Conformational Studies Of The Beta Amyloid Protein And In Vitro Models For The Effects Of Apolipoprotein E On Fibril Formation In Alzheimer S Disease
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Conformational Studies Of The Beta Amyloid Protein And In Vitro Models For The Effects Of Apolipoprotein E On Fibril Formation In Alzheimer S Disease
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Author : Krista Carole Evans
language : en
Publisher:
Release Date : 1996
Conformational Studies Of The Beta Amyloid Protein And In Vitro Models For The Effects Of Apolipoprotein E On Fibril Formation In Alzheimer S Disease written by Krista Carole Evans and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 1996 with categories.
Apolipoprotein E And Alzheimer S Disease
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Author : A.D. Roses
language : en
Publisher: Springer Science & Business Media
Release Date : 2012-12-06
Apolipoprotein E And Alzheimer S Disease written by A.D. Roses 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 2012-12-06 with Medical categories.
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.
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 : 2006-11-22
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 2006-11-22 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.
The Nature And Origin Of Amyloid Fibrils
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Author : Gregory R. Bock
language : en
Publisher: John Wiley & Sons
Release Date : 2008-04-30
The Nature And Origin Of Amyloid Fibrils written by Gregory R. Bock and has been published by John Wiley & Sons this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008-04-30 with Medical categories.
Amyloid fibrils are associated with a range of pathological disorders including Alzheimer's Disease, Down's syndrome, diabetes, cardiomyopathies, and transmissible spongiform encephalopathies. This volume is a comprehensive account of recent developments in the understanding of the process of amyloid fibrils. Contains up-to-date data on all of the clinical problems which, despite their pathological significance, are still largely unsolved.
Tau Oligomers
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Author : Jesus Avila
language : en
Publisher: Frontiers E-books
Release Date : 2014-08-18
Tau Oligomers written by Jesus Avila and has been published by Frontiers E-books this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014-08-18 with Medicine (General) categories.
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”.
Structural Studies Of Amyloid Fibril Polymorphism
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Author : Angela Binamira Soriaga
language : en
Publisher:
Release Date : 2013
Structural Studies Of Amyloid Fibril Polymorphism written by Angela Binamira Soriaga and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2013 with categories.
I began my research in the Eisenberg laboratory by studying the polymorphic nature of amyloid proteins Islet Amyloid Polypeptide (IAPP), a protein whose plaques are implicated in Type II Diabetes, and Amyloid-beta (Abeta), whose aggregates were implicated in Alzheimer's Disease. Both polypeptides are cleavage products of precursor proteins, are intrinsically disordered, and contain a highly amyloidogenic C-terminus. Later, I expanded the study of polymorphism to tumor suppressor protein p53, whose aggregation has recently been associated with tumor progression. The last part of my dissertation involves the studies on what may constitute the toxic species of amyloid, involving work with segments from alpha-B-crystallin, IAPP, and paralogs of 53. This dissertation begins with work on structural and kinetic characterization of IAPP using transmission electron microscopy (TEM) and thioflavin T dye-binding assays. Here, I worked under Jed Wiltzius, who had solved several crystal structures of segments of the polypeptide each of which formed in-register steric zippers. I aided in his studies by performing EM on several of the segments and confirmed they indeed formed fibrils in vitro. I also performed EM and kinetic assays on full-length mutant and wild-type human IAPP, providing evidence that IAPP is capable of forming two distinct fibril polymorphs originating from two different steric zipper spines. These results that illustrate the molecular basis for fibril polymorphism of IAPP suggests a mechanism of protein-only encoded information transfer of different prion strains. To further understand the polymorphic nature of amyloid proteins, I then focused on structural characterization of Abeta. To elucidate Abeta polymorphism in atomic detail, my colleagues Jacques-Philippe Colletier, Arthur Laganowsky, Meytal Landau and I determined eight new micro-crystal structures of fibril-forming segments of Abeta. These structures, all of various forms of steric zippers, reveal a variety of modes of self-association of Abeta. Combining these atomic structures with previous nuclear magnetic resonance and electron tomography studies, we propose several fiber models, offering molecular models that further illustrate the polydispersity of Abeta assemblies. These structures and molecular models contribute fundamental information for understanding Abeta polymorphic nature and pathogenesis. We furthermore suggest that steric zipper interactions are also the core of protafilaments binding together, explaining the immense heterogeneity in fibril morphologies as visualized under EM and various other characterization methods. Structural characterization of fibril formation was carried to a third protein, tumor suppressor p53. It had recently been suggested that amyloid aggregation of mutant p53 may account for its gain of toxic function in cancer cells. Working with Alice Soragni, we elucidated the atomic details of the spine of p53 fibrils by identifying the aggregation-prone region and crystallizing two overlapping segments within the region. I also characterized a third segment that appears to exhibit a different type of steric zipper packing than other two segments. Results show that this short region within p53 displays the amyloid fibril polymorphism exhibited by Abeta and IAPP. In addition, these structures provide the basis for structure-based design of inhibitors of p53 aggregation as a potential cancer therapeutic. A recent structure of a toxic amyloid oligomer, termed cylindrin, led me to also focus on a preliminary analysis of the mechanism of toxicity of this segment from alpha-B-crystallin. This was work done in collaboration with Arthur Laganowsky. I performed liposome disruption assays on the peptide, which suggests that the mechanism of toxicity of cylindrin may not be through membrane disruption. In addition, in collaboration with Professor Alex Van der Bliek, I attempted to transgenically express the peptide in C. elegans, as an in vivo model to examine toxicity. It appears cylindrin expression in C. elegans may induce slight toxicity, as it induces autophagosome accumulation and a slightly longer lifespan and larger brood size in the worms. Finally, motivated by the extreme difficulty in crystallizing segments of amyloid proteins longer than eight residues, I helped in developing a methodology that has the potential to improve the chances of crystallizing proteins whose structure has remained elusive. In collaboration with Arthur Laganowsky, Minglei Zhao and Professor Todd Yeates, we developed a new crystallization approach, termed metal-mediated synthetic symmetrization, that introduces pairs of histidine or cysteine mutations onto the surface of target proteins, and, upon coordination with metal, generates novel crystal lattice contacts or oligomeric assemblies, thus producing a variety of new crystal forms, and increasing the chances of growing diffraction-quality crystals. We examined the method on two model fusion proteins, T4 lysozyme (T4L) and maltose-binding protein (MBP), and the approach resulted in 16 new crystal structures displaying a variety of oligomeric assemblies and packing modes, representing new and distinct crystal forms for these proteins. The results suggest this method has potential utlility for crystallizing target proteins of unknown structure through either direct mutations on the target protein or fusion of the target protein to metal-site mutants of T4L or MBP, which could serve as crystallization chaperones. Current work involves exploring non-typical steric zipper interactions. I have recently solved 3 more crystal structures of various segments of IAPP, one of which forms an out-of-register steric zipper. I have also solved 2 more out-of-register zipper structures of segments within p63 and p73, both paralogs of p53 and suggested to co-aggregate with mutant p53. Analysis of these out-of-register structures show that there is no weak interface among the hydrogen bonding interactions, unlike other structures that have displayed out-of-register packing. Interestingly, cell viability assays showed that these peptides are not very toxic, suggesting the importance of these weak interfaces in amyloid toxicity. This work further confirms the polymorphic nature of amyloids. The results embodied in this dissertation have assisted in advancing our understanