in the deep sea in response to mounting anthropogenic pressures, including seafloor massive sulfide (SMS mining. The feasibility of using archived material was assessed using the New Zealand-endemic vent mussel Gigantidas gladius, which inhabits areas licensed for the prospecting phase of SMS mining. Four molecular markers were tested, but only one (mitochondrial COI provided suitable sequences. Of 942 specimens, only 150 individuals were informative, largely due to poor tissue quality of archived samples. Seven populations spanning the distributional range of G. gladius were assessed. The results indicate that G. gladius has high levels of gene flow among sites 10s to 100s km apart and limited genetic structure. Haplotypic diversity was not equally distributed among populations, with lower diversity for the Macauley Volcano population at the northern extent of the species distribution and greater diversity within central populations. Migrant exchange was also greatest between central populations, with one population at Rumble V Seamount appearing important in terms of maintaining genetic diversity within the Kermadec Volcanic Arc region. However, interpretation of the results should be viewed with caution as small sample sizes may have limited the ability to detect genetic structure. Despite these limitations, mitigation strategies that protect areas of seabed from mining activities should consider the genetic vulnerability of the population at the northern edge of the species’ distribution and the

  17. Dewetting transition assisted clearance of (NFGAILS) amyloid fibrils from cell membranes by graphene

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jiajia; Yang, Zaixing; Gu, Zonglin [Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123 (China); Li, Haotian [Bio-X Lab, Department of Physics, Zhejiang University, Hangzhou 310027 (China); Garate, Jose Antonio [IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598 (United States); Zhou, Ruhong, E-mail: ruhongz@us.ibm.com [Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123 (China); IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598 (United States); Department of Chemistry, Columbia University, New York, New York 10027 (United States)

    2014-12-14

    Clearance of partially ordered oligomers and monomers deposited on cell membrane surfaces is believed to be an effective route to alleviate many potential protein conformational diseases (PCDs). With large-scale all-atom molecular dynamics simulations, here we show that graphene nanosheets can easily and quickly win a competitive adsorption of human islet amyloid polypeptides (hIAPP{sub 22-28}) NFGAILS and associated fibrils against cell membrane, due to graphene's unique two-dimensional, highly hydrophobic surface with its all-sp{sup 2} hybrid structure. A nanoscale dewetting transition was observed at the interfacial region between the fibril (originally deposited on the membrane) and the graphene nanosheet, which significantly assisted the adsorption of fibrils onto graphene from the membrane. The π–π stacking interaction between Phe23 and graphene played a crucial role, providing the driving force for the adsorption at the graphene surface. This study renders new insight towards the importance of water during the interactions between amyloid peptides, the phospholipidic membrane, and graphene, which might shed some light on future developments of graphene-based nanomedicine for preventing/curing PCDs like type II diabetes mellitus.

  18. 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

  19. Dewetting transition assisted clearance of (NFGAILS) amyloid fibrils from cell membranes by graphene

    International Nuclear Information System (INIS)

    Clearance of partially ordered oligomers and monomers deposited on cell membrane surfaces is believed to be an effective route to alleviate many potential protein conformational diseases (PCDs). With large-scale all-atom molecular dynamics simulations, here we show that graphene nanosheets can easily and quickly win a competitive adsorption of human islet amyloid polypeptides (hIAPP22-28) NFGAILS and associated fibrils against cell membrane, due to graphene's unique two-dimensional, highly hydrophobic surface with its all-sp2 hybrid structure. A nanoscale dewetting transition was observed at the interfacial region between the fibril (originally deposited on the membrane) and the graphene nanosheet, which significantly assisted the adsorption of fibrils onto graphene from the membrane. The π–π stacking interaction between Phe23 and graphene played a crucial role, providing the driving force for the adsorption at the graphene surface. This study renders new insight towards the importance of water during the interactions between amyloid peptides, the phospholipidic membrane, and graphene, which might shed some light on future developments of graphene-based nanomedicine for preventing/curing PCDs like type II diabetes mellitus

  20. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography

    OpenAIRE

    Palmqvist, Sebastian; Mattsson, Niklas; Hansson, Oskar; ,

    2016-01-01

    See Rabinovici (doi:10.1093/brain/aww025) for a scientific commentary on this article. Cerebral accumulation of amyloid-β is thought to be the starting mechanism in Alzheimer’s disease. Amyloid-β can be detected by analysis of cerebrospinal fluid amyloid-β42 or amyloid positron emission tomography, but it is unknown if any of the methods can identify an abnormal amyloid accumulation prior to the other. Our aim was to determine whether cerebrospinal fluid amyloid-β42 change before amyloid PET ...

  1. Influence of apolipoprotein E and its receptors on cerebral amyloid precursor protein metabolism following traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shuai; SUN Xiao-chuan

    2012-01-01

    Traumatic brain injury (TBI) is the leading cause of mortality and disability among young individuals in our society,and globally the incidence of TBI is rising sharply.Mounting evidence has indicated that apolipoprotein E (apoE:protein; APOE:gene) genotype influences the outcome after TBI.The proposed mechanism by which APOE affects the clinicopathological consequences of TBI is multifactorial and includes amyloid deposition,disruption of lipid distribution,dysfunction of mitochondrial energy production,oxidative stress and increases intracellular calcium in response to injury.This paper reviews the current state of knowledge regarding the influence of apoE and its receptors on cerebral amyloid betaprotein precursor metabolism following TBI.

  2. Functional Hydrogel Materials Inspired by Amyloid

    Science.gov (United States)

    Schneider, Joel

    2012-02-01

    Protein assembly resulting in the formation of amyloid fibrils, assemblies rich in cross beta-sheet structure, is normally thought of as a deleterious event associated with disease. However, amyloid formation is also involved in a diverse array of normal biological functions such as cell adhesion, melanin synthesis, insect defense mechanism and modulation of water surface tension by fungi and bacteria. These findings indicate that Nature has evolved to take advantage of large, proteinaceous fibrillar assemblies to elicit function. We are designing functional materials, namely hydrogels, from peptides that self-assembled into fibrillar networks, rich in cross beta-sheet structure. These gels can be used for the direct encapsulation and delivery of small molecule-, protein- and cell-based therapeutics. Loaded gels exhibit shear-thinning/self-healing mechanical properties enabling their delivery via syringe. In addition to their use for delivery, we have found that some of these gels display antibacterial activity. Although cytocompatible towards mammalian cells, the hydrogels can kill a broad spectrum of bacteria on contact.

  3. Magnetite nanoparticle interactions with insulin amyloid fibrils

    Science.gov (United States)

    Chen, Yun-Wen; Chang, Chiung-Wen; Hung, Huey-Shan; Kung, Mei-Lang; Yeh, Bi-Wen; Hsieh, Shuchen

    2016-10-01

    Accumulation of amyloid fibrils is one of the likely key factors leading to the development of Alzheimer’s disease and other amyloidosis associated diseases. Magnetic nanoparticles (NPs) have been developed as promising medical materials for many medical applications. In this study, we have explored the effects of Fe3O4 NPs on the fibrillogenesis process of insulin fibrils. When Fe3O4 NPs were co-incubated with insulin, Fe3O4 NPs had no effect on the structural transformation into amyloid-like fibrils but had higher affinity toward insulin fibrils. We demonstrated that the zeta potential of insulin fibrils and Fe3O4 NPs were both positive, suggesting the binding forces between Fe3O4 NPs and insulin fibrils were van der Waals forces but not surface charge. Moreover, a different amount of Fe3O4 NPs added had no effect on secondary structural changes of insulin fibrils. These results propose the potential use of Fe3O4 NPs as therapeutic agents against diseases related to protein aggregation or contrast agents for magnetic resonance imaging.

  4. Looking for a generic inhibitor of amyloid-like fibril formation among flavone derivatives

    OpenAIRE

    Šneideris, Tomas; Baranauskienė, Lina; Jonathan G Cannon; Rutkienė, Rasa; Meškys, Rolandas; Smirnovas, Vytautas

    2015-01-01

    A range of diseases is associated with amyloid fibril formation. Despite different proteins being responsible for each disease, all of them share similar features including beta-sheet-rich secondary structure and fibril-like protein aggregates. A number of proteins can form amyloid-like fibrils in vitro, resembling structural features of disease-related amyloids. Given these generic structural properties of amyloid and amyloid-like fibrils, generic inhibitors of fibril formation would be of i...

  5. Protein-induced Photophysical Changes to the Amyloid Indicator Dye Thioflavin T

    Energy Technology Data Exchange (ETDEWEB)

    L Wolfe; M Calabrese; A Nath; D Blaho; A Miranker; Y Xiong

    2011-12-31

    The small molecule thioflavin T (ThT) is a defining probe for the identification and mechanistic study of amyloid fiber formation. As such, ThT is fundamental to investigations of serious diseases such as Alzheimer's disease, Parkinson disease, and type II diabetes. For each disease, a different protein undergoes conformational conversion to a {beta}-sheet rich fiber. The fluorescence of ThT exhibits an increase in quantum yield upon binding these fibers. Despite its widespread use, the structural basis for binding specificity and for the changes to the photophysical properties of ThT remain poorly understood. Here, we report the co-crystal structures of ThT with two alternative states of {beta}-2 microglobulin ({beta}2m); one monomeric, the other an amyloid-like oligomer. In the latter, the dye intercalates between {beta}-sheets orthogonal to the {beta}-strands. Importantly, the fluorophore is bound in such a manner that a photophysically relevant torsion is limited to a range of angles generally associated with low, not high, quantum yield. Quantum mechanical assessment of the fluorophore shows the electronic distribution to be strongly stabilized by aromatic interactions with the protein. Monomeric {beta}2m gives little increase in ThT fluorescence despite showing three fluorophores, at two binding sites, in configurations generally associated with high quantum yield. Our efforts fundamentally extend existing understanding about the origins of amyloid-induced photophysical changes. Specifically, the {beta}-sheet interface that characterizes amyloid acts both sterically and electronically to stabilize the fluorophore's ground state electronic distribution. By preventing the fluorophore from adopting its preferred excited state configuration, nonradiative relaxation pathways are minimized and quantum yield is increased.

