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Amyloid Protein (amyloid + protein)
Selected AbstractsAll or none fibrillogenesis of a prion peptideFEBS JOURNAL, Issue 18 2001Wen-Quan Zou Amyloid proteins and peptides comprise a diverse group of molecules that vary both in size and amino-acid sequence, yet assemble into amyloid fibrils that have a common core structure. Kinetic studies of amyloid fibrillogenesis have revealed that certain amyloid proteins form oligomeric intermediates prior to fibril formation. We have investigated fibril formation with a peptide corresponding to residues 195,213 of the human prion protein. Through a combination of kinetic and equilibrium studies, we have found that the fibrillogenesis of this peptide proceeds as an all-or-none reaction where oligomeric intermediates are not stably populated. This variation in whether oligomeric intermediates are stably populated during fibril formation indicates that amyloid proteins assemble into a common fibrillar structure; however, they do so through different pathways. [source] Osmolyte controlled fibrillation kinetics of insulin: New insight into fibrillation using the preferential exclusion principleBIOTECHNOLOGY PROGRESS, Issue 5 2009Arpan Nayak Abstract Amyloid proteins are converted from their native-fold to long ,-sheet-rich fibrils in a typical sigmoidal time-dependent protein aggregation curve. This reaction process from monomer or dimer to oligomer to nuclei and then to fibrils is the subject of intense study. The main results of this work are based on the use of a well-studied model amyloid protein, insulin, which has been used in vitro by others. Nine osmolyte molecules, added during the protein aggregation process for the production of amyloid fibrils, slow-down or speed up the process depending on the molecular structure of each osmolyte. Of these, all stabilizing osmolytes (sugars) slow down the aggregation process in the following order: tri > di > monosaccharides, whereas destabilizing osmolytes (urea, guanidium hydrochloride) speed up the aggregation process in a predictable way that fits the trend of all osmolytes. With respect to kinetics, we illustrate, by adapting our earlier reaction model to the insulin system, that the intermediates (trimers, tetramers, pentamers, etc.) are at very low concentrations and that nucleation is orders of magnitude slower than fibril growth. The results are then collated into a cogent explanation using the preferential exclusion and accumulation of osmolytes away from and at the protein surface during nucleation, respectively. Both the heat of solution and the neutral molecular surface area of the osmolytes correlate linearly with two fitting parameters of the kinetic rate model, that is, the lag time and the nucleation rate prior to fibril formation. These kinetic and thermodynamic results support the preferential exclusion model and the existence of oligomers including nuclei and larger structures that could induce toxicity. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009 [source] Alpha2 macroglobulin elevation without an acute phase response in depressed adults with Down's syndrome: implications,JOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 6 2000J. A. Tsiouris Abstract Studies of immune function during depression in persons without intellectual disability (ID) have revealed elevated levels of ,2 macroglobulin (,2M) and an acute phase protein (APP) response. Clinical observation suggests that people with Down's syndrome (DS) may have associated genetic abnormalities in their immune systems. The APP response and ,2M changes in depressed versus non-depressed adults with DS was the subject of the present study. The serum pan-proteinase inhibitor ,2M, and the AP proteins c-reactive protein (CRP), ,1 antitrypsin (,1AT), ceruloplasmin (Cp), ,2 Macroglobulin (,2M), transthyretin (Trans), serum amyloid protein (SAP), and albumin (Alb) were measured in 38 adults with DS, 19 of whom were diagnosed with and 19 without depression using a sandwich enzyme-linked immunosorbent assay (ELISA). The DSM-IV criteria were used for diagnoses. Medical and neurological examinations excluded medical disorders associated with APP response. Only ,2M and CRP were significantly different in the depressed versus non-depressed groups. The ,2M was higher, a response similar to one observed in depressed people without ID, but the CRP was lower in the depressed group, especially in those subjects not on psychotropic medications, contrary to the expected APP response to depression. The results suggest that ,2M elevation in depressed adults with DS is independent of the APP response. An alternative explanation for its elevation is proposed linking the core symptom of depression with the mammalian dormancy/hibernation process. Further studies are needed to confirm that ,2M elevation is specific to depression and that it might provide a helpful marker for the diagnosis of depression in people with ID. [source] Inhibition of A, aggregation and neurotoxicity