[PDF] Mechanisms Of Cellular Binding And Internalisation Of The Beta Amyloid Protein Of Alzheimers Disease eBook

Author : Megan Laura Kerr
Publisher :
Page : 496 pages
File Size : 29,22 MB
Release : 2012
Category :
ISBN :

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Alzheimer's disease (AD) is characterised by an accumulation of the [beta]-amyloid (A[beta]) in the brain. A[beta]-induced neuronal dysfunction in AD is probably mediated via a direct interaction with components of the neuronal cell membrane. Genetic and molecular evidence suggests that cholesterol and lipoprotein homeostasis influence AD pathogenesis, however the mechanism by which this occurs is unclear. The present study aimed to examine whether cholesterol or lipoprotein factors regulate the binding of A[beta] to neuronal cells. To examine A[beta]-cell binding, an N-terminal fluorescein (Fluo) conjugate of the 42-amino acid isoform of A[beta] (A[beta]1-42; FluoA[beta]1-42) was incubated with SH-SY5Y human neuroblastoma cells, and cell-¬associated fluorescence was measured by confocal microscopy and flow cytometry. FluoA[beta]1-42 bound to cells in an aggregation-dependent manner, and was internalised to late endocytic compartments. The cell binding and uptake of FluoA[beta]1-42 was not mediated by binding sites for either cholera toxin B subunit, or antibodies to the low-density lipoprotein-related protein 1 (LRPl). These data suggested that FluoA[beta]1-42 did not bind to GMl gangliosides or LRPI on the cell surface. However, FluoA[beta]1-42 did colocalise to the binding sites of the LRPI ligand, receptor-associated protein (RAP), on the plasma membrane. Moreover, co¬incubation with RAP enhanced the binding of A[beta] to cells, and A[beta] was immunoprecipitated by an anti-RAP antibody following the incubation of RAP with A[beta] in vitro. By SDS-PAGE, it was also observed that RAP inhibited the oligomerisation of A[beta], and formed an SDS-stable complex with A[beta]. An inhibition of A[beta] aggregation was also noted by atomic force microscopy. Since A[beta] aggregation alters its toxicity, the effect of RAP on A[beta]-induced neurotoxicity was tested. RAP inhibited both the A[beta]-induced increase in intracellular calcium of SH-SY5Y cells, and A[beta]-induced amnesia in chicks. Since the aggregation of A[beta] into SDS-stable low molecular weight oligomers has been closely linked to A[beta] neurotoxicity and AD, the effect of RAP on A[beta] oligomerisation was examined in more detail. RAP inhibited the formation of SDS-stable dimers of A[beta]. The binding and uptake of A[beta] and RAP-A[beta] by SH-SY5Y cells was inhibited by heparin. However, heparin did not inhibit the formation of the RAP-A[beta] complex, suggesting that the binding of A[beta] to cells involves its heparin-binding domains, whereas the binding of A[beta] to RAP does not. Together, these findings suggest that RAP alters A[beta] aggregation, cellular uptake of A[beta], and A[beta]-induced neuronal dysfunction. Therefore, the RAP-A[beta] interaction may be a viable target for the development of AD therapies.

Author : J. Robin Harris
Publisher : Springer Science & Business Media
Page : 416 pages
File Size : 31,27 MB
Release : 2006-11-22
Category : Science
ISBN : 0387232265

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To understand Alzheimer's disease (AD) is one of the major thrusts of present-day clinical research, strongly supported by more fimdamental cellular, biochemical, immunological and structural studies. It is these latter that receive attention within this book. This compilation of 20 chapters indicates the diversity of work currently in progress and summarizes the current state of knowledge. Experienced authors who are scientifically active in their fields of study have been selected as contributors to this book, in an attempt to present a reasonably complete survey of the field. Inevitably, some exciting topics for one reason or another have not been included, for which we can only apologize. Standardization of terminology is often a problem in science, not least in the Alzheimer field; editorial effort has been made to achieve standardization between the Chapters, but some minor yet acceptable personal / author variation is still present, i. e. P-amyloid/amyloid-P; Ap42/Apl-42/APi. 42! The book commences with a broad survey of the contribution that the range of available microscopical techniques has made to the study of Alzheimer's amyloid plaques and amyloid fibrillogenesis. This chapter also serves as an Introduction to the book, since several of the topics introduced here are expanded upon in later chapters. Also, it is significant to the presence of this chapter that the initial discovery of brain plaques, by Alois Alzheimer, utilized light microscopy, a technique that continues to be extremely valuable in present-day AD research.