  6. Microglial activation in the hippocampus of hypercholesterolemic rabbits occurs independent of increased amyloid production

    Directory of Open Access Journals (Sweden)

    Streit Wolfgang J

    2007-08-01

    Full Text Available Abstract Background Rabbits maintained on high-cholesterol diets are known to show increased immunoreactivity for amyloid beta protein in cortex and hippocampus, an effect that is amplified by presence of copper in the drinking water. Hypercholesterolemic rabbits also develop sporadic neuroinflammatory changes. The purpose of this study was to survey microglial activation in rabbits fed cholesterol in the presence or absence of copper or other metal ions, such as zinc and aluminum. Methods Vibratome sections of the rabbit hippocampus and overlying cerebral cortex were examined for microglial activation using histochemistry with isolectin B4 from Griffonia simplicifolia. Animals were scored as showing either focal or diffuse microglial activation with or without presence of rod cells. Results Approximately one quarter of all rabbits fed high-cholesterol diets showed evidence of microglial activation, which was always present in the hippocampus and not in the cortex. Microglial activation was not correlated spatially with increased amyloid immunoreactivity or with neurodegenerative changes and was most pronounced in hypercholesterolemic animals whose drinking water had been supplemented with either copper or zinc. Controls maintained on normal chow were largely devoid of neuroinflammatory changes, but revealed minimal microglial activation in one case. Conclusion Because the increase in intraneuronal amyloid immunoreactivity that results from administration of cholesterol occurs in both cerebral cortex and hippocampus, we deduce that the microglial activation reported here, which is limited to the hippocampus, occurs independent of amyloid accumulation. Furthermore, since neuroinflammation occurred in the absence of detectable neurodegenerative changes, and was also not accompanied by increased astrogliosis, we conclude that microglial activation occurs because of metabolic or biochemical derangements that are influenced by dietary factors.

  7. Amyloid plaque imaging in vivo: current achievement and future prospects

    Energy Technology Data Exchange (ETDEWEB)

    Nordberg, Agneta [Karolinska University Hospital Huddinge, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Alzheimer Neurobiology, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden)

    2008-03-15

    Alzheimer's disease (AD) is a very complex neurodegenerative disorder, the exact cause of which is still not known. The major histopathological features, amyloid plaques and neurofibrillary tangles, already described by Alois Alzheimer, have been the focus in research for decades. Despite a probable whole cascade of events in the brain leading to impairment of cognition, amyloid is still the target for diagnosis and treatment. The rapid development of molecular imaging techniques now allows imaging of amyloid plaques in vivo in Alzheimer patients by PET amyloid ligands such as Pittsburgh compound B (PIB). Studies so far have revealed high {sup 11}C-PIB retention in brain at prodromal stages of AD and a possibility to discriminate AD from other dementia disorders by {sup 11}C-PIB. Ongoing studies are focussing to understand the relationship between brain and CSF amyloid processes and cognitive processes. In vivo imaging of amyloid will be important for early diagnosis and evaluation of new anti-amyloid therapies in AD. (orig.)

  8. SERF Protein Is a Direct Modifier of Amyloid Fiber Assembly

    Directory of Open Access Journals (Sweden)

    S. Fabio Falsone

    2012-08-01

    Full Text Available The inherent cytotoxicity of aberrantly folded protein aggregates contributes substantially to the pathogenesis of amyloid diseases. It was recently shown that a class of evolutionary conserved proteins, called MOAG-4/SERF, profoundly alter amyloid toxicity via an autonomous but yet unexplained mode. We show that the biological function of human SERF1a originates from its atypical ability to specifically distinguish between amyloid and nonamyloid aggregation. This inherently unstructured protein directly affected the aggregation kinetics of a broad range of amyloidogenic proteins in vitro, while being inactive against nonamyloid aggregation. A representative biophysical analysis of the SERF1a:α-synuclein (aSyn complex revealed that the amyloid-promoting activity resulted from an early and transient interaction, which was sufficient to provoke a massive increase of soluble aSyn amyloid nucleation templates. Therefore, the autonomous amyloid-modifying activity of SERF1a observed in living organisms relies on a direct and dedicated manipulation of the early stages in the amyloid aggregation pathway.

  9. 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 amyloid-β peptides 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

  10. Tissue transglutaminase colocalizes with extracellular matrix proteins in cerebral amyloid angiopathy.

    Science.gov (United States)

    de Jager, Mieke; van der Wildt, Berend; Schul, Emma; Bol, John G J M; van Duinen, Sjoerd G; Drukarch, Benjamin; Wilhelmus, Micha M M

    2013-04-01

    Cerebral amyloid angiopathy (CAA) is a key histopathological hallmark of Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). CAA is characterized by amyloid-beta (Aβ) depositions and remodeling of the extracellular matrix (ECM) in brain vessels and plays an important role in the development and progression of both AD and HCHWA-D. Tissue transglutaminase (tTG) modulates the ECM by molecular cross-linking of ECM proteins. Here, we investigated the distribution pattern, cellular source, and activity of tTG in CAA in control, AD, and HCHWA-D cases. We observed increased tTG immunoreactivity and colocalization with Aβ in the vessel wall in early stage CAA, whereas in later CAA stages, tTG and its cross-links were present in halos enclosing the Aβ deposition. In CAA, tTG and its cross-links at the abluminal side of the vessel were demonstrated to be either of astrocytic origin in parenchymal vessels, of fibroblastic origin in leptomeningeal vessels, and of endothelial origin at the luminal side of the deposited Aβ. Furthermore, the ECM proteins fibronectin and laminin colocalized with the tTG-positive halos surrounding the deposited Aβ in CAA. However, we observed that in situ tTG activity was present throughout the vessel wall in late stage CAA. Together, our data suggest that tTG and its activity might play a differential role in the development and progression of CAA, possibly evolving from direct modulation of Aβ aggregation to cross-linking of ECM proteins resulting in ECM restructuring.

  11. Prevalence of amyloid PET positivity in dementia syndromes

    DEFF Research Database (Denmark)

    Ossenkoppele, Rik; Jansen, Willemijn J; Rabinovici, Gil D;

    2015-01-01

    IMPORTANCE: Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. OBJECTIVE: To use...... years; noncarriers [n = 77], 7% [95% CI, 3%-18%] at 60 years to 29% [95% CI, 17%-43%] at 80 years. CONCLUSIONS AND RELEVANCE: Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential...

  12. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders

    Directory of Open Access Journals (Sweden)

    Yazan S. Batarseh

    2016-03-01

    Full Text Available Amyloid-β (Aβ pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer’s disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer’s disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia.

  13. Evaluation of uncertainty and detection limits in {sup 210}Pb and {sup 210}Po measurement in water by alpha spectrometry using {sup 210}Po spontaneous deposition onto a silver disk

    Energy Technology Data Exchange (ETDEWEB)

    Fernandez, Pedro L., E-mail: pedroluis.fernandez@unican.es [Department of Medical and Surgical Sciences (Medical Physics Section), Faculty of Medicine, University of Cantabria, 39011 Santander (Cantabria) (Spain); Gomez, Jose; Rodenas, Carmen [Department of Medical and Surgical Sciences (Medical Physics Section), Faculty of Medicine, University of Cantabria, 39011 Santander (Cantabria) (Spain)

    2012-04-15

    An easy and accurate method for the determination of {sup 210}Pb and {sup 210}Po in water using {sup 210}Po spontaneous deposition onto a silver disk is proposed and assessed for its detection capabilities according to the ISO Guide for the expression of uncertainty in measurement (GUM) and ISO Standard 11929-7 concerning the evaluation of the characteristic limits for ionizing radiation measurements. The method makes no assumption on the initial values of the activity concentrations of {sup 210}Pb, {sup 210}Bi and {sup 210}Po in the sample to be analyzed, and is based on the alpha spectrometric measurement of {sup 210}Po in two different aliquots: the first one measured five weeks after the sampling date to ensure radioactive equilibrium between {sup 210}Pb and {sup 210}Bi and the second after a sufficient time for the ingrowth of {sup 210}Po from {sup 210}Pb to be significant. As shown, for a recommended time interval of seven months between {sup 210}Po measurements, the applicability of the proposed method is limited to water samples with a {sup 226}Ra to {sup 210}Pb activity ratio C{sub Ra}/C{sub Pb}{<=}4, as usual in natural waters. Using sample and background counting times of 24 h and 240 h, respectively, the detection limit of the activity concentration of each radionuclide at the sampling time for a 1 L sample typically varies between 0.7 and 16 mBq L{sup -1} for {sup 210}Pb in water samples with an initial activity of {sup 210}Po in the range 0-200 mBq L{sup -1}, and between 0.6 and 8.5 mBq L{sup -1} for {sup 210}Po in water samples with an initial activity of {sup 210}Pb in the same range. - Highlights: Black-Right-Pointing-Pointer {sup 210}Pb and {sup 210}Po measurement in water by {sup 210}Po spontaneous deposition onto silver disks. Black-Right-Pointing-Pointer {sup 210}Pb and {sup 210}Po determination based on {sup 210}Po measurement in two different aliquots. Black-Right-Pointing-Pointer Evaluation of characteristic limits in radioactivity

  14. Early oligomerization stages for the non-amyloid component of α-synuclein amyloid

    Science.gov (United States)

    Eugene, Cindie; Laghaei, Rozita; Mousseau, Normand

    2014-10-01

    In recent years, much effort has focused on the early stages of aggregation and the formation of amyloid oligomers. Aggregation processes for these proteins are complex and their non-equilibrium nature makes any experimental study very difficult. Under these conditions, simulations provide a useful alternative for understanding the dynamics of the early stages of oligomerization. Here, we focus on the non-Aβ amyloid component (NAC) of the monomer, dimer, and trimer of α-synuclein, an important 35-residue sequence involved in the aggregation and fibrillation of this protein associated with Parkinson's disease. Using Hamiltonian and temperature replica exchange molecular dynamics simulations combined with the coarse grained Optimized Potential for Efficient peptide structure Prediction potential, we identify the role of the various regions and the secondary structures for the onset of oligomerization. For this sequence, we clearly observe the passage from α-helix to β-sheet, a characteristic transition of amyloid proteins. More precisely, we find that the NAC monomer is highly structured with two α-helical regions, between residues 2-13 and 19-25. As the dimer and trimer form, β-sheet structures between residues 2-14 and 26-34 appear and rapidly structure the system. The resulting conformations are much more structured than similar dimers and trimers of β-amyloid and amylin proteins and yet display a strong polymorphism at these early stages of aggregation. In addition to its inherent experimental interest, comparison with other sequences shows that NAC could be a very useful numerical model for understanding the onset of aggregation.

  15. Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders

    OpenAIRE

    Yazan S. Batarseh; Quoc-Viet Duong; Youssef M. Mousa; Al Rihani, Sweilem B.; Khaled Elfakhri; Amal Kaddoumi

    2016-01-01

    Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer’s disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process m...