by the 39-kDa receptor-associated proteinJOURNAL OF NEUROCHEMISTRY, Issue 5 2010Megan L. Kerr J. Neurochem. (2010) 112, 1199,1209. Abstract Aggregation of ,-amyloid protein (A,) to form oligomers is considered to be a key step in generating neurotoxicity in the Alzheimer's disease brain. Agents that bind to A, and inhibit oligomerization have been proposed as Alzheimer's disease therapeutics. In this study, we investigated the binding of fluorescein-labeled A,1,42 (FluoA,1,42) to SH-SY5Y neuroblastoma cells and examined the effect of the 39-kDa receptor-associated protein (RAP), on the A, cell interaction. FluoA,1,42 bound to the cells in a punctate pattern. Surprisingly, when RAP was added to the incubations, FluoA,1,42 and RAP were found to be co-localized on the cell surface, suggesting that RAP and A, may bind to each other. Experiments using the purified proteins confirmed that a RAP,A, complex was stable and resistant to sodium dodecyl sulfate. RAP also inhibited A, oligomerization. We next examined whether RAP could inhibit the neurotoxic effects of A,. Addition of A,1,42 to SH-SY5Y cells caused an increase in intracellular Ca2+ that was inhibited by treatment of the A, peptide with RAP. RAP also blocked an A,-induced inhibition of long-term memory consolidation in 1-day-old chicks. This study demonstrates that RAP binds to A, and is an inhibitor of the neurotoxic effects of A,. [source] The ,-amyloid protein of Alzheimer's disease binds to membrane lipids but does not bind to the ,7 nicotinic acetylcholine receptorJOURNAL OF NEUROCHEMISTRY, Issue 6 2007David H. Small Abstract Accumulation of the amyloid protein (A,) in the brain is an important step in the pathogenesis of Alzheimer's disease. However, the mechanism by which A, exerts its neurotoxic effect is largely unknown. It has been suggested that the peptide can bind to the ,7 nicotinic acetylcholine receptor (,7nAChR). In this study, we examined the binding of A,1-42 to endogenous and recombinantly expressed ,7nAChRs. A,1-42 did neither inhibit the specific binding of ,7nAChR ligands to rat brain homogenate or slice preparations, nor did it influence the activity of ,7nAChRs expressed in Xenopus oocytes. Similarly, A,1-42 did not compete for ,-bungarotoxin-binding sites on SH-SY5Y cells stably expressing ,7nAChRs. The effect of the A,1-42 on tau phosphorylation was also examined. Although A,1-42 altered tau phosphorylation in ,7nAChR-transfected SH-SY5Y cells, the effect of the peptide was unrelated to ,7nAChR expression or activity. Binding studies using surface plasmon resonance indicated that the majority of the A, bound to membrane lipid, rather than to a protein component. Fluorescence anisotropy experiments indicated that A, may disrupt membrane lipid structure or fluidity. We conclude that the effects of A, are unlikely to be mediated by direct binding to the ,7nAChR. Instead, we speculate that A, may exert its effects by altering the packing of lipids within the plasma membrane, which could, in turn, influence the function of a variety of receptors and channels on the cell surface. [source] Alois Alzheimer and Alzheimer's disease: a centennial perspectiveJOURNAL OF NEUROCHEMISTRY, Issue 3 2006David H. Small The year 2006 is the centenary of the famous presentation of Alois Alzheimer which first described the neuropathology of Alzheimer's disease (AD). Since this presentation, enormous progress has been made in understanding the biology of AD. The central role of the ,-amyloid protein (A,) in the pathogenesis of AD and the relationship between plaque and tangle pathology is now much better understood. In this article, we review the current status of the amyloid hypothesis of AD and its role in the development of future therapy. [source] The two-hydrophobic domain tertiary structure of reticulon proteins is critical for modulation of ,-secretase BACE1JOURNAL OF NEUROSCIENCE RESEARCH, Issue 13 2009Hideaki Kume Abstract ,-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a membrane-bound protease that is essential for the production of ,-amyloid protein (A,). Given the crucial role of A, accumulation in Alzheimer's disease (AD), inhibition of BACE1 activity may represent a feasible therapeutic strategy in the treatment of AD. Recently, we and others identified reticulon 3 (RTN3) and reticulon 4-B/C (RTN4-B/C or Nogo-B/C) as membrane proteins that interact with BACE1 and inhibit its ability to produce A,. In this study, we employed various mutants of RTN3 and RTN4-C and C. elegans RTN to investigate the molecular mechanisms by which RTNs regulate BACE1. We found that RTN3 mutants lacking the N-terminal or C-terminal or loop domain as well as a RTN4-C mutant lacking the C-terminal domain bound to BACE1 comparably to wild-type RTN3 and RTN4-C. Furthermore, overexpression of wild-type RTN3, RTN4-C, and these RTN mutants similarly reduced A,40 and A,42 secretion by cells expressing Swedish mutant APP. C. elegans RTN, which has low homology to human RTNs, also interacted with BACE1 and inhibited