[PDF] Structure Aggregation And Inhibition Of Alzheimers Beta Amyloid Peptide Abeta eBook

Author : Qiuming Wang
Publisher :
Page : 193 pages
File Size : 17,83 MB
Release : 2013
Category : Alzheimer's disease
ISBN :

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Alzheimer's disease (AD) is the most common age related neurodegenerative disorder pathologically linked with the accumulation of the extracellular senile plaques of [Beta]-Amyloid peptide (A[Beta]) and the intracellular neurofibrillary tangles of tau protein in AD's brains. The deposition of A[Beta] is regarded as the primary causative factor in AD, which involves both neuron cytotoxicity and tau protein hydrophosphorylation. Amyloid formation on the cell membrane involves multiple self-assembly processes in which A[Beta] peptides undergo complex conformational change, aggregation, and reorganization to form characteristic [Beta]-sheet rich fibrils. The kinetics of this self-assembly process and the inhibition of A[Beta] aggregation and toxicity remains an important but open question because of 1) the small size, fast transition, and heterogeneous intermediates of A[Beta] oligomers, 2) complicated surface environment of cell membrane, and 3) no effective pharmaceutical agent was produced to date to treat AD. In this dissertation, both computational and experimental approaches were conducted to (1) investigate the conformation, orientation, and aggregation of amyloid oligomers upon adsorption on artificial surfaces; (2) determine seeding effect of A[Beta] adsorption and kinetic on different artificial surfaces; (3) examine inhibition effect of tanshiones on A[Beta] aggregation and toxicity; (4) explore novel process for A[Beta] inhibitor design. Throughout this week, we for the first time determine the effect of surface chemistry on A[Beta] aggregation and adsorption (Chapter II); and reveal the role of size, conformation, and orientation of A[Beta] oligomer on A[Beta]-surface interaction (Chapter III and Chapter IV). As compared to A[Beta] aggregation in solution, all of the Self-Assembled Monolayers (SAMs) can greatly accelerate A[Beta] aggregation and promote the structural conversion from an unstructured conformation to a [Beta]-sheet-containing structure. Our results suggest that A[Beta] undergoes different aggregation pathways on different SAMs. All these experimental and simulation results represent the first important step towards a better fundamental understanding of amyloid aggregation and toxicity mechanisms at the molecular level. We also discover a type of novel inhibitors of tanshionones from herb extracts which possess multifunction of inhibiting A[Beta] aggregation, disaggregating A[Beta] fibers, and reducing A[Beta]-induced cell toxicity in vitro (Chapter V). Tanshinone-derived compounds constitute a new class of amyloid inhibitors with multiple advantages in amyloid inhibition, fibril disruption, and cell protection, as well as their well-known anti-inflammatory activity, which may hold great promise in treating amyloid diseases. In addition of investigating the naturally existed compounds, a novel technique for the design and identification of amyloidogenic hexapeptide-based A[Beta] inhibitor was developed (Chapter VI). We have suggested a novel hypothesis for the development of hexapeptide-based A[Beta] inhibitors and developed a high-throughput protocol for the design and screen of amyloidogenic hexapeptide sequences as A[Beta] aggregation and cytotoxicity inhibitors. The successful identification of A[Beta] inhibitors through this work highly confirmed that analyzing the self-recognition short peptide fragments is a promising strategy for developing peptide-based inhibitors of Alzheimer's disease. And the common concept of cross-amylid interaction could also potentially be used to the identification of inhibitors for other amyloid diseases. The self-recognition hexapeptide fragments designed in QSAR model, in together with the high throughput MD simulation model, can be widely used for amyloidosis mechanism study and amyloid inhibitor screen.

Author : Xiang Yu
Publisher :
Page : 258 pages
File Size : 28,33 MB
Release : 2012
Category : Alzheimer's disease
ISBN :

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Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, pathologically linked to the abnormal self-aggregation of amyloid peptides ([Amyloid-beta] and tau) into amyloid fibrils. Accumulating evidence supports the "toxic oligomer hypothesis" that small soluble amyloid oligomers (intermediate species), rather than monomers (initial species) and insoluble fibrils (final species), are major toxic species responsible for neuron dysfunction and death. However, due to the polymorphic and transit nature of amyloid oligomers, atomic structures of amyloid oligomers are not available to date, causing the difficulty in the fundamental understanding of the mechanisms of amyloid formation and toxicity and in the rational design of structural-based inhibitors to treat AD. In this dissertation, we develop a multiscale computational framework to (1) determine atomic structures of amyloid oligomers; (2) investigate the conformation, orientation, and aggregation of amyloid oligomers upon adsorption on biological and artificial surfaces; (3) probe binding and inhibitory ability of organic ligands to amyloid oligomers. Throughout this work, we for the first time determine a series of atomic structures of [Amyloid-beta] micelles (Chapter II), [Amyloid-beta] globulomers (Chapter III), and tau fibrillar-like oligomers (Chapter IV). These oligomers vary considerably in overall structural morphologies, reflecting a highly polymorphic nature of amyloid oligomers in a rugged energy landscape. We also study the effects of cholesterol level on the mutual structure, dynamics, and interaction of [Amyloid-beta] and lipid bilayer (Chapter V). Increased cholesterol level greatly enhances [Amyloid-beta] binding to the bilayer, which provides atomic-level explanation as to why high-level cholesterol may have a higher risk for AD development. In parallel to lipid bilayer, molecular dynamics simulations of [Amyloid-beta] peptides on graphite reveal the important role of hydrophobic interactions in facilitating [Amyloid-beta] adsorption, reorientation, structural transition, and aggregation (Chapter VI). With the assistance of atomic structures of [Amyloid-beta] oligomers, we computationally examine binding events between tanshinones and [Amyloid-beta] oligomer (Chapter VII). Strong binding affinity of tanshinone-I, rather tanshinone-IIA, to [Amyloid-beta] is well correlated with inhibitory activity to [Amyloid-beta] aggregation. Combination of our computational and experimental results represent an important step towards a better understanding of the aggregation, toxicity, and inhibition mechanisms of amyloid peptides at atomic level.

Author : Colin J. Barrow
Publisher : Springer Science & Business Media
Page : 298 pages
File Size : 22,66 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 : Philippe Derreumaux
Publisher : World Scientific
Page : 465 pages
File Size : 20,46 MB
Release : 2012-12-31
Category : Medical
ISBN : 1908979658

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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

Author : Philippe Derreumaux
Publisher : World Scientific
Page : 465 pages
File Size : 20,74 MB
Release : 2012
Category : Medical
ISBN : 1848167555

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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."

Author : Jesus Avila
Publisher : Frontiers E-books
Page : 114 pages
File Size : 37,56 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 : J. Robin Harris
Publisher : Springer Science & Business Media
Page : 416 pages
File Size : 29,65 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 : Jeffrey Cummings
Publisher : Cambridge University Press
Page : 575 pages
File Size : 39,59 MB
Release : 2022-03-31
Category : Business & Economics
ISBN : 1108838669

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Provides a definitive overview of the complex ecosystem facilitating Alzheimer's Disease drug research and development. Demonstrates a drug's journey from in the lab, clinical trial testing, regulatory review, and marketing by pharmaceutical companies. Details the use of artificial intelligence, clinical trial management, and financing models.

Author : Faisal Abedin
Publisher :
Page : 99 pages
File Size : 15,75 MB
Release : 2021
Category :
ISBN :

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Alzheimer’s disease (AD) is the major cause of dementia and is characterized by neuronal death and brain atrophy. The amyloid [beta] (A[beta]) peptide is tightly associated with neuronal dysfunction during AD, but the molecular mechanism underlying the neurotoxic effect of A[beta] is poorly understood. Extracellular fibrillar deposits (plaques) of A[beta] were initially believed to be the cause of AD, but currently there is overwhelming evidence that the prefibrillar A[beta] oligomers are the major toxic entities. Structural characterization of A[beta] oligomers and fibrils is important for understanding the structural features determining the toxic potency of the peptide. This project has studied the aggregation and accompanying structural transitions of A[beta], a naturally occurring hypertoxic species, i.e. pyroglutamylated A[beta], and their combination, using biophysical approaches (circular dichroism, fluorescence, infrared spectroscopy). In addition, aggregation and structure of overlapping peptide fragments have been studied to identify the specific stretch of A[beta] that serves as seeding region initiating the aggregation and fibril formation by the full-length A[beta]peptide. These studies elucidate the structural features of A[beta] responsible for the peptide’s neurotoxic action.