  16. siRNA against presenilin 1 (PS1 down regulates amyloid β42 production in IMR-32 cells

    Directory of Open Access Journals (Sweden)

    Kandimalla Ramesh JL

    2012-01-01

    Full Text Available Abstract Background One of the pathological hallmarks of Alzheimer's disease (AD is the deposition of the ~4 kDa amyloid β protein (Aβ within lesions known as senile plaques. Aβ is also deposited in the walls of cerebral blood vessels in many cases of AD. A substantial proportion of the Aβ that accumulates in the AD brain is deposited as Amyloid, which is highly insoluble, proteinaceous material with a β-pleated-sheet conformation and deposited extracellularly in the form of 5-10 nm wide straight fibrils. As γ-secretase catalyzes the final cleavage that releases the Aβ42 or 40 from amyloid β -protein precursor (APP, therefore, it is a potential therapeutic target for the treatment of AD. γ-Secretase cleavage is performed by a high molecular weight protein complex containing presenilins (PSs, nicastrin, Aph-1 and Pen-2. Previous studies have demonstrated that the presenilins (PS1 and PS2 are critical components of a large enzyme complex that performs γ-secretase cleavage. Methods In this study we used RNA interference (RNAi technology to examine the effects of small-interfering RNA (siRNA against PS1 on expression levels of PS1 and Aβ42 in IMR-32 Cells using RTPCR, western blotting and immunofluorescence techniques. Results The results of the present study showed down regulation of PS1 and Aβ42 in IMR32 cells transfected with siRNA against PS1. Conclusion Our results substantiate the concept that PS1 is involved in γ-secretase activity and provides the rationale for therapeutic strategies aimed at influencing Aβ42 production.

  17. Objectively measured sleep and β-amyloid burden in older adults: A pilot study

    Directory of Open Access Journals (Sweden)

    Adam P Spira

    2014-08-01

    Full Text Available Background/aims: Although disturbed sleep is associated with cognitive deficits, the association between sleep disturbance and Alzheimer’s disease pathology is unclear. In this pilot study, we examined the extent to which sleep duration, sleep quality, and sleep-disordered breathing are associated with β-amyloid (Aβ deposition in the brains of living humans. Methods: We studied 13 older adults (8 with normal cognition and 5 with mild cognitive impairment. Participants completed neuropsychological testing, polysomnography, and Aβ imaging with [11C]-Pittsburgh compound B. Results: Among participants with mild cognitive impairment, higher apnea–hypopnea index and oxygen desaturation index were associated with greater Aβ deposition, globally and regionally in the precuneus. There were no significant associations between sleep-disordered breathing and Aβ deposition among cognitively normal participants. There were no significant associations between sleep duration or sleep fragmentation and Aβ deposition. Conclusion: These preliminary results suggest that among older adults with mild cognitive impairment, greater sleep-disordered breathing severity is associated with greater Aβ deposition.

  18. Amyloid β Oligomeric Species Present in the Lag Phase of Amyloid Formation.

    Directory of Open Access Journals (Sweden)

    Martin Wolff

    Full Text Available Alzheimer's disease (AD-associated amyloid β peptide (Aβ is one of the main actors in AD pathogenesis. Aβ is characterized by its high tendency to self-associate, leading to the generation of oligomers and amyloid fibrils. The elucidation of pathways and intermediates is crucial for the understanding of protein assembly mechanisms in general and in conjunction with neurodegenerative diseases, e.g., for the identification of new therapeutic targets. Our study focused on Aβ42 and its oligomeric assemblies in the lag phase of amyloid formation, as studied by sedimentation velocity (SV centrifugation. The assembly state of Aβ during the lag phase, the time required by an Aβ solution to reach the exponential growth phase of aggregation, was characterized by a dominant monomer fraction below 1 S and a population of oligomeric species between 4 and 16 S. From the oligomer population, two major species close to a 12-mer and an 18-mer with a globular shape were identified. The recurrence of these two species at different initial concentrations and experimental conditions as the smallest assemblies present in solution supports the existence of distinct, energetically favored assemblies in solution. The sizes of the two species suggest an Aβ42 aggregation pathway that is based on a basic hexameric building block. The study demonstrates the potential of SV analysis for the evaluation of protein aggregation pathways.

  19. 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.

  20. Tensile deformation and failure of amyloid and amyloid-like protein fibrils

    Science.gov (United States)

    Solar, Max; Buehler, Markus J.

    2014-03-01

    Here we report a series of full atomistic molecular dynamics simulations of six amyloid or amyloid-like protein fibrils in order to systematically understand the effect of different secondary structure motifs on the mechanical tensile and failure response of cross-\\beta protein fibrils. We find a similar failure behavior across the six structures; an initial failure event occurs at small strains involving cooperative rupture of a group of hydrogen bonds, followed by a slow one-by-one hydrogen bond rupture process as the remaining \\beta -sheets peel off with very low applied stress. We also find that the ultimate tensile strength of the protein fibrils investigated scales directly with the number of hydrogen bonds per unit area which break in the initial rupture event. Our results provide insights into structure-property relationships in protein fibrils important for disease and engineering applications and lay the groundwork for the development of materials selection criteria for the design of de novo amyloid-based functional biomaterials.

  1. Yeast and Fungal Prions: Amyloid-Handling Systems, Amyloid Structure, and Prion Biology.

    Science.gov (United States)

    Wickner, R B; Edskes, H K; Gorkovskiy, A; Bezsonov, E E; Stroobant, E E

    2016-01-01

    Yeast prions (infectious proteins) were discovered by their outré genetic properties and have become important models for an array of human prion and amyloid diseases. A single prion protein can become any of many distinct amyloid forms (called prion variants or strains), each of which is self-propagating, but with different biological properties (eg, lethal vs mild). The folded in-register parallel β sheet architecture of the yeast prion amyloids naturally suggests a mechanism by which prion variant information can be faithfully transmitted for many generations. The yeast prions rely on cellular chaperones for their propagation, but can be cured by various chaperone imbalances. The Btn2/Cur1 system normally cures most variants of the [URE3] prion that arise. Although most variants of the [PSI+] and [URE3] prions are toxic or lethal, some are mild in their effects. Even the most mild forms of these prions are rare in the wild, indicating that they too are detrimental to yeast. The beneficial [Het-s] prion of Podospora anserina poses an important contrast in its structure, biology, and evolution to the yeast prions characterized thus far.

  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. Binuclear ruthenium(II) complexes for amyloid fibrils recognition

    Energy Technology Data Exchange (ETDEWEB)

    Hanczyc, Piotr, E-mail: piotr.hanczyc@chalmers.se

    2014-12-05

    Highlights: • Interactions of binuclear ruthenium(II) complexes with amyloid fibrils. • Dimer ruthenium(II) compounds are sensitive amyloid fibrils biomarkers. • Recognition of amyloid-chromophore adducts by two-photon excited emission. - Abstract: Metal–organic compounds represent a unique class of biomarkers with promising photophysical properties useful for imaging. Here interactions of insulin fibrils with two binuclear complexes [μ-(11,11′-bidppz)(phen){sub 4}Ru{sub 2}]{sup 4+} (1) and [μ-C4(cpdppz)(phen){sub 4}Ru{sub 2}]{sup 4+} (2) are studied by linear dichroism (LD) and fluorescence. These ruthenium(II) compounds could provide a new generation of amyloid binding chromophores with long lived lifetimes, good luminescence quantum yields for the bound molecules and photo-stability useful in multiphoton luminescence imaging.

  4. Transformation of amyloid-like fibers, formed from an elastin-based biopolymer, into a hydrogel: an X-ray photoelectron spectroscopy and atomic force microscopy study.

    Science.gov (United States)

    Flamia, R; Salvi, A M; D'Alessio, L; Castle, J E; Tamburro, A M

    2007-01-01

    Previous studies have revealed the propensity of elastin-based biopolymers to form amyloid-like fibers when dissolved in water. These are of interest when considered as "ancestral units" of elastin in which they represent the simplest sequences in the hydrophobic regions of the general type XxxGlyGlyZzzGly (Xxx, Zzz = Val, Leu). We normally refer to these biopolymers based on elastin or related to elastin units as "elastin-like polypeptides". The requirement of water for the formation of amyloids seems quite interesting and deserves investigation, the water representing the natural transport medium in human cells. As a matter of fact, the "natural" supramolecular organization of elastin is in the form of beaded-string-like filaments and not in the form of amyloids whose "in vivo" deposition is associated with some important human diseases. Our work is directed, therefore, to understanding the mechanism by which such hydrophobic sequences form amyloids and any conditions by which they might regress to a non-amyloid filament. The elastin-like sequence here under investigation is the ValGlyGlyValGly pentapeptide that has been previously analyzed both in its monomer and polymer form. In particular, we have focused our investigation on the apparent stability of amyloids formed from poly(ValGlyGlyValGly), and we have observed these fibers evolving to a hydrogel after prolonged aging in water. We will show how atomic force microscopy can be combined with X-ray photoelectron spectroscopy to gain an insight into the spontaneous organization of an elastin-like polypeptide driven by interfacial interactions. The results are discussed also in light of fractal-like assembly and their implications from a biomedical point of view. PMID:17206798

  5. Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane.

    Science.gov (United States)

    Engel, Maarten F M; Khemtémourian, Lucie; Kleijer, Cécile C; Meeldijk, Hans J D; Jacobs, Jet; Verkleij, Arie J; de Kruijff, Ben; Killian, J Antoinette; Höppener, Jo W M

    2008-04-22

    Fibrillar protein deposits (amyloid) in the pancreatic islets of Langerhans are thought to be involved in death of the insulin-producing islet beta cells in type 2 diabetes mellitus. It has been suggested that the mechanism of this beta cell death involves membrane disruption by human islet amyloid polypeptide (hIAPP), the major constituent of islet amyloid. However, the molecular mechanism of hIAPP-induced membrane disruption is not known. Here, we propose a hypothesis that growth of hIAPP fibrils at the membrane causes membrane damage. We studied the kinetics of hIAPP-induced membrane damage in relation to hIAPP fibril growth and found that the kinetic profile of hIAPP-induced membrane damage is characterized by a lag phase and a sigmoidal transition, which matches the kinetic profile of hIAPP fibril growth. The observation that seeding accelerates membrane damage supports the hypothesis. In addition, variables that are well known to affect hIAPP fibril formation, i.e., the presence of a fibril formation inhibitor, hIAPP concentration, and lipid composition, were found to have the same effect on hIAPP-induced membrane damage. Furthermore, electron microscopy analysis showed that hIAPP fibrils line the surface of distorted phospholipid vesicles, in agreement with the notion that hIAPP fibril growth at the membrane and membrane damage are physically connected. Together, these observations point toward a mechanism in which growth of hIAPP fibrils, rather than a particular hIAPP species, is responsible for the observed membrane damage. This hypothesis provides an additional mechanism next to the previously proposed role of oligomers as the main cytotoxic species of amyloidogenic proteins. PMID:18408164

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

    Science.gov (United States)

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

    2009-07-01

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

  7. Evidence for Novel [beta]-Sheet Structures in Iowa Mutant [beta]-Amyloid Fibrils

    Energy Technology Data Exchange (ETDEWEB)

    Tycko, Robert; Sciarretta, Kimberly L.; Orgel, Joseph P.R.O.; Meredith, Stephen C.; (IIT); (NIH); (UC)

    2009-07-24

    Asp23-to-Asn mutation within the coding sequence of {beta}-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-A{beta}40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-A{beta}40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10{sup -3} min{sup -1} and 1.07 x 10{sup -4} min{sup -1} for D23N-A{beta}40 and the wild-type peptide WT-A{beta}40, respectively) and without a lag phase. Electron microscopy shows that D23N-A{beta}40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-{beta} pattern, with a sharp reflection at 4.7 {angstrom} and a broad reflection at 9.4 {angstrom}, which is notably smaller than the value for WT-A{beta}40 fibrils (10.4 {angstrom}). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-A{beta}40 fibrils containing the in-register, parallel {beta}-sheet structure commonly found in WT-A{beta}40 fibrils and most other amyloid fibrils. Antiparallel {beta}-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through 13C-13C and 15N-13C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-A{beta}40 fibrils and the unusual vasculotropic clinical picture in these patients.