A, secretion. In contrast, two RTN3 mutants containing deletions of the first or second potential transmembrane domains and an RTN3 swap mutant of the second transmembrane domain bound BACE1 but failed to inhibit A, secretion. Collectively, these results suggest that the two-transmembrane-domain tertiary structure of RTN proteins is critical for the ability of RTNs to modulate BACE1 activity, whereas N-terminal, C-terminal and loop regions are not essential for this function. © 2009 Wiley-Liss, Inc. [source] Pyruvate protection against ,-amyloid-induced neuronal death: Role of mitochondrial redox stateJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2003Gema Alvarez Abstract The mechanism by which ,-amyloid protein (A,) causes degeneration in cultured neurons is not completely understood, but several lines of evidence suggest that A,-mediated neuronal death is associated with an enhanced production of reactive oxygen species (ROS) and oxidative damage. In the present study, we address whether supplementation of glucose-containing culture media with energy substrates, pyruvate plus malate (P/M), protects rat primary neurons from A,-induced degeneration and death. We found that P/M addition attenuated cell death evoked by ,-amyloid peptides (A,25,35 and A,1,40) after 24 hr treatment and that this effect was blocked by ,-ciano-3-hydroxycinnamate (CIN), suggesting that it requires mitochondrial pyruvate uptake. P/M supply to control and A,-treated neuronal cultures increases cellular reducing power, as indicated by the ability to reduce the dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The early increases in ROS levels, measured by dichlorofluorescein (DCF) fluorescence, and caspase-3 activity that follow exposure to A, were notably reduced in the presence of P/M. These results place activation of caspase-3 most likely downstream of oxidative damage to the mitochondria and indicate that mitochondrial NAD(P) redox status plays a central role in the neuroprotective effect of pyruvate. Inhibition of respiratory chain complexes and mitochondrial uncoupling did not block the early increase in ROS levels, suggesting that A, could initiate oxidative stress by activating a source of ROS that is not accesible to the antioxidant defenses fueled by mitochondrial substrates. © 2003 Wiley-Liss, Inc. [source] Familial amyloidotic polyneuropathy (ATTR Val30Met) with widespread cerebral amyloid angiopathy and lethal cerebral hemorrhagePATHOLOGY INTERNATIONAL, Issue 6 2001Naomi Sakashita We report an autopsy case of familial amyloidotic polyneuropathy (FAP) with cerebral hemorrhage. A 38-year-old woman with a typical FAP pedigree started developing severe diarrhea and sensori-motor polyneuropathy at the age of 28 years; autonomic nervous system, heart and renal dysfunction manifested themselves in the following years. Genetic analysis revealed a single amino acid substitution at codon 30 of transthyretin (ATTR Val30Met). Ten years after her initial symptoms, the patient died of a sudden convulsive attack and respiratory failure. Autopsy revealed lethal cerebral hemorrhages and uremic lungs. Histochemical and immunohistochemical analyses revealed TTR-derived amyloid protein in every tissue examined, particularly in glomeruli and peripheral vessels. Severe meningo-cerebrovascular amyloidosis was also detected. Because uremia causes oxidative damage to the vascular system and amyloid formation is closely associated with oxidative stress, it is possible that uremic endothelial damage facilitated an unusual cerebral amyloid deposition. In typical FAP (ATTR Val30Met), cerebral amyloid angiopathy does not usually have clinical manifestations. However, cerebral amyloid angiopathy should be considered to explain FAP symptoms when some risk factors such as uremic vascular damage are accompanying features. [source] Inflammatory protein profile during systemic high dose interleukin-2 administrationPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 2 2006Leonardo Rossi Abstract Systemic interleukin-2 (IL-2) administration induces an assortment of downstream effects whose biological and therapeutic significance remains unexplored mostly because of the methodological inability to globally address their complexity. Protein array analysis of sera from patients with renal cell carcinoma obtained prior and during high-dose IL-2 therapy had previously revealed extensive alterations in expression of the soluble factors analyzed, whose discovery was limited by the number of capture antibodies selected for protein detection. Here, we expanded the analysis to SELDI-TOF-MS and quantitative protein analysis (nephelometry). All cytokines/chemokines detected by protein arrays were below the SELDI detection limit, while novel IL-2-specific changes in expression of acute-phase reactants and high-density lipoprotein metabolites could be identified. Serum amyloid protein,A (SAA) and C-reactive protein expression were consistently up-regulated after four doses of IL-2, while other proteins were down-regulated. These