Alzheimer S Disease Insights Into Low Molecular Weight And Cytotoxic Aggregates From In Vitro And Computer Experiments Molecular Basis Of Amyloid Beta Protein Aggregation And Fibril Formation
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Alzheimer S Disease Insights Into Low Molecular Weight And Cytotoxic Aggregates From In Vitro And Computer Experiments Molecular Basis Of Amyloid Beta Protein Aggregation And Fibril Formation
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Author : Philippe Derreumaux
language : en
Publisher: World Scientific
Release Date : 2012-12-31
Alzheimer S Disease Insights Into Low Molecular Weight And Cytotoxic Aggregates From In Vitro And Computer Experiments Molecular Basis Of Amyloid Beta Protein Aggregation And Fibril Formation written by Philippe Derreumaux and has been published by World Scientific this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-12-31 with Medical categories.
Alzheimer's disease is the most common form of senile dementia, affecting more than 24 million people worldwide. It is characterised pathologically by abnormally high levels of neurofibrillary tangles resulting from the accumulation of tau protein in dead and dying neurons, and by elevated numbers of senile plaques in the cortex and hippocampus of the brain. The major component of senile plaques is a small protein of 39-43 amino acids called amyloid-β (Aβ). Thus far, no treatment has been shown to slow the progression of sporadic and familial Alzheimer's disease.A large body of evidence points, however, to the early Aβ-formed oligomers as the primary toxic species in Alzheimer's disease. A powerful strategy for developing pharmaceutical treatments against Alzheimer's is to elucidate the pathways of oligomer formation and determine the structures of the toxic aggregates.This book provides a panoramic view across recent in vitro and in vivo studies along with state-of-the-art computer simulations, designed to increase the readers' understanding of Aβ oligomerisation and fibril formation. At the same time, the book delves into the pathogenesis of familial and sporadic Alzheimer's disease at the atomic level of detail.Written by leading authors in their respective fields, this book will be valuable to all scientists working on Alzheimer's disease./a
Alzheimer S Disease
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Author : Philippe Derreumaux
language : en
Publisher: World Scientific
Release Date : 2013
Alzheimer S Disease written by Philippe Derreumaux and has been published by World Scientific this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013 with Medical categories.
Alzheimer's disease is the most common form of senile dementia, affecting more than 24 million people worldwide. It is characterised pathologically by abnormally high levels of brain lesions in dead and dying neurons, and by elevated numbers of amyloid deposits in the walls of cerebral blood vessels. This book provides a panoramic view across recent in vitro and in vivo studies along with state-of-the-art computer simulations, designed to increase the readers' understanding of oligomerisation and fibril formation.
Alzheimer S Disease
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Author : Philippe Derreumaux
language : en
Publisher: World Scientific
Release Date : 2012
Alzheimer S Disease written by Philippe Derreumaux and has been published by World Scientific this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012 with Medical categories.
Alzheimer's disease is the most common form of senile dementia, affecting more than 24 million people worldwide. It is characterised pathologically by abnormally high levels of neurofibrillary tangles resulting from the accumulation of tau protein in dead and dying neurons, and by elevated numbers of senile plaques in the cortex and hippocampus of the brain. The major component of senile plaques is a small protein of 39OCo43 amino acids called amyloid-? (A?). Thus far, no treatment has been shown to slow the progression of sporadic and familial Alzheimer's disease.A large body of evidence points, however, to the early A?-formed oligomers as the primary toxic species in Alzheimer's disease. A powerful strategy for developing pharmaceutical treatments against Alzheimer's is to elucidate the pathways of oligomer formation and determine the structures of the toxic aggregates.This book provides a panoramic view across recent in vitro and in vivo studies along with state-of-the-art computer simulations, designed to increase the readers' understanding of A? oligomerisation and fibril formation. At the same time, the book delves into the pathogenesis of familial and sporadic Alzheimer's disease at the atomic level of detail.Written by leading authors in their respective fields, this book will be valuable to all scientists working on Alzheimer's disease."