  8. Extracellular matrix-anchored serum amyloid A preferentially induces mast cell adhesion.

    Science.gov (United States)

    Hershkoviz, R; Preciado-Patt, L; Lider, O; Fridkin, M; Dastych, J; Metcalfe, D D; Mekori, Y A

    1997-07-01

    Mast cells are known to accumulate in various inflammatory processes, some of which are known to be associated with increased local and systemic levels of acute-phase reactants such as serum amyloid A (SAA) or with amyloid deposition. The mechanism(s) by which mast cells are recruited to these sites, however, has not been fully elucidated. It has recently been shown that SAA interacts with extracellular matrix (ECM) components and thereby acts as a chemoattractant and regulator of immune cell migration. On the basis of these observations, we examined the effect of SAA on mast cell adhesion to ECM, an essential step in cellular transmigration. We could first demonstrate strong specific binding of recombinant human SAA (rSAA) to murine mast cells using flow cytometry. Moreover, radiolabeled rSAA was found to bind, in a saturable manner, to mast cells, reaching a binding affinity of 10(-8) M. When immobilized by preincubation with ECM, SAA or its proteolytically degraded amyloid A fragment (amino acid residues 2-82), which contains RGD-related adhesion motif but not the COOH-terminal portion of SAA (amino acid residues 77-104), induced the adhesion of resting mast cells to ECM or laminin. SAA and AA, in soluble or immobilized forms, did not activate mast cells to release mediators. Mast cell adhesion to the immobilized ECM-SAA complex appeared to occur through an integrin recognition, inasmuch as adhesion was calcium dependent and could be blocked by an RGD-containing peptide or by anti-CD29 monoclonal antibody. Genistein also inhibited adhesion, indicating that tyrosine kinase activity was involved. These data suggest that SAA bound to ECM may serve as an important inducer of mast cell adhesion, thus regulating mast cell recruitment and accumulation at these sites, which in turn could potentiate further pathology. PMID:9252455

  9. Interactions driving the collapse of islet amyloid polypeptide: Implications for amyloid aggregation

    Science.gov (United States)

    Cope, Stephanie M.

    Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-residue intrinsically disordered hormone involved in glucose regulation and gastric emptying. The aggregation of hIAPP into amyloid fibrils is believed to play a causal role in type 2 diabetes. To date, not much is known about the monomeric state of hIAPP or how it undergoes an irreversible transformation from disordered peptide to insoluble aggregate. IAPP contains a highly conserved disulfide bond that restricts hIAPP(1-8) into a short ring-like structure: N_loop. Removal or chemical reduction of N_loop not only prevents cell response upon binding to the CGRP receptor, but also alters the mass per length distribution of hIAPP fibers and the kinetics of fibril formation. The mechanism by which N_loop affects hIAPP aggregation is not yet understood, but is important for rationalizing kinetics and developing potential inhibitors. By measuring end-to-end contact formation rates, Vaiana et al. showed that N_loop induces collapsed states in IAPP monomers, implying attractive interactions between N_loop and other regions of the disordered polypeptide chain . We show that in addition to being involved in intra-protein interactions, the N_loop is involved in inter-protein interactions, which lead to the formation of extremely long and stable beta-turn fibers. These non-amyloid fibers are present in the 10 muM concentration range, under the same solution conditions in which hIAPP forms amyloid fibers. We discuss the effect of peptide cyclization on both intra- and inter-protein interactions, and its possible implications for aggregation. Our findings indicate a potential role of N_loop-N_loop interactions in hIAPP aggregation, which has not previously been explored. Though our findings suggest that N_loop plays an important role in the pathway of amyloid formation, other naturally occurring IAPP variants that contain this structural feature are incapable of forming amyloids. For example, hIAPP readily

  10. Amyloid/Melanin distinctive mark in invertebrate immunity

    OpenAIRE

    A Grimaldi; R Girardello; D Malagoli; P Falabella; Tettamanti, G.; R Valvassori; E Ottaviani; M de Eguileor

    2012-01-01

    Protostomes and Deuterostomes show the same nexus between melanin production, and amyloid fibril production, i.e., the presence of melanin is indissolubly linked to amyloid scaffold that, in turn, is conditioned by the redox status/cytoplasmic pH modification, pro-protein cleavage presence, adrenocorticotropin hormone (ACTH), melanocyte-stimulating hormone (α-MSH), and neutral endopeptidase (NEP) overexpressions. These events represent the crucial component of immune response in invertebrates...

  11. Face-name Associative Memory Performance is Related To Amyloid Burden in Normal Elderly

    Science.gov (United States)

    Rentz, Dorene M.; Amariglio, Rebecca. E.; Becker, J. Alex; Frey, Meghan; Olson, Lauren E.; Frishe, Katherine; Carmasin, Jeremy; Maye, Jacqueline E.; Johnson, Keith A.; Sperling, Reisa A.

    2011-01-01

    Cerebral amyloid beta (Aβ) deposition occurs in a substantial fraction of cognitively normal (CN) older individuals. However, it has been difficult to reliably detect evidence of amyloid-related cognitive alterations in CN using standard neuropsychological measures. We sought to determine whether a highly demanding face-name associative memory exam (FNAME) could detect evidence of Aβ-related memory impairment in CN. We studied 45 CN subjects (mean age = 71.7 ± 8.8) with Clinical Dementia Rating (CDR) scores = 0 and MMSE ≥ 28, using Positron Emission Tomography with Pittsburgh Compound B (PiB PET). Memory factor scores were derived from a principal components analysis for FNAME name retrieval (FN-N), FNAME occupation retrieval (FN-O) and the 6-Trial Selective Reminding Test (SRT). Using multiple linear and logistic regression analyses, we related the memory factor scores to PiB distribution volume ratios (DVR, cerebellar reference) as either a continuous or a dichotomous variable in frontal cortex and a posterior cortical region representing the precuneus, posterior cingulate and lateral parietal cortices (PPCLP), co-varying for age and AMNART IQ (a proxy of cognitive reserve (CR)). A significant inverse relationship for FN-N was found with Aβ deposition in frontal (R2 = .29, β = −2.2, p = 0.02) and PPCLP cortices (R2 = .26, β = −2.4, p = 0.05). In contrast, neither FN-O nor the SRT were significantly related to Aβ deposition. Performance on a demanding test of face-name associative memory was related to Aβ burden in brain regions associated with memory systems. Associative memory for faces and names, a common complaint among older adults, may be a sensitive marker of early Aβ-related impairment. PMID:21689670

  12. Force generation by the growth of amyloid aggregates.

    Science.gov (United States)

    Herling, Therese W; Garcia, Gonzalo A; Michaels, Thomas C T; Grentz, Wolfgang; Dean, James; Shimanovich, Ulyana; Gang, Hongze; Müller, Thomas; Kav, Batuhan; Terentjev, Eugene M; Dobson, Christopher M; Knowles, Tuomas P J

    2015-08-01

    The generation of mechanical forces are central to a wide range of vital biological processes, including the function of the cytoskeleton. Although the forces emerging from the polymerization of native proteins have been studied in detail, the potential for force generation by aberrant protein polymerization has not yet been explored. Here, we show that the growth of amyloid fibrils, archetypical aberrant protein polymers, is capable of unleashing mechanical forces on the piconewton scale for individual filaments. We apply microfluidic techniques to measure the forces released by amyloid growth for two systems: insulin and lysozyme. The level of force measured for amyloid growth in both systems is comparable to that observed for actin and tubulin, systems that have evolved to generate force during their native functions and, unlike amyloid growth, rely on the input of external energy in the form of nucleotide hydrolysis for maximum force generation. Furthermore, we find that the power density released from growing amyloid fibrils is comparable to that of high-performance synthetic polymer actuators. These findings highlight the potential of amyloid structures as active materials and shed light on the criteria for regulation and reversibility that guide molecular evolution of functional polymers.

  13. Complexation of amyloid fibrils with charged conjugated polymers.

    Science.gov (United States)

    Ghosh, Dhiman; Dutta, Paulami; Chakraborty, Chanchal; Singh, Pradeep K; Anoop, A; Jha, Narendra Nath; Jacob, Reeba S; Mondal, Mrityunjoy; Mankar, Shruti; Das, Subhadeep; Malik, Sudip; Maji, Samir K

    2014-04-01

    It has been suggested that conjugated charged polymers are amyloid imaging agents and promising therapeutic candidates for neurological disorders. However, very less is known about their efficacy in modulating the amyloid aggregation pathway. Here, we studied the modulation of Parkinson's disease associated α-synuclein (AS) amyloid assembly kinetics using conjugated polyfluorene polymers (PF, cationic; PFS, anionic). We also explored the complexation of these charged polymers with the various AS aggregated species including amyloid fibrils and oligomers using multidisciplinary biophysical techniques. Our data suggests that both polymers irrespective of their different charges in the side chains increase the fibrilization kinetics of AS and also remarkably change the morphology of the resultant amyloid fibrils. Both polymers were incorporated/aligned onto the AS amyloid fibrils as evident from electron microscopy (EM) and atomic force microscopy (AFM), and the resultant complexes were structurally distinct from their pristine form of both polymers and AS supported by FTIR study. Additionally, we observed that the mechanism of interactions between the polymers with different species of AS aggregates were markedly different.

  14. Switchable photooxygenation catalysts that sense higher-order amyloid structures

    Science.gov (United States)

    Taniguchi, Atsuhiko; Shimizu, Yusuke; Oisaki, Kounosuke; Sohma, Youhei; Kanai, Motomu

    2016-10-01

    Proteins can misfold into amyloid structures that are associated with diseases; however, the same proteins often have important biological roles. To degrade selectively the amyloid form without affecting the fraction of functional protein is, therefore, an attractive goal. Here we report target-state-dependent photooxygenation catalysts that are active only when bound to the cross-β-sheet structure that is characteristic of pathogenic aggregated amyloid proteins. We show these catalysts can selectively oxygenate the amyloid form of amyloid β-protein (Aβ) 1-42 in the presence of non-amyloid off-target substrates. Furthermore, photooxygenation with a catalyst that bears an Aβ-binding peptide attenuated the Aβ pathogenicity in the presence of cells. We also show that selective photooxygenation is generally applicable to other amyloidogenic proteins (amylin, insulin, β2-microglobulin, transthyretin and α-synuclein) and does not affect the physiologically functional non-aggregate states of these proteins. This is the first report of an artificial catalyst that can be selectively and reversibly turned on and off depending on the structure and aggregation state of the substrate protein.

