[PDF] Structural Characterization Of Interactions Between The Alzheimers Disease Amyloid Beta Peptide And Small Molecules And Peptide Inhibitors eBook

Author : Xiang Yu
Publisher :
Page : 258 pages
File Size : 31,16 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 : Einar M. Sigurdsson
Publisher : Springer Science & Business Media
Page : 390 pages
File Size : 30,50 MB
Release : 2008-02-02
Category : Science
ISBN : 1592598749

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A proven collection of readily reproducible techniques for studying amyloid proteins and their involvement in the etiology, pathogenesis, diagnosis, and therapy of amyloid diseases. The contributors provide methods for the preparation of amyloid and its precursors (oligomers and protofibrils), in vitro assays and analytical techniques for their study, and cell culture models and assays for the production of amyloid proteins. Additional chapters present readily reproducible techniques for amyloid extraction from tissue, its detection in vitro and in vivo, as well as nontransgenic methods for developing amyloid mouse models. The protocols follow the successful Methods in Molecular BiologyTM series format, each offering step-by-step laboratory instructions, an introduction outlining the principle behind the technique, lists of the necessary equipment and reagents, and tips on troubleshooting and avoiding known pitfalls.

Author : Qiuming Wang
Publisher :
Page : 193 pages
File Size : 31,61 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 : Lila K. Habib
Publisher :
Page : 128 pages
File Size : 25,61 MB
Release : 2011
Category :
ISBN : 9781267019424

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Although the pathological aggregation and deposition of A[beta]-amyloid (A[beta]) peptides in the brain has long been implicated as the key event leading to the onset of Alzheimer's disease (AD), there is still no disease-modifying therapeutic or definitive diagnostic method to diagnose, monitor, or treat AD. Compelling evidence has shown a strong correlation between accumulation of neurotoxic A[beta] peptides and oxidative damage in the brains of AD sufferers. One hypothesis for this correlation involves the direct and harmful interaction of aggregated A[beta] peptides with enzymes responsible for maintaining normal levels of reactive oxygen species. Identification of specific, destructive interactions of A[beta] peptides with cellular anti-oxidant enzymes would represent an important step towards understanding the pathogenicity of A[beta] peptides in AD and designing an effective strategy to manage this disease. Therefore, the focus of this dissertation is to : 1) identify direct and harmful binding interactions between aggregated A[beta] peptides and anti-oxidant enzymes that contribute to the pathogenesis of AD, 2) inhibit these destructive interactions using A[beta]-binding small molecules capable of generating protein-resistive surface coatings on aggregated A[beta] peptides, and 3) develop a general strategy to deliver diagnostic and therapeutic agents across the restrictive blood-brain barrier (BBB). In this dissertation, small molecules capable of generating protein-resistive surface coatings on aggregated A[beta] peptides were used to probe the interaction of A & beta; with cellular anti-oxidant enzymes. This dissertation supports the important role of intracellular catalase-amyloid interactions in A[beta]-induced oxidative stress and proposes a novel molecular strategy of generating protein-resistive surface coatings on aggregated A[beta] peptides to inhibit such harmful interactions in AD. The development of high payload brain-targeting magnetic nanoparticles that have the ability to act as a diagnostic imaging agent while simultaneously providing a multivalent scaffold for conjugation of drugs and brain-targeting vectors was also explored. This dissertation provides evidence that magnetic nanoparticles conjugated to transferrin enhances the transport of nanoparticles across the BBB by receptor-mediated transcytosis. Collectively, these findings provide new information on the interaction of aggregated A[beta] peptides with cellular components that contribute to AD, propose a strategy to inhibit these interactions, and suggest that receptor-mediated transcytosis may be a promising route for the delivery of molecules across the BBB.

Author :
Publisher :
Page : pages
File Size : 43,69 MB
Release : 2006
Category :
ISBN :

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Polymerization of the soluble beta-amyloid peptide into highly ordered fibrils is hypothesized to be a causative event in the development of Alzheimer’s Disease. Structural information of beta-amyloid fibril formation is fundamental for the development of diagnostics and therapeutic approaches, and in addition might be valuable for elucidating fundamental mechanisms of protein folding and assembly. Study of interactions of Abeta with inhibitors can provide important indirect information of the amyloid fibril structure. In this work, the structure of peptide inhibitors to Abeta fibril formation is studied with the aid of synthetic peptides and NMR spectroscopy, as well as Electron Microscopy and Circular Dichroism Spectroscopy. The short fragment of the beta-amyloid peptide Abeta14-23 and its peptide inhibitors iAbeta5 (LPFFD) and iAbeta5inv (DPFFL) are synthesized manually with and without 19F-, 13C- and 15N-labelling using standard Fmoc peptide synthesis protocols. Distance restraints for peptide inhibitors.

Author : Jesus Avila
Publisher : Frontiers E-books
Page : 114 pages
File Size : 39,97 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 : 442 pages
File Size : 44,51 MB
Release : 2004-12-17
Category : Science
ISBN : 9780387232256

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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 : E. Edward Bittar
Publisher : JAI Press(NY)
Page : 0 pages
File Size : 46,12 MB
Release : 1997
Category : Cell-mediated cytotoxicity
ISBN : 9780762301416

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Cellular toxicology has entered a new era. No longer are we concerned only with necrotic cell death produced by severe, acute insult (often to multiple intracellular targets) leading to disruption of the cell membrane. New advances in molecular and cellular biology are allowing the dissection of mechanisms of cell death involving more subtle targets within the cell. Toxicology has been very important, not only in understanding the mechanisms, nature, and severity of toxicity and thereby helping in risk assessment, but toxicology has also played a very important role in helping to understand basic biological processes. Historically this has perhaps been most evident in the use of toxic agents to interfere with specific reactions in the body and hence help to dissect out the mechanisms of metabolic processes. For example, the use of chemical inhibitors was very important in understanding the process of oxidative phosphorylation, or the tricarboxylic acid cycle. More recent examples are seen herein where toxicology interfaces with, for example structural biology in the study of the cytoskeletal components and their interactions. Indirectly, an understanding of the mechanisms of endogenous protective systems also improves knowledge of basic cell biology. Toxic insult and manipulation of cell signalling and control mechanisms in cell growth and differentation also highlight how important the discipline of cell toxicity has been and will continue to be a major contributor to our understanding of basic issues in the biological and biomedical sciences. This book offers selected reviews of some of the principal molecular mechanisms of cell toxicity.