Protein Aggregation And Fibrillogenesis In Cerebral And Systemic Amyloid Disease
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Author : J. Robin Harris
language : en
Publisher: Springer Science & Business Media
Release Date : 2012-12-09
Protein Aggregation And Fibrillogenesis In Cerebral And Systemic Amyloid Disease written by J. Robin Harris and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-12-09 with Medical categories.
This volume of the Subcellular Biochemistry series is the result of the long-standing research interest of the editor in the molecular mechanism underlying Alzheimer’s disease and other amyloid diseases, indicated also by the earlier book in the series (Volume 38), devoted to Alzheimer’s disease. The broad coverage within the present amyloidogenesis book represents an attempt to collate current knowledge relating to the proteins and peptides involved in most of the known amyloid diseases, together with some amyloid/fibril-forming proteins and peptides that are not involved in diseases. Thus, the range of topics included is comprehensive and furthermore it was thought appropriate to include both basic science and clinical presentation of the subjects under discussion.
Alzheimer S Disease Cellular And Molecular Aspects Of Amyloid Beta
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Author : J. Robin Harris
language : en
Publisher: Springer Science & Business Media
Release Date : 2004-12-17
Alzheimer S Disease Cellular And Molecular Aspects Of Amyloid Beta written by J. Robin Harris and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2004-12-17 with Science categories.
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.
Biophysics And Biochemistry Of Protein Aggregation Experimental And Theoretical Studies On Folding Misfolding And Self Assembly Of Amyloidogenic Peptides
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Author : Jian-min Yuan
language : en
Publisher: World Scientific
Release Date : 2017-06-02
Biophysics And Biochemistry Of Protein Aggregation Experimental And Theoretical Studies On Folding Misfolding And Self Assembly Of Amyloidogenic Peptides written by Jian-min Yuan and has been published by World Scientific this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017-06-02 with Science categories.
This book reviews current research on the important processes involved in neurodegenerative diseases (e.g. Alzheimer's disease) and the peptides and proteins involved in the amyloidogenic processes. It covers the design and developments of anti-amyloid inhibitors, and gives readers a fundamental understanding of the underlying oligomerization and aggregation processes of these diseases from both computational and experimental points of view.
Mechanisms Of Cellular Binding And Internalisation Of The Beta Amyloid Protein Of Alzheimer S Disease
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Author : Megan Laura Kerr
language : en
Publisher:
Release Date : 2012
Mechanisms Of Cellular Binding And Internalisation Of The Beta Amyloid Protein Of Alzheimer S Disease written by Megan Laura Kerr and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012 with categories.
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.
The Effect Of Osaka Mutation On Oligomer Formation Of Full Length Amyloid Beta Protein Oligomers
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Author : Riya Shah
language : en
Publisher:
Release Date : 2022
The Effect Of Osaka Mutation On Oligomer Formation Of Full Length Amyloid Beta Protein Oligomers written by Riya Shah and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2022 with Alzheimer's disease categories.
Alzheimer's disease (AD) is the leading cause of dementia among the elderly and is characterized by loss of memory due to neuronal death. In vitro and in vivo experiments have identified soluble, low-molecular weight, non-covalently bonded oligomeric forms of amyloid [beta]-protein (A) as the likely toxic species that leads to AD. The Osaka mutation ([E22[delta]]), discovered in a Japanese family, is associated with an early-onset AD in the carriers of this mutation, and involves a deletion of the glutamic acid at the twenty-second position in A[beta]. A[beta] with Osaka mutation can be used to probe the effect of singular deletions on oligomerization and protein conformations. We use discrete molecular dynamics (DMD) simulations with a four-bead protein model and implicit solvent to study the oligomerization of the two most predominant alloforms, A[beta]1-40 and A[beta]1-42, and their Osaka mutants. Our findings suggest that the Osaka mutation alters A[beta]1-40 structure and assembly mechanics to be more similar to A[beta]1-42 and [E22[delta]]A[beta]1-42. Specifically, the Osaka mutation greatly affects the secondary structure of A[beta]1-40 in the N-terminal region to make it resemble A[beta]1-42. We also show that [E22[delta]]A[beta]1-40 and [E22[delta]]A[beta]1-42 tend to assemble into larger oligomers than their wild-type (WT) counterparts and that both mutants are more prone than wild type A[beta] to forming a tertiary contact between D23 and K28. The proximity of negatively charged D23 and positively charged K28 is expected to induce an intrapeptide salt bridge, stabilization of which is known for speeding up fibril formation. These results provide a plausible explanation of why Osaka mutants aggregate into fibrils much faster than WT peptides. The early-onset properties of the Osaka mutation might be attributed to the resemblance of [E22[delta]]A[beta]1-40 oligomer conformations to those formed by A[beta]1-42, specifically the property of A[beta]1-42 possessing disordered and solvent accessible N-termini, which would readily interact with and potentially disrupt cellular membranes.