  15. 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

  16. Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides

    Energy Technology Data Exchange (ETDEWEB)

    Robakis, N.K.; Ramakrishna, N.; Wolfe, G.; Wisniewski, H.M.

    1987-06-01

    Deposits of amyloid fibers are found in large numbers in the walls of blood vessels and in neuritic plaques in the brains of patients with Alzheimer disease and adults with Down syndrome. The authors used the amino acid sequence of the amyloid peptide to synthesize oligonucleotide probes specific for the gene encoding this peptide. When a human brain cDNA library was screened with this probe, a clone was found with a 1.7-kilobase insert that contains a long open reading frame coding for 412 amino acid residues including the 28 amino acids of the amyloid peptide. RNA gel blots revealed that a 3.3-kilobase mRNA species was present in the brains of individuals with Alzheimer disease, with Down syndrome, or with not apparent neurological disorders. Southern blots showed that homologous genes are present in the genomic DNA of humans, rabbits, sheep, hamsters, and mice, suggesting that this gene has been conserved through mammalian evolution. Localization of the corresponding genomic sequences on human chromosome 21 suggest a genetic relationship between Alzheimer disease and Down syndrome, and it may explain the early appearance of large numbers of neuritic plaques in adult Down syndrome patients.

  17. A setup for simultaneous measurement of infrared spectra and light scattering signals: Watching amyloid fibrils grow from intact proteins

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yang; Maurer, Jürgen; Roth, Andreas; Vogel, Vitali; Winter, Ernst; Mäntele, Werner, E-mail: maentele@biophysik.uni-frankfurt.de [Institut für Biophysik, Goethe-Universität Frankfurt am Main, Max-von Laue-Straße 1, D-60438 Frankfurt am Main (Germany)

    2014-08-15

    A setup for the simultaneous measurement of mid-infrared spectra and static light scattering is described that can be used for the analysis of the formation of nanoscale and microscopic aggregates from smaller molecules to biopolymers. It can be easily integrated into sample chambers of infrared spectrometers or combined with laser beams from tunable infrared lasers. Here, its use for the analysis of the formation of amyloid fibrils from intact proteins is demonstrated. The formation of amyloid fibrils or plaques from proteins is a widespread and pathogenetic relevant process, and a number of diseases are caused and correlated with the deposition of amyloid fibrils in cells and tissues. The molecular mechanisms of these transformations, however, are still unclear. We report here the simultaneous measurement of infrared spectra and static light scattering for the analysis of fibril formation from egg-white lysozyme. The transformation of the native form into non-native forms rich in β-sheet structure is measured by analysis of the amide I spectral region in the infrared spectra, which is sensitive for local structures. At the same time, light scattering signals at forward direction as well as the forward/backward ratio, which are sensitive for the number of scattering centers and their approximate sizes, respectively, are collected for the analysis of fibril growth. Thermodynamic and kinetic parameters as well as mechanistic information are deduced from the combination of the two complementary techniques.

  18. 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)

    Rania M. Bakkar

    2010-01-01

    Full Text Available Down's syndrome (DS, trisomy 21 represents a complex genetic abnormality that leads to pathology in later life that is similar to Alzheimer's disease (AD. We compared two cases of DS with APOE 3/3 genotypes, a similar age at death, and comparable amyloid-beta 42 peptide (A42 burdens in the brain but that differed markedly in the severity of AD-like pathology. One exhibited extensive neurofibrillary pathology whereas the other showed minimal features of this type. Comparable loads of A42 could relate to the cases' similar life-time accumulation of A due to trisomy 21-enhanced metabolism of amyloid precursor protein (APP. The cases' significant difference in AD-like pathology, however, suggests that parenchymal deposition of A42, even when extensive, may not inevitably trigger AD-like tau pathology (though it may be necessary. Thus, these observations of a natural experiment may contribute to understanding the nuances of the amyloid cascade hypothesis of AD pathogenesis.

  19. 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.)

  20. Brain beta-amyloid accumulation in transgenic mice expressing mutant superoxide dismutase 1.

    Science.gov (United States)

    Turner, Bradley J; Li, Qiao-Xin; Laughton, Katrina M; Masters, Colin L; Lopes, Elizabeth C; Atkin, Julie D; Cheema, Surindar S

    2004-12-01

    Oxidative stress is implicated in both the deposition and pathogenesis of beta-amyloid (Abeta) protein in Alzheimer's disease (AD). Accordingly, overexpression of the antioxidant enzyme superoxide dismutase 1 (SOD1) in neuronal cells and transgenic AD mice reduces Abeta toxicity and accumulation. In contrast, mutations in SOD1 associated with amyotrophic lateral sclerosis (ALS) confer enhanced pro-oxidative enzyme activities. We therefore examined whether ALS-linked mutant SOD1 overexpression in motor neuronal cells or transgenic ALS mice modulates Abeta toxicity or its accumulation in the brain. Aggregated, but not freshly solubilised, substrate-bound Abeta peptides induced degenerative morphology and cytotoxicity in motor neuron-like NSC-34 cells. Transfection of NSC-34 cells with human wild-type SOD1 attenuated Abeta-induced toxicity, however this neuroprotective effect was also observed for ALS-linked mutant SOD1. Analysis of the cerebral cortex, brainstem, cerebellum and olfactory bulb from transgenic SOD1G93A mice using enzyme-linked immunosorbent assay of acid-guanidine extracts revealed age-dependent elevations in Abeta levels, although not significantly different from wild-type mouse brain. In addition, brain amyloid protein precursor (APP) levels remained unaltered as a consequence of mutant SOD1 expression. We therefore conclude that mutant SOD1 overexpression promotes neither Abeta toxicity nor brain accumulation in these ALS models.

  1. [beta subsccript 2]-microglobulin forms three-dimensional domain-swapped amyloid fibrils with disulfide linkages

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Cong; Sawaya, Michael R.; Eisenberg, David (UCLA)

    2011-08-09

    {beta}{sub 2}-microglobulin ({beta}{sub 2}-m) is the light chain of the type I major histocompatibility complex. It deposits as amyloid fibrils within joints during long-term hemodialysis treatment. Despite the devastating effects of dialysis-related amyloidosis, full understanding of how fibrils form from soluble {beta}{sub 2}-m remains elusive. Here we show that {beta}{sub 2}-m can oligomerize and fibrillize via three-dimensional domain swapping. Isolating a covalently bound, domain-swapped dimer from {beta}{sub 2}-m oligomers on the pathway to fibrils, we were able to determine its crystal structure. The hinge loop that connects the swapped domain to the core domain includes the fibrillizing segment LSFSKD, whose atomic structure we also determined. The LSFSKD structure reveals a class 5 steric zipper, akin to other amyloid spines. The structures of the dimer and the zipper spine fit well into an atomic model for this fibrillar form of {beta}{sub 2}-m, which assembles slowly under physiological conditions.

  2. 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

  3. 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

  4. H2S- and NO-signaling pathways in Alzheimer’s amyloid vasculopathy: synergism or antagonism?

    Directory of Open Access Journals (Sweden)

    Alla B. Salmina

    2015-12-01

    Full Text Available Alzheimer’s type of neurodegeneration dramatically affects H2S and NO synthesis and interactions in the brain, which results in deregulated vasomotor function, brain tissue hypoperfusion and hypoxia, development of perivascular inflammation, promotion of Aβ deposition, and impairment of neurogenesis/angiogenesis. H2S- and NO-signaling pathways have been described to offer protection against Alzheimer’s amyloid vasculopathy and neurodegeneration. This review describes recent developments of the increasing relevance of H2S and NO in Alzheimer’s disease. More studies are however needed to fully determine their potential use as therapeutic targets in Alzheimer’s and other forms of neurodegeneration.

  5. Designed Trpzip-3 β-Hairpin Inhibits Amyloid Formation in Two Different Amyloid Systems.

    Science.gov (United States)

    Hopping, Gene; Kellock, Jackson; Caughey, Byron; Daggett, Valerie

    2013-09-12

    The trpzip peptides are small, monomeric, and extremely stable β-hairpins that have become valuable tools for studying protein folding. Here, we show that trpzip-3 inhibits aggregation in two very different amyloid systems: transthyretin and Aβ(1-42). Interestingly, Trp → Leu mutations renders the peptide ineffective against transthyretin, but Aβ inhibition remains. Computational docking was used to predict the interactions between trpzip-3 and transthyretin, suggesting that inhibition occurs via binding to the outer region of the thyroxine-binding site, which is supported by dye displacement experiments. PMID:24900756

  6. Peripheral Amyloid-β Levels Regulate Amyloid-β Clearance from the Central Nervous System

    OpenAIRE

    Marques, Marcos A.; Kulstad, J. Jacob; Savard, Christopher E.; Green, Pattie S.; Lee, Sum P.; Craft, Suzanne; Watson, G. Stennis; Cook, David G.

    2009-01-01

    Amyloid-β (Aβ) is cleared from the brain by both proteolytic digestion and transport across the blood-brain-barrier into the peripheral circulatory system. To investigate the role peripheral Aβ levels play in regulating Aβ brain clearance, we measured the clearance of [125I]-Aβ-{1-40 injected into the brains of liver-ligated rats that allowed peripheral Aβ levels to be maintained at elevated levels for approximately one hour with/without a single peripheral bolus of unlabeled Aβ-{1-40. We fou...

  7. Multiple low-dose infusions of human umbilical cord blood cells improve cognitive impairments and reduce amyloid-β-associated neuropathology in Alzheimer mice.

    Science.gov (United States)

    Darlington, Donna; Deng, Juan; Giunta, Brian; Hou, Huayan; Sanberg, Cyndy D; Kuzmin-Nichols, Nicole; Zhou, Hua-Dong; Mori, Takashi; Ehrhart, Jared; Sanberg, Paul R; Tan, Jun

    2013-02-01

    Alzheimer's disease (AD) is the most common progressive age-related dementia in the elderly and the fourth major cause of disability and mortality in that population. The disease is pathologically characterized by deposition of β-amyloid plaques neurofibrillary tangles in the brain. Current strategies for the treatment of AD are symptomatic only. As such, they are less than efficacious in terms of significantly slowing or halting the underlying pathophysiological progression of the disease. Modulation by cell therapy may be new promising disease-modifying therapy. Recently, we showed reduction in amyloid-β (Aβ) levels/β-amyloid plaques and associated astrocytosis following low-dose infusions of mononuclear human umbilical cord blood cells (HUCBCs). Our current study extended our previous findings by examining cognition via (1) the rotarod test, (2) a 2-day version of the radial-arm water maze test, and (3) a subsequent observation in an open pool platform test to characterize the effects of monthly peripheral HUCBC infusion (1×10(6) cells/μL) into the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) from 6 to 12 months of age. We show that HUCBC therapy correlates with decreased (1) cognitive impairment, (2) Aβ levels/β-amyloid plaques, (3) amyloidogenic APP processing, and (4) reactive microgliosis after a treatment of 6 or 10 months. As such, this report lays the groundwork for an HUCBC therapy as potentially novel alternative to oppose AD at the disease-modifying level.