Author : Jorg Tatzelt
Publisher :
Page : 80 pages
File Size : 16,72 MB
Release : 2010
Category : Prions
ISBN : 9780954333522

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A conformational transition of the cellular prion protein (PrPC) into an aberrantly folded isoform designated scrapie prion protein (PrPSc) is the hallmark of a variety of neurodegenerative disorders collectively called prion diseases. They include Creutzfeldt-Jakob disease and Gerstmann-Stäussler-Scheinker syndrome in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in free-ranging deer. In contrast to the deadly properties of misfolded PrP, PrPC seems to possess a neuroprotective activity. More-over, animal models indicated that the stress-protective activity of PrPC and the neurotoxic effects of PrPSc are somehow interconnected. In this timely book, leading scientists in the field have come together to highlight the apparently incongruous activities of different PrP conformers. The articles outline current research on celluar pathways implicated in the formation and signaling of neurotoxic and physiological PrP isoforms and delineate future research direction. Topics covered include the physiologcial activity of PrPC and its possible role as a neurotrophic factor, the finding that aberrant PrP conformers can cause neurodegeneration in the absence of infectious prion propagation, the requirement of the GPI anchor of PrPC for the neurotoxic effects of scrapie prions, the pathways implicated in the formation and neurotoxic properties of cytosolically localized PrP, the impact of metal ions on the processing of PrP, and the role of autophagy in the propagation and clearance of PrPSc. The book is fully illustrated and chapters include comprehensive reference sections. Essential reading for scientists involved in prion research.

Author : Hirokawa
Publisher : CRC Press
Page : 360 pages
File Size : 36,72 MB
Release : 1994-01-12
Category : Science
ISBN : 9780849377419

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This book discusses the primary functions of microtubule-associated proteins (MAPs) such as MAP2 and tau in neuronal morphogenesis, as well as relationships between neuronal differentiation and the expression of neuronal intermediate filaments (nestin, alpha internexin, and neurofilament triplet proteins). It emphasizes the importance of several cytoskeletal proteins for neuronal differentiation and morphogenesis, organelle transport, and synaptic functions. The book considers the involvement of tau MAPs in the formation of paired helical filaments in Alzheimer's disease, and it examines the mechanisms of organelle transports and molecular motors such as kinesin, braindynein, and kinesin superfamily proteins. Cytoskeletal proteins involved in synaptic formation and transmitter release and new synaptic junctional-associated proteins are explored as well.

Author : A.D. Roses
Publisher : Springer Science & Business Media
Page : 208 pages
File Size : 16,27 MB
Release : 2012-12-06
Category : Medical
ISBN : 3642801099

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There is now considerable genetic evidence that the type 4 allele of the apolipoprotein E gene is a major susceptibility factor associated with late-onset Alzheimer's disease, the common form of the disease defined as starting after sixty years of age. The role of apolipoprotein E in normal brain metabolism and in the pathogenesis of Alzheimer's disease are new and exciting avenues of research. This book, written by the most outstanding scientists in this new filed, is the first presentation of results concerning the implications of apolipoprotein E on the genetics, cell biology, neuropathology, biochemistry, and therapeutic management of Alzheimer's disease.

Author : Jesus Avila
Publisher : Frontiers E-books
Page : 114 pages
File Size : 46,73 MB
Release : 2014-08-18
Category : Medicine (General)
ISBN : 288919261X

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Neurofibrillary tangles (NFTs) composed of intracellular aggregates of tau protein are a key neuropathological feature of Alzheimer’s Disease (AD) and other neurodegenerative diseases, collectively termed tauopathies. The abundance of NFTs has been reported to correlate positively with the severity of cognitive impairment in AD. However, accumulating evidences derived from studies of experimental models have identified that NFTs themselves may not be neurotoxic. Now, many of tau researchers are seeking a “toxic” form of tau protein. Moreover, it was suggested that a “toxic” tau was capable to seed aggregation of native tau protein and to propagate in a prion-like manner. However, the exact neurotoxic tau species remain unclear. Because mature tangles seem to be non-toxic component, “tau oligomers” as the candidate of “toxic” tau have been investigated for more than one decade. In this topic, we will discuss our consensus of “tau oligomers” because the term of “tau oligomers” [e.g. dimer (disulfide bond-dependent or independent), multimer (more than dimer), granular (definition by EM or AFM) and maybe small filamentous aggregates] has been used by each researchers definition. From a biochemical point of view, tau protein has several unique characteristics such as natively unfolded conformation, thermo-stability, acid-stability, and capability of post-translational modifications. Although tau protein research has been continued for a long time, we are still missing the mechanisms of NFT formation. It is unclear how the conversion is occurred from natively unfolded protein to abnormally mis-folded protein. It remains unknown how tau protein can be formed filaments [e.g. paired helical filament (PHF), straight filament and twisted filament] in cells albeit in vitro studies confirmed tau self-assembly by several inducing factors. Researchers are still debating whether tau oligomerization is primary event rather than tau phosphorylation in the tau pathogenesis. Inhibition of either tau phosphorylation or aggregation has been investigated for the prevention of tauopathies, however, it will make an irrelevant result if we don’t know an exact target of neurotoxicity. It is a time to have a consensus of definition, terminology and methodology for the identification of “tau oligomers”.