Amyloid And Lysozyme Proteotoxicity In Drosophila
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Author : Liza Bergkvist
language : en
Publisher: Linköping University Electronic Press
Release Date : 2017-05-16
Amyloid And Lysozyme Proteotoxicity In Drosophila written by Liza Bergkvist and has been published by Linköping University Electronic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017-05-16 with categories.
In the work presented this thesis, two different conditions that are classified as protein misfolding diseases: Alzheimer's disease and lysozyme amyloidosis and proteins that could have a beneficial effect in these diseases, have been studied using Drosophila melanogaster, commonly known as the fruit fly. The fruit fly has been used for over 100 years to study and better understand fundamental biological processes. Although the fruit fly, unlike humans, is an invertebrate, many of its central biological mechanisms are very similar to ours. The first transgenic flies were designed in the early 1980s, and since then, the fruit fly has been one of the most widely used model organisms in studies on the effects of over-expressed human proteins in a biological system; one can regard the fly as a living, biological test tube. For most proteins, it is necessary that they fold into a three-dimensional structure to function properly. But sometimes the folding goes wrong; this may be due to mutations that make the protein unstable and subject to misfolding. A misfolded protein molecule can then aggregate with other misfolded proteins. In Alzheimer's disease, which is the most common form of dementia, protein aggregates are present in the brains of patients. These aggregates are composed of the amyloid-β (Aβ) peptide, a small peptide of around 42 amino acids which is cleaved from the larger, membrane-bound, protein AβPP by two different enzymes, BACE1 and γ-secretase. In the first part of this thesis, two different fly models for Alzheimer’s disease were used: the Aβ fly model, which directly expresses the Aβ peptide, and the AβPP-BACE1 fly model, in which all the components necessary to produce the Aβ peptide in the fly are expressed in the fly central nervous system (CNS). The two different fly models were compared and the results show that a significantly smaller amount of the Aβ peptide is needed to achieve the same, or an even greater, toxic effect in the AβPP-BACE1 model compared to the Aβ model. In the second part of the thesis, these two fly models for Alzheimer’s disease were again used, but now to investigate whether lysozyme, a protein involved in our innate immune system, can counteract the toxic effect of Aβ generated in the fly models. And indeed, lysozyme is able to save the flies from Aβ-induced toxicity. Aβ and lysozyme were found to interact with each other in vivo. The second misfolding disease studied in this thesis is lysozyme amyloidosis. It is a rare, dominantly inherited amyloid disease in which mutant variants of lysozyme give rise to aggregates, weighing up to several kilograms, that accumulate around the kidneys and liver, eventually leading to organ failure. In the third part of this thesis, a fly model for lysozyme amyloidosis was used to study the effect of co-expressing the serum amyloid P component (SAP), a protein that is part of all protein aggregates found within this disease class. SAP is able to rescue the toxicity induced by expressing the mutant variant of lysozyme, F57I, in the fly's CNS. To further investigate how SAP was able to do this, double-expressing lysozyme flies, which exhibit stronger disease phenotypes than those of the single-expressing lysozyme flies previously studied, were used in the fourth part of this thesis. SAP was observed to reduce F57I toxicity and promote F57I to form aggregates with more distinct amyloid characteristics. In conclusion, the work included in this thesis demonstrates that: i) Aβ generated from AβPP processing in the fly CNS results in higher proteotoxicity compared with direct expression of Aβ from the transgene, ii) lysozyme can prevent Aβ proteotoxicity in Drosophila and could thus be a potential therapeutic molecule to treat Alzheimer’s disease and iii) in a Drosophila model of lysozyme amyloidosis, SAP can prevent toxicity from the disease-associated lysozyme variant F57I and promote formation of aggregated lysozyme morphotypes with amyloid properties; this is important to take into account when a reduced level of SAP is considered as a treatment strategy for lysozyme amyloidosis.