  8. Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia.

    Science.gov (United States)

    Tabner, Brian J; El-Agnaf, Omar M A; Turnbull, Stuart; German, Matthew J; Paleologou, Katerina E; Hayashi, Yoshihito; Cooper, Leanne J; Fullwood, Nigel J; Allsop, David

    2005-10-28

    Alzheimer disease and familial British dementia are neurodegenerative diseases that are characterized by the presence of numerous amyloid plaques in the brain. These lesions contain fibrillar deposits of the beta-amyloid peptide (Abeta) and the British dementia peptide (ABri), respectively. Both peptides are toxic to cells in culture, and there is increasing evidence that early "soluble oligomers" are the toxic entity rather than mature amyloid fibrils. The molecular mechanisms responsible for this toxicity are not clear, but in the case of Abeta, one prominent hypothesis is that the peptide can induce oxidative damage via the formation of hydrogen peroxide. We have developed a reliable method, employing electron spin resonance spectroscopy in conjunction with the spin-trapping technique, to detect any hydrogen peroxide generated during the incubation of Abeta and other amyloidogenic peptides. Here, we monitored levels of hydrogen peroxide accumulation during different stages of aggregation of Abeta-(1-40) and ABri and found that in both cases it was generated as a short "burst" early on in the aggregation process. Ultrastructural studies with both peptides revealed that structures resembling "soluble oligomers" or "protofibrils" were present during this early phase of hydrogen peroxide formation. Mature amyloid fibrils derived from Abeta-(1-40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases.

  9. Nonequilibrium and generalized-ensemble molecular dynamics simulations for amyloid fibril

    International Nuclear Information System (INIS)

    Amyloids are insoluble and misfolded fibrous protein aggregates and associated with more than 20 serious human diseases. We perform all-atom molecular dynamics simulations of amyloid fibril assembly and disassembly

  10. Nonequilibrium and generalized-ensemble molecular dynamics simulations for amyloid fibril

    Science.gov (United States)

    Okumura, Hisashi

    2015-12-01

    Amyloids are insoluble and misfolded fibrous protein aggregates and associated with more than 20 serious human diseases. We perform all-atom molecular dynamics simulations of amyloid fibril assembly and disassembly.

  11. Endogenously generated amyloid β increases membrane fluidity in neural 2a cells

    Institute of Scientific and Technical Information of China (English)

    NIU Ying; SHENG BaiYang; SONG Bo; LIU LingLing; ZHANG XiuFang; ZHAO NanMing; GONG YanDao

    2009-01-01

    The effect of endogenously generated amyloid β on membrane fluidity was investigated in Neural 2a cells stably expressing Swedish mutant amyloid precursor protein (APPswe). Membrane fluidity was studied by fluorescence polarizability using 1,6-Diphenyl-1,3,5-Hexatriene (DPH) as the fluorescence probe. It was found that the membrane fluidity in APPswe cells was significantly higher than that in its wild type counterparts. Alleviating the effect of amyloid β either by y secretase activity inhibition or by amyloid antibody treatment decreased membrane fluidity, which indicated an important role of amyloid β in increasing membrane fluidity. Treatment using amyloid β channel blocker, tromethamine and NA4 suggested that channel formed by amyloid β on the cell membrane is a way through which amyloid β takes its membrane fluidizing effect.

  12. Nonequilibrium and generalized-ensemble molecular dynamics simulations for amyloid fibril

    Energy Technology Data Exchange (ETDEWEB)

    Okumura, Hisashi [Research Center for Computational Science, Institute for Molecular Science, Okazaki, Aichi 444-8585 (Japan); Department of Structural Molecular Science, The Graduate University for Advanced Studies, Okazaki, Aichi 444-8585 (Japan)

    2015-12-31

    Amyloids are insoluble and misfolded fibrous protein aggregates and associated with more than 20 serious human diseases. We perform all-atom molecular dynamics simulations of amyloid fibril assembly and disassembly.

  13. 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.

  14. Subjective cognitive complaints and amyloid burden in cognitively normal older individuals

    Science.gov (United States)

    Amariglio, Rebecca E.; Becker, J. Alex; Carmasin, Jeremy; Wadsworth, Lauren P.; Lorius, Natacha; Sullivan, Caroline; Maye, Jacqueline E.; Gidicsin, Christopher; Pepin, Lesley C.; Sperling, Reisa A.; Johnson, Keith A.; Rentz, Dorene M.

    2012-01-01

    Accumulating evidence suggests that subjective cognitive complaints (SCC) may indicate subtle cognitive decline characteristic of individuals with preclinical Alzheimer’s disease (AD). In this study, we sought to build upon previous studies by associating SCC and amyloiddeposition using Positron Emission Tomography with Pittsburg Compound B (PiB-PET) in cognitively normal older individuals. One-hundred thirty one subjects (mean age 73.5 ± 6) were administered three subjective cognitive questionnaires and a brief neuropsychological battery. A relationship between a subjective memory complaints composite score and cortical PiB binding was found to be significant, even after controlling for depressive symptoms. By contrast, there were no significant relationships between objective cognitive measures of memory and executive functions and cortical PiB binding. Our study suggests that SCC may be an early indicator of AD pathology detectable prior to significant objective impairment. PMID:22940426

  15. Recent Development of Bifunctional Small Molecules to Study Metal-Amyloid-β Species in Alzheimer's Disease.

    Science.gov (United States)

    Braymer, Joseph J; Detoma, Alaina S; Choi, Jung-Suk; Ko, Kristin S; Lim, Mi Hee

    2010-12-08

    Alzheimer's disease (AD) is a multifactorial neurodegenerative disease related to the deposition of aggregated amyloid-β (Aβ) peptides in the brain. It has been proposed that metal ion dyshomeostasis and miscompartmentalization contribute to AD progression, especially as metal ions (e.g., Cu(II) and Zn(II)) found in Aβ plaques of the diseased brain can bind to Aβ and be linked to aggregation and neurotoxicity. The role of metal ions in AD pathogenesis, however, is uncertain. To accelerate understanding in this area and contribute to therapeutic development, recent efforts to devise suitable chemical reagents that can target metal ions associated with Aβ have been made using rational structure-based design that combines two functions (metal chelation and Aβ interaction) in the same molecule. This paper presents bifunctional compounds developed by two different design strategies (linkage or incorporation) and discusses progress in their applications as chemical tools and/or potential therapeutics.

  16. 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

  17. The Amyloid Precursor Protein Controls PIKfyve Function.

    Science.gov (United States)

    Balklava, Zita; Niehage, Christian; Currinn, Heather; Mellor, Laura; Guscott, Benjamin; Poulin, Gino; Hoflack, Bernard; Wassmer, Thomas

    2015-01-01

    While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease. PMID:26125944

  18. The Amyloid Precursor Protein Controls PIKfyve Function.

    Directory of Open Access Journals (Sweden)

    Zita Balklava

    Full Text Available While the Amyloid Precursor Protein (APP plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD, thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease.

  19. Sympathetic re-innervation of myocardium after liver transplant in the hereditary amyloid neuropathy; Reinnervation sympathique du myocarde apres transplantation hepatique dans la neuropathie amyloide hereditaire

    Energy Technology Data Exchange (ETDEWEB)

    Delahaye, N.; Le Guludec, D. [Medecine Nucleaire, Hopital Bichat, Paris (France); Slama, M. [Cardiologie, Hopital A.Beclere, Paris (France); Guyen, C.N. [SHFJ, DSV-CEA, Orsay (France); Dinanian, S. [Cardiologie, Hopital A.Beclere, Paris (France); Merlet, P. [SHFJ, DSV-CEA, Orsay (France)

    1997-12-31

    The hereditary amyloid neuropathy (HAN) is characterized by a progressive sensory-motor poly-neuropathy and a dysautonomia with myocardium sympathetic denervation. This is established by MIBL scintigraphy and may enhance the troubles of conduction and of cardiac rhythm. The amyloid deposits are constituted of anomalous pre-albumin fabricated by liver. The hepatic transplant (HT) is the only known treatment. Four patients (GI: 39 {+-} 5 years) have been studied by MIBG scintigraphy, 2.2 {+-} 0.7 years after HT, and compared with 12 patients (GII: 39 {+-} 12 years) studied before HT. The left ventricular function, the coronary arteries and the at-rest scintigraphy with thallium were normal for all of them. The cardiac capture of MIBG, evaluated by the cardio-mediastinal activity ratio (C/M), measured on an anterior thoracic planar acquisition performed 4 hours after the intravenous injection of 300 MBq, was higher for GI than for GII (1.49 {+-} 0.12 vs 1.29 {+-} 0.13, p 0.02). The washouts (4 h / 20 min) were not different. In tomography, the patients of GI presented focal anomalies with a more-or-less extended apical defect, a satisfying fixation of the basal half of the anterior wall, more-or-less overflowing the septal and lateral walls, and for 2 patients, a satisfying inferior fixation. On the contrary, 9/12 patients of GII have had a diffuse absence of fixation, the other three heaving a satisfying antero-basal fixation ({chi}{sup 2}, p = 0.05). The results are not explained by difference of severity or evolution duration of HAN. Thus, it appears that there exists a sympathetic re-innervation of myocardium after HT in the HAN, debuting by the heart base, similarly with the effect of anatomic interruption of innervation in cardiac transplants

  20. New Insights in the Amyloid-Beta Interaction with Mitochondria

    Directory of Open Access Journals (Sweden)

    Carlos Spuch

    2012-01-01

    Full Text Available Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD. Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease.

  1. On the adsorption of magnetite nanoparticles on lysozyme amyloid fibrils.

    Science.gov (United States)

    Majorosova, Jozefina; Petrenko, Viktor I; Siposova, Katarina; Timko, Milan; Tomasovicova, Natalia; Garamus, Vasil M; Koralewski, Marceli; Avdeev, Mikhail V; Leszczynski, Błażej; Jurga, Stefan; Gazova, Zuzana; Hayryan, Shura; Hu, Chin-Kun; Kopcansky, Peter

    2016-10-01

    An adsorption of magnetic nanoparticles (MNP) from electrostatically stabilized aqueous ferrofluids on amyloid fibrils of hen egg white lysozyme (HEWL) in 2mg/mL acidic dispersions have been detected for the MNP concentration range of 0.01-0.1vol.%. The association of the MNP with amyloid fibrils has been characterized by transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS) and magneto-optical measurements. It has been observed that the extent of adsorption is determined by the MNP concentration. When increasing the MNP concentration the formed aggregates of magnetic particles repeat the general rod-like structure of the fibrils. The effect is not observed when MNP are mixed with the solution of lysozyme monomers. The adsorption has been investigated with the aim to clarify previously found disaggregation activity of MNP in amyloid fibrils dispersions and to get deeper insight into interaction processes between amyloids and MNP. The observed effect is also discussed with respect to potential applications for ordering lysozyme amyloid fibrils in a liquid crystal phase under external magnetic fields. PMID:27451367

  2. 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

    to the application of different assay formats, study results indicate a potentially altered amyloid-beta metabolism in affective disorder. Limitations: Since most studies used a cross-sectional design, causality is difficult to establish. Moreover, methodological rigor of included studies varied and several studies......-beta concentrations change over time and are associated with cognition as well as affective symptomatology, future research should include prospective, longitudinal studies, implemented in large study populations, where peripheral and central amyloid-p ratios are quantified concomitantly and continuously across...... various affective phases. Also, to enable inter survey comparisons, the use of standardized pre-analytical/analytical procedures is crucial. (C) 2014 Elsevier B.V. All rights reserved....

  3. Association of amyloid burden, brain atrophy and memory deficits in aged apolipoprotein ε4 mice.

    Science.gov (United States)

    Yin, Junxiang; Turner, Gregory H; Coons, Stephen W; Maalouf, Marwan; Reiman, Eric M; Shi, Jiong

    2014-03-01

    Apolipoprotein E ε4 allele (ApoE4) has been associated with increased risk of sporadic Alzheimer's disease (AD) and of conversion from mild cognitive impairment to AD. But the underlying mechanism of ApoE4 affecting brain atrophy and cognition is not fully understood. We investigated the effect of ApoE4 on amyloid beta (Aβ) protein burden and its correlation with the structure change of hippocampus and cortex, cognitive and behavioral changes in ApoE4 transgenic mice. Male ApoE4 transgenic mice and age-matched control mice at age 12 months and 24 months were tested in the Morris Water Maze (MWM). Brain volume changes (including whole brain, hippocampus, cortex, total ventricles and caudate putamen) were assessed by using small animal 7T-MRI. Aβ level was assessed by immunohistochemistry (IHC) and immunoprecipitation/western blot. In MWM, escape latency was longer and time spent in the target quadrant was shorter in aged ApoE4 mice (12- and 24-month-old), suggesting age- and ApoE4-dependent visuospatial deficits. Atrophy on MRI was prominent in the hippocampus (p=0.039) and cortex (p=0.013) of ApoE4 mice (24-month-old) as compared to age-matched control mice. IHC revealed elevated Aβ deposition in the hippocampus. Consistently, both soluble and insoluble Aβ aggregates were increased in aged ApoE4 mice. This increase was correlated inversely with hippocampal atrophy and cognitive deficits. These data give further evidence that ApoE4 plays an important role in brain atrophy and memory impairment by modulating amyloid production and deposition.

  4. 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.

  5. Central acylated ghrelin improves memory function and hippocampal AMPK activation and partly reverses the impairment of energy and glucose metabolism in rats infused with β-amyloid.

    Science.gov (United States)

    Kang, Suna; Moon, Na Rang; Kim, Da Sol; Kim, Sung Hoon; Park, Sunmin

    2015-09-01

    Ghrelin is a gastric hormone released during the fasting state that targets the hypothalamus where it induces hunger; however, emerging evidence suggests it may also affect memory function. We examined the effect of central acylated-ghrelin and DES-acetylated ghrelin (native ghrelin) on memory function and glucose metabolism in an experimentally induced Alzheimer's disease (AD) rat model. AD rats were divided into 3 groups and Non-AD rats were used as a normal-control group. Each rat in the AD groups had intracerebroventricular (ICV) infusion of β-amyloid (25-35; 16.8nmol/day) into the lateral ventricle for 3 days, and then the pumps were changed to infuse either acylated-ghrelin (0.2nmol/h; AD-G), DES-acylated ghrelin (0.2nmol/h; AD-DES-G), or saline (control; AD-C) for 3 weeks. The Non-AD group had ICV infusion of β-amyloid (35-25) which does not deposit in the hippocampus. During the next 3 weeks memory function, food intake, body weight gain, body fat composition, and glucose metabolism were measured. AD-C exhibited greater β-amyloid deposition compared to Non-AD-C, and AD-G suppressed the increased β-amyloid deposition and potentiated the phosphorylation AMPK. In addition, AD-G increased the phosphorylation GSK and decreased the phosphorylation of Tau in comparison to AD-C and AD-DES-G. Cognitive function, measured by passive avoidance and water maze tests, was much lower in AD-C than Non-AD-C whereas AD-G but not AD-DES-G prevented the decrease (pintermittent fasting to facilitate sustained elevations of acyl-ghrelin should be investigated for cognitive and metabolic benefits, especially in person with early symptoms of memory impairment. PMID:26188171

  6. NONMETALS DEPOSITS

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    <正>20102406 Chen Gang(China University of Geosciences,Beijing 100083,China);Li Fengming Discussion on Geological Characteristics and Genesis of Yuquanshan Graphite Deposit of Xinjiang(Xinjiang Geology,ISSN1000-8845,CN65-1092/P,27(4),2009,p.325-329,4 illus.,4 tables,5 refs.)Key words:graphite deposit,XinjiangYuquanshan graphite deposit of Xinjiang occurs in mica-quartz schist of Xingeer Information which belongs to Xinditate Group of Lower Pt in Kuluketage Block of Tarim paleo-continent,and experiences two mineralizing periods of

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

    NARCIS (Netherlands)

    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.

    2015-01-01

    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

  8. NONMETALS DEPOSITS

    Institute of Scientific and Technical Information of China (English)

    2014-01-01

    <正>20140876 Gao Junbo(College of Resources and Environmental Engineering,Guizhou University,Guiyang 550025,China);Yang Ruidong Study on the Strontium Isotopic Composition of Large Devonian Barite Deposits from Zhenning,Guizhou Province(Geochimica,

  9. NONMETALS DEPOSITS

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    <正>20122457 Cai Jianshe ( Fujian Institute of Geological Survey and Drawing,Fuzhou 350011,China ) On the Geologic Characteristics and Genesis of the Longtangsi Fluorite Deposit in Pucheng County,Fujian Province ( Geology of Fujian,ISSN1001-3970,CN35-1080 / P,30 ( 4 ), 2011,p.301-306,3illus.,1table,6 refs.,with English abstract ) Key words:fluorspar deposit,Fujian Province

  10. 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

  11. Destroying activity of magnetoferritin on lysozyme amyloid fibrils

    Energy Technology Data Exchange (ETDEWEB)

    Kopcansky, Peter; Siposova, Katarina [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Melnikova, Lucia, E-mail: melnikova@saske.sk [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Bednarikova, Zuzana [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Institute of Chemical Sciences, Faculty of Sciences, Safarik University, Kosice (Slovakia); Timko, Milan; Mitroova, Zuzana; Antosova, Andrea [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Garamus, Vasil M. [Helmholtz-Zentrum Geesthacht: Centre for Materials and Coastal Research, Max-Planck-Street 1, 21502 Geesthacht (Germany); Petrenko, Viktor I. [Joint Institute for Nuclear Research, Joliot-Curie 6, Dubna, 141980 Moscow Region (Russian Federation); Kyiv Taras Shevchenko National University, Volodymyrska Street 64, Kyiv 01033 (Ukraine); Avdeev, Mikhail V. [Joint Institute for Nuclear Research, Joliot-Curie 6, Dubna, 141980 Moscow Region (Russian Federation); Gazova, Zuzana [Institute of Experimental Physics, SAS, Watsonova 47, 040 01 Kosice (Slovakia); Department of Medical and Clinical Biochemistry and LABMED, Tr. SNP 1, 040 11 Kosice (Slovakia)

    2015-03-01

    Presence of protein amyloid aggregates (oligomers, protofilaments, fibrils) is associated with many diseases as diabetes mellitus or Alzheimer's disease. The interaction between lysozyme amyloid fibrils and magnetoferritin loaded with different amount of iron atoms (168 or 532 atoms) has been investigated by small-angle X-rays scattering and thioflavin T fluorescence measurements. Results suggest that magnetoferritin caused an iron atom-concentration dependent reduction of lysozyme fibril size. - Highlights: • The interaction between lysozyme amyloid fibrils and magnetoferritin loaded with different amount of iron atoms (168 or 532 atoms) has been investigated by small-angle X-rays scattering and thioflavin T fluorescence measurements. • Results suggest that magnetoferritin caused an iron atom-concentration dependent reduction of lysozyme fibril size.

  12. Molecular dynamics simulations of amyloid fibrils: an in silico approach

    Institute of Scientific and Technical Information of China (English)

    Wei Ye; Wei Wang; Cheng Jiang; Qingfen Yu; Haifeng Chen

    2013-01-01

    Amyloid fibrils play causal roles in the pathogenesis of amyloid-related degenerative diseases such as Alzheimer's disease,type Ⅱ diabetes mellitus,and the prion-related transmissible spongiform encephalopathies.The mechanism of fibril formation and protein aggregation is still hotly debated and remains an important open question in order to develop therapeutic method of these diseases.However,traditional molecular biological and crystallographic experiments could hardly observe atomic details and aggregation process.Molecular dynamics (MD) simulations could provide explanations for experimental results and detailed pathway of protein aggregation.In this review,we focus on the applications of MD simulations on several amyloidogenic protein systems.Furthermore,MD simulations could help us to understand the mechanism of amyloid aggregation and how to design the inhibitors.

  13. Atomic-resolution structures of prion AGAAAAGA amyloid fibrils

    CERN Document Server

    Zhang, Jiapu

    2011-01-01

    To the best of the author's knowledge, there is little structural data available on the AGAAAAGA palindrome in the hydrophobic region (113-120) of prion proteins due to the unstable, noncrystalline and insoluble nature of the amyloid fibril, although many experimental studies have shown that this region has amyloid fibril forming properties and plays an important role in prion diseases. In view of this, the present study is devoted to address this problem from computational approaches such as local optimization steepest descent, conjugate gradient, discrete gradient and Newton methods, global optimization simulated annealing and genetic algorithms, canonical dual optimization theory, and structural bioinformatics. The optimal atomic-resolution structures of prion AGAAAAGA amyloid fibils reported in this Chapter have a value to the scientific community in its drive to find treatments for prion diseases or at least be useful for the goals of medicinal chemistry.

  14. 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.

  15. 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.)

  16. 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

  17. Quantitative amyloid imaging using image-derived arterial input function.

    Directory of Open Access Journals (Sweden)

    Yi Su

    Full Text Available Amyloid PET imaging is an indispensable tool widely used in the investigation, diagnosis and monitoring of Alzheimer's disease (AD. Currently, a reference region based approach is used as the mainstream quantification technique for amyloid imaging. This approach assumes the reference region is amyloid free and has the same tracer influx and washout kinetics as the regions of interest. However, this assumption may not always be valid. The goal of this work is to evaluate an amyloid imaging quantification technique that uses arterial region of interest as the reference to avoid potential bias caused by specific binding in the reference region. 21 participants, age 58 and up, underwent Pittsburgh compound B (PiB PET imaging and MR imaging including a time-of-flight (TOF MR angiography (MRA scan and a structural scan. FreeSurfer based regional analysis was performed to quantify PiB PET data. Arterial input function was estimated based on coregistered TOF MRA using a modeling based technique. Regional distribution volume (VT was calculated using Logan graphical analysis with estimated arterial input function. Kinetic modeling was also performed using the estimated arterial input function as a way to evaluate PiB binding (DVRkinetic without a reference region. As a comparison, Logan graphical analysis was also performed with cerebellar cortex as reference to obtain DVRREF. Excellent agreement was observed between the two distribution volume ratio measurements (r>0.89, ICC>0.80. The estimated cerebellum VT was in line with literature reported values and the variability of cerebellum VT in the control group was comparable to reported variability using arterial sampling data. This study suggests that image-based arterial input function is a viable approach to quantify amyloid imaging data, without the need of arterial sampling or a reference region. This technique can be a valuable tool for amyloid imaging, particularly in population where reference

  18. BETASCAN: probable beta-amyloids identified by pairwise probabilistic analysis.

    Directory of Open Access Journals (Sweden)

    Allen W Bryan

    2009-03-01

    Full Text Available Amyloids and prion proteins are clinically and biologically important beta-structures, whose supersecondary structures are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Recent work has indicated the utility of pairwise probabilistic statistics in beta-structure prediction. We develop here a new strategy for beta-structure prediction, emphasizing the determination of beta-strands and pairs of beta-strands as fundamental units of beta-structure. Our program, BETASCAN, calculates likelihood scores for potential beta-strands and strand-pairs based on correlations observed in parallel beta-sheets. The program then determines the strands and pairs with the greatest local likelihood for all of the sequence's potential beta-structures. BETASCAN suggests multiple alternate folding patterns and assigns relative a priori probabilities based solely on amino acid sequence, probability tables, and pre-chosen parameters. The algorithm compares favorably with the results of previous algorithms (BETAPRO, PASTA, SALSA, TANGO, and Zyggregator in beta-structure prediction and amyloid propensity prediction. Accurate prediction is demonstrated for experimentally determined amyloid beta-structures, for a set of known beta-aggregates, and for the parallel beta-strands of beta-helices, amyloid-like globular proteins. BETASCAN is able both to detect beta-strands with higher sensitivity and to detect the edges of beta-strands in a richly beta-like sequence. For two proteins (Abeta and Het-s, there exist multiple sets of experimental data implying contradictory structures; BETASCAN is able to detect each competing structure as a potential structure variant. The ability to correlate multiple alternate beta-structures to experiment opens the possibility of computational investigation of prion strains and structural heterogeneity of amyloid

  19. Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils.

    Science.gov (United States)

    Colvin, Michael T; Silvers, Robert; Ni, Qing Zhe; Can, Thach V; Sergeyev, Ivan; Rosay, Melanie; Donovan, Kevin J; Michael, Brian; Wall, Joseph; Linse, Sara; Griffin, Robert G

    2016-08-01

    Amyloid-β (Aβ) is a 39-42 residue protein produced by the cleavage of the amyloid precursor protein (APP), which subsequently aggregates to form cross-β amyloid fibrils that are a hallmark of Alzheimer's disease (AD). The most prominent forms of Aβ are Aβ1-40 and Aβ1-42, which differ by two amino acids (I and A) at the C-terminus. However, Aβ42 is more neurotoxic and essential to the etiology of AD. Here, we present an atomic resolution structure of a monomorphic form of AβM01-42 amyloid fibrils derived from over 500 (13)C-(13)C, (13)C-(15)N distance and backbone angle structural constraints obtained from high field magic angle spinning NMR spectra. The structure (PDB ID: 5KK3 ) shows that the fibril core consists of a dimer of Aβ42 molecules, each containing four β-strands in a S-shaped amyloid fold, and arranged in a manner that generates two hydrophobic cores that are capped at the end of the chain by a salt bridge. The outer surface of the monomers presents hydrophilic side chains to the solvent. The interface between the monomers of the dimer shows clear contacts between M35 of one molecule and L17 and Q15 of the second. Intermolecular (13)C-(15)N constraints demonstrate that the amyloid fibrils are parallel in register. The RMSD of the backbone structure (Q15-A42) is 0.71 ± 0.12 Å and of all heavy atoms is 1.07 ± 0.08 Å. The structure provides a point of departure for the design of drugs that bind to the fibril surface and therefore interfere with secondary nucleation and for other therapeutic approaches to mitigate Aβ42 aggregation. PMID:27355699

  20. Biotechnologically engineered protein binders for applications in amyloid diseases.

    Science.gov (United States)

    Haupt, Christian; Fändrich, Marcus

    2014-10-01

    The aberrant self-assembly of polypeptide chains into amyloid structures is a common phenomenon in several neurodegenerative diseases, systemic amyloidosis, and 'normal' aging. Improvements in laboratory-scale detection of these structures, their clinical diagnosis, and the treatment of disease likely depend on the advent of new molecules that recognize particular states or induce their clearance in vivo. This review will describe what biotechnology can do to generate proteinaceous amyloid-binders, explain their molecular recognition mechanisms, and summarize possibilities to functionalize further these ligands for specific applications.

  1. Functional bacterial amyloid increases Pseudomonas biofilm hydrophobicity and stiffness

    DEFF Research Database (Denmark)

    Zeng, Guanghong; Vad, Brian S; Dueholm, Morten S;

    2015-01-01

    The success of Pseudomonas species as opportunistic pathogens derives in great part from their ability to form stable biofilms that offer protection against chemical and mechanical attack. The extracellular matrix of biofilms contains numerous biomolecules, and it has recently been discovered...... stiffness 20-fold. Deletion of any one of the individual members of in the fap operon (except the putative chaperone FapA) abolishes this ability to increase biofilm stiffness and correlates with the loss of amyloid. We conclude that amyloid makes major contributions to biofilm mechanical robustness....

  2. Native human serum amyloid P component is a single pentamer

    DEFF Research Database (Denmark)

    Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH;

    1995-01-01

    Serum amyloid P component (SAP) and C-reactive protein (CRP) are members of the pentraxin protein family. SAP is the precursor protein to amyloid P component present in all forms of amyloidosis. The prevailing notion is that SAP in circulation has the form of a double pentameric molecule (decamer...... by rocket immunoelectrophoresis and electron microscopy. Thus, electron micrographs of purified SAP showed a predominance of decamers. However, the decamer form of SAP reversed to single pentamers when purified SAP was incorporated into SAP-depleted serum....

  3. β-Amyloid binding in elderly subjects with declining or stable episodic memory function measured with PET and [{sup 11}C]AZD2184

    Energy Technology Data Exchange (ETDEWEB)

    Mattsson, Patrik [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Karolinska University Hospital, Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (Sweden); Forsberg, Anton; Halldin, Christer [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Persson, Jonas; Nilsson, Lars-Goeran [Karolinska Institute and Stockholm University, Aging Research Center (ARC), Stockholm (Sweden); Nyberg, Lars [Umeaa University, Department of Radiation Sciences (Diagnostic Radiology), Umeaa (Sweden); Farde, Lars [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); AstraZeneca Translational Science Center at Karolinska Institutet, Stockholm (Sweden)

    2015-09-15

    Cognitive decline has been suggested as an early marker for later onset of Alzheimer's disease. We therefore explored the relationship between decline in episodic memory and β-amyloid using positron emission tomography (PET) and [{sup 11}C]AZD2184, a radioligand with potential to detect low levels of amyloid deposits. Healthy elderly subjects with declining (n = 10) or stable (n = 10) episodic memory over 15 years were recruited from the population-based Betula study and examined with PET. Brain radioactivity was measured after intravenous administration of [{sup 11}C]AZD2184. The binding potential BP{sub ND} was calculated using linear graphical analysis with the cerebellum as reference region. The binding of [{sup 11}C]AZD2184 in total grey matter was generally low in the declining group, whereas some binding could be observed in the stable group. Mean BP{sub ND} was significantly higher in the stable group compared to the declining group (p = 0.019). An observation was that the three subjects with the highest BP{sub ND} were ApoE ε4 allele carriers. We conclude that cognitive decline in the general population does not seem to stand by itself as an early predictor for amyloid deposits. (orig.)

  4. Influence of the Human and Rat Islet Amyloid Polypeptides on Structure of Phospholipid Bilayers: Neutron Reflectometry and Fluorescence Microscopy Studies.

    Science.gov (United States)

    Junghans, Ann; Watkins, Erik B; Majewski, Jaroslaw; Miranker, Andrew; Stroe, Izabela

    2016-05-01

    Neutron reflectivity (NR) and fluorescent microscopy (FM) were used to study the interactions of human (hIAPP) and rat (rIAPP) islet amyloid polypeptides with several formulations of supported model lipid bilayers at the solid-liquid interface. Aggregation and deposition of islet amyloid polypeptide is correlated with the pathology of many diseases, including Alzheimer's, Parkinson, and type II diabetes (T2DM). A central component of T2DM pathology is the deposition of fibrils in the endocrine pancreas, which is toxic to the insulin secreting β-cells. The molecular mechanism by which the cell death occurs is not yet understood, but existing evidence points toward interactions of IAPP oligomers with cellular membranes in a manner leading to loss of their integrity. Our NR and FM results showed that the human sequence variant, hIAPP, had little or no effect on bilayers composed of saturated-acyl chains like zwitterionic DPPC, anionic DPPG, and mixed 80:20 mol % DPPC:DPPG bilayers. In marked contrast, the bilayer structure and stability of anionic unsaturated DOPG were sensitive to protein interaction, and the bilayer was partly solubilized by hIAPP under the conditions used here. The rIAPP, which is considered less toxic, had no perturbing effects on any of the above membrane formulations. Understanding the conditions that result in membrane disruption by hIAPP can be crucial in developing counter strategies to fight T2DM and also physicochemically similar neurodegenerative diseases such as Alzheimer's. PMID:27065348

  5. NONMETALS DEPOSITS

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    <正>20110947 Chen Xinglong(Guizhou Bureau of Nonferrous Metal and Nuclear Geology,Guiyang 550005,China);Gong Heqiang Endowment Factors and Development & Utilization Strategy of Bauxite Resource in North Guizhou Province(Guizhou Geology,ISSN1000-5943,CN52-1059/P,27(2),2010,p.106-110,6 refs.,with English abstract)Key words:bauxite deposit,Guizhou Province20110948 Dang Yanxia(Mineral Resource & Reservoir Evaluation Center,Urumiq 830000,China);Fan Wenjun Geological Features and a Primary Study of Metallogenesis of the Wucaiwang Zeolite Deposit,Fuyun County(Xinjiang Geology,ISSN1000-8845,CN65-1092/P,28(2),2010,p.167-170,2 illus.,1 table,5 refs.)Key words:zeolite deposit,Xinjiang Nearly all zeolite