Author : Ezio Giacobini
Publisher : Springer Science & Business Media
Page : 673 pages
File Size : 40,23 MB
Release : 2012-12-06
Category : Medical
ISBN : 1461581494

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Since the apoE4 allele is a risk factor or susceptibility gene in late-onset familial and sporadic AD, the mechanism of disease expression may involve metabolic effects that are isoform specific. Isoform-specific interactions of apoE therefore become critical in the mechanism of AD pathogenesis. Detailed characterization of the binding of the apoE isoforms with proteins and peptides relevant to the pathology of the disease may be critical in understanding disease pathogenesis. These critical isoform-specific interactions of apoE may involve interactions with proteins and pep tides in the defining neuropathologic lesions of the disease, the neurofibrillary tangle and senile plaque. Other possible critical isoform-specific interactions include the mechanism of internalization, intracellular trafficking, and subsequent metabolism. In addition, differential post-translational modifications of apoE isoforms may determine differences in metabolism contributing to the pathogenesis of the disease. Oxidation of apoE may confer several isoform-specific, biochemically distinct properties. Since {3A peptide binds apoE in the lipoprotein binding domain of the protein and not in the receptor-binding domain, apoE could target bound {3A4 peptide to neurons via the LRP receptor. Internalization of the apoEI {3A peptide complex into the cell, by the same route as the apoE-containing lipoproteins, would result in incorporation into primary lysosomes and pH dependent dissociation. The demonstration of apoE in the cytoplasm of neurons, with isoform-specific interactions of apoE with the microtubule-binding protein tau demonstrated in vitro, suggest additional, testable hypotheses of disease pathogenesis.

Author : Colin J. Barrow
Publisher : Springer Science & Business Media
Page : 298 pages
File Size : 33,53 MB
Release : 2006-12-22
Category : Medical
ISBN : 1846284406

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Recent advances in genetics and brain biochemistry point to the Abeta peptide as the major culprit in causing neurodegeneration in Alzheimer’s Disease (AD). This book summarizes current knowledge of the Abeta peptide and its role in AD. Written by specialists in this fast moving area, the book covers fundamental biochemical studies on this peptide, the genetic impact on Abeta expression and processing, and various AD therapeutic strategies that target Abeta.

Author :
Publisher : Elsevier
Page : 273 pages
File Size : 13,37 MB
Release : 1995-10-17
Category : Medical
ISBN : 0080538495

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Neuroscience Perspectives provides multidisciplinary reviews of topics in one of the most diverse and rapidly advancing fields in the life sciences.Whether you are a new recruit to neuroscience, or an established expert, look to this series for 'one-stop' sources of the historical, physiological, pharmacological, biochemical, molecular biological and therapeutic aspects of chosen research areas.The last decade has seen tremendous advances in our understanding of the pathobiology of Alzheimer's disease. These will lead to the first generation of drugs aimed at prevention rather than cure. This book covers some of the most important and exciting of these advances, with chapters written by many of the leading researchers in the field.With genetic studies as a backbone to this volume many chapters are devoted to the function and regulation of amyloid b-protein precursor (APP) and apolipoprotein E (ApoE). Other chapters describe cell biological approaches helping to piece together the link between the genetic alterations and the phenotype we call Alzheimer's disease.Although APP and its proteolytic cleavage product, amyloid b-protein, do not answer all the questions, detailed research into this system has undoubtedly increased our knowledge of the pathobiology of AD and has lead to the identification of other risk factors. Understanding the role of ApoE in the pathology of Alzheimer's disease promises to open a whole new field in AD research. * * Reviews the current knowledge of the pathogenesis of Alzheimer's Disease from a clinical perspective to a genetic and cell biological perspective* A comprehensive description of the role of amyloid B-protein precursor in Alzheimer's disease.* Up-to-date research data* Clear illustrations complement the text