Structure And Energetics Of Amyloid
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Author : Sarah J. Siegel
language : en
Publisher:
Release Date : 2008
Structure And Energetics Of Amyloid written by Sarah J. Siegel and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008 with Amyloid beta-protein categories.
The transformation of a soluble protein into an amyloid fibril, a process thought to cause a number of diseases including Alzheimer's disease and Parkinson's disease, is not yet well understood. To discover new therapeutic strategies for these diseases, it is important to understand the process by which these proteins aggregate and cause disease. The actual structures of the aggregates formed during in vitro aggregation experiments of disease-related amyloid proteins depend strongly on the misassembly conditions. A frustrated folding energy landscape describes a system in which changes in environmental conditions dramatically affect the free energy landscape and thus the morphology of aggregate formed. Because proteins associated with pathology did not evolve their sequences to adopt amyloid structures, these proteins could have more frustrated energy landscapes for amyloid formation than those of evolved monomer folds or evolved functional amyloidogenic proteins. A[beta] 1-40, whose aggregation is associated with Alzheimer's disease, reacts with the oxidative metabolite 4-hydroxynonenal. This aberrant post-translational modification covalently cross-links A[beta] 1-40 peptides, causing A[beta] 1-40 to aggregate more quickly into protofibrils and eventually into long, curly fibrils. While enhancing aggregation, the Schiff base and/or Michael reactions between A[beta] 1-40 and 4-hydroxynonenal prevent the formation of long, straight fibrils. Not only is this apparently relevant to disease onset, as 4-hydroxynonenal is found at elevated levels in Alzheimer's patients as compared to age-matched controls and is detected in A[beta] plaques, but it also indicates a frustrated folding energy landscape for A[beta] amyloid, where the addition of a small molecule can change the quaternary structure of aggregates formed. This change in aggregate structure may lead to a more toxic conformation that induces sporadic Alzheimer's disease. [alpha]-Synuclein, associated with Parkinson's disease, also shows signs of frustration in its amyloid formation reaction. Upon the addition of 3 M guanidine hydrochloride, [alpha]-synuclein fibrils convert into an alternate structure with differences in their morphology, surface properties, protease resistance, and pattern of exchange with solvent that indicates a different molecular packing of monomer within the fibril. That different structures are populated under different amyloidogenesis conditions indicates that there are multiple accessible quaternary structures of similar energy that these pathological amyloid proteins can adopt, as expected when aggregation is governed by a frustrated energy landscape. Unlike pathological amyloid proteins, native amyloid proteins require an amyloid quaternary structure to carry out their function, suggesting that they evolved their sequences to form an amyloid structure that is stable to changes in the environment. Therefore, we hypothesize that native amyloid exhibits a funneled folding energy landscape comparable to that of a globular folded protein, unlike the rough aggregation energy landscapes exhibited by pathological amyloidogenesis. We compared the aggregation of [alpha]-synuclein and CsgA, the latter of which is a native amyloid, and found that CsgA aggregates more quickly, forms larger associations of fibrils, and exhibits higher fibril stability in denaturant than [alpha]-synuclein. These properties seem to logically support CsgA's role in biofilm formation, and the hypothesis that CsgA may have evolved specifically for this purpose. [alpha]-Synuclein, which does not function in an amyloid structure as far as we know, had no evolutionary imperative to evolve its primary structure for robust amyloidogenesis characteristics. We suggest that pathological amyloid proteins have rough or frustrated energy landscapes, and that since native amyloid proteins appear to have evolved to form amyloid, they likely have smoother, funneled energy landscapes. This affects how we think about and manipulate the process of amyloidogenesis for combating disease and utilize the amyloid structure for its material properties.