findings were confirmed by SELDI immunoaffinity capture and nephelometry. Immunoaffinity capture revealed different, otherwise undetectable, isoforms of SAA. A linear correlation between peak area by SELDI and protein concentration by nephelometry was observed. Overall distinct yet complementary information was obtained using different platforms, which may better illustrate complex phenomena such as the systemic response to biological response modifiers. [source] Cathepsin protease activity modulates amyloid load in extracerebral amyloidosisTHE JOURNAL OF PATHOLOGY, Issue 4 2006C Röcken Abstract In cerebral amyloidoses, such as Alzheimer's disease, proteolytic processing of the precursor protein is a fundamental mechanism of the disease, since it generates the amyloid protein. However, the putative significance of proteases in extracerebral amyloidoses is less well defined. In this study, we investigated the biological significance of cathepsin (Cath) B, CathK, and CathL in the pathology and pathogenesis of extracerebral amyloidoses by using the murine model of reactive or secondary AA amyloidosis with three different cathepsin-deficient mouse strains. Extracerebral AA amyloid was induced by injecting amyloid-enhancing factor and silver nitrate into CathB,/,, CathK,/,, and CathL,/, mice. Wild-type mice served as a control. CathK,/, mice deposited over 90% more amyloid and CathL,/, mice 60% less amyloid than the control (p < 0.0001). The amyloid load in CathB,/, mice did not differ from that in wild-type mice. In vitro degradation experiments with recombinant human and murine serum amyloid A (SAA) 1.1 and CathK and CathL showed that CathL generates a large number of differently sized SAA cleavage products. One of these fragments spans the heparin/heparan sulphate binding site and the neutral cholesterol ester hydrolase activating region of SAA. CathK showed only endoproteolytic activity and did not generate any AA amyloid-like peptides. This study provides unequivocal evidence that proteases modulate amyloid load in extracerebral amyloidosis. CathL was identified as an amyloid-promoting and CathK as an amyloid-retarding cysteine protease. CathB may only modulate the primary structure of the amyloid peptide without affecting amyloid load. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Successful Hepatorenal Transplantation in Hereditary Amyloidosis Caused by a Frame-Shift Mutation in Fibrinogen A,-Chain GeneAMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2006C. Mousson Hereditary systemic amyloidosis comprises several autosomal dominant diseases caused by mutations in a number of plasma proteins, including the fibrinogen A,-chain. Four mutations in the fibrinogen A,-chain that are able to induce amyloidosis have been identified so far, the most common being the Glu526Val mutation. We have observed a family in which the father and his son reached end-stage renal failure because of renal amyloidosis induced by a frame-shift mutation in the fibrinogen A,-chain gene producing a novel amyloid protein. Two kidney transplantations in the father and one in the son resulted in fast graft loss caused by recurrence of amyloid deposition. We then performed hepatorenal transplantation in the son. Three years later, liver and kidney functions are normal without recurrence of amyloid deposition. This case, together with three others with the Glu526Val mutation in the extensive literature, suggests that liver transplantation can cure hereditary fibrinogen amyloidosis, whatever the mutation may be. [source] Osmolyte controlled fibrillation kinetics of insulin: New insight into fibrillation using the preferential exclusion principleBIOTECHNOLOGY PROGRESS, Issue 5 2009Arpan Nayak Abstract Amyloid proteins are converted from their native-fold to long ,-sheet-rich fibrils in a typical sigmoidal time-dependent protein aggregation curve. This reaction process from monomer or dimer to oligomer to nuclei and then to fibrils is the subject of intense study. The main results of this work are based on the use of a well-studied model amyloid protein, insulin, which has been used in vitro by others. Nine osmolyte molecules, added during the protein aggregation process for the production of amyloid fibrils, slow-down or speed up the process depending on the molecular structure of each osmolyte. Of these, all stabilizing osmolytes (sugars) slow down the aggregation process in the following order: tri > di > monosaccharides, whereas destabilizing osmolytes (urea, guanidium hydrochloride) speed up the aggregation process in a predictable way that fits the trend of all osmolytes. With respect to kinetics, we illustrate, by adapting our earlier reaction model to the insulin system, that the intermediates (trimers, tetramers, pentamers, etc.) are at very low concentrations and that nucleation is orders of magnitude slower than fibril growth. The results are then collated into a cogent explanation using the preferential exclusion and accumulation of osmolytes away from and at the protein surface during nucleation, respectively. Both the heat of solution and the neutral molecular surface area of the osmolytes correlate linearly with two fitting parameters of the kinetic rate model, that is, the lag time and the nucleation rate prior to fibril formation. These kinetic and thermodynamic results support the preferential exclusion model and the existence of oligomers including nuclei and larger structures that could induce toxicity. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009 [source] The Role of Cystatin C in Cerebral Amyloid Angiopathy and Stroke: Cell Biology and Animal ModelsBRAIN PATHOLOGY, Issue 1 2006Efrat Levy A variant of the cysteine protease inhibitor, cystatin c, forms amyloid deposited in the cerebral vasculature of patients with hereditary cerebral hemorrhage with amyloidosis, icelandic type (hchwa-i), leading to cerebral hemorrhages early in life. however, cystatin c is also implicated in neuronal degenerative diseases in which it does not form the amyloid protein, such as alzheimer disease (ad). accumulating data suggest involvement of cystatin c in the pathogenic processes leading to amyloid deposition in cerebral vasculature and most significantly to cerebral hemorrhage in patients with cerebral amyloid angiopathy (caa). This review focuses on cell culture and animal models used to study the role of cystatin c in these processes. [source] All or none fibrillogenesis of a prion peptideFEBS JOURNAL, Issue 18 2001Wen-Quan Zou Amyloid proteins and peptides comprise a diverse group of molecules that vary both in size and amino-acid sequence, yet assemble into amyloid fibrils that have a common core structure. Kinetic studies of amyloid fibrillogenesis have revealed that certain amyloid proteins form oligomeric intermediates prior to fibril formation. We have investigated fibril formation with a peptide corresponding to residues 195,213 of the human prion protein. Through a combination of kinetic and equilibrium studies, we have found that the fibrillogenesis of this peptide proceeds as an all-or-none reaction where oligomeric intermediates are not stably populated. This variation in whether oligomeric intermediates are stably populated during fibril formation indicates that amyloid proteins assemble into a common fibrillar structure; however, they do so through different pathways. [source] Cerebral amyloid angiopathy: An overviewNEUROPATHOLOGY, Issue 1 2000Masahito Yamada Cerebral amyloid angiopathy (CAA) is characterized by amyloid deposition in cortical and leptomeningeal vessels. Several cerebrovascular amyloid proteins (amyloid ,-protein (A,), cystatin C (ACys), prion protein (AScr), transthyretin (ATTR), gelsolin (AGel), and ABri (or A-WD)) have been identified, leading to the classification of several types of CAA. Sporadic CAA of A, type is commonly found in elderly individuals and patients with Alzheimer's disease. Cerebral amyloid angiopathy is an important cause of cerebrovascular disorders including lobar cerebral hemorrhage, leukoencephalopathy, and small cortical hemorrhage and infarction. We review the clinicopathological and molecular aspects of CAA and discuss the pathogenesis of CAA with future perspectives. [source] Immunohistochemical study of cytokeratins in amyloid deposits associated with squamous cell carcinoma and dysplasia in the oral cavity, pharynx and larynxPATHOLOGY INTERNATIONAL, Issue 5 2003Tohru Ueno The frequency of amyloid deposits associated with squamous cell carcinoma (SCC) and dysplasia in the oral cavity, pharynx and larynx was examined. In addition, the origin of amyloid proteins by immunohistochemical staining with a panel of anticytokeratin monoclonal antibodies was investigated. Amyloid deposits were found in eight of 73 (11.0%) SCC and one of seven (14.3%) dysplasias in the oral cavity, in eight of 22 (36.4%) SCC and zero of two (0%) dysplasias in the pharynx, and in 22 of 37 (59.5%) SCC and four of 10 (40.0%) dysplasias in the larynx. Eight of 12 different cytokeratin (CK) antibodies reacted with these deposits: 34,E12 (CK1, -5, -10, -14) reacted with amyloid deposits in 19 of 19 cases (100%), LL002 (CK14) in eight of 18 cases (44.4%), MNF116 (CK5, -6, -8, -17) in eight of 19 cases (42.1%), D5/16B4 (CK5, -6) in five of 18 cases (27.8%), DE-K10 (CK10) in four of 17 cases (23.5%), RCK108 (CK19) in three of 18 cases (16.7%), 34,B4 (CK1) in three of 19 cases (15.8%) and AE8 (CK13) in two of 17 cases (11.8%). These antibodies always reacted with the cytoplasm of squamous cell lesions. Amyloid deposits in two cases contained a CK5 and CK14 pair, and in another two cases they contained both a CK5 and CK14 pair, and a CK1 and CK10 pair. Anti-CK antibodies, including OV-TL12/30 (CK7), c-51 (CK8), DC10 (CK18) and IT-Ks20.8 (CK20) did not react with the amyloid deposits. We conclude that the amyloid deposits associated with SCC or dysplasia in the oral cavity, pharynx or larynx were derived from CK of cancer cells and that some amyloid deposits might be assembled by two or more different CK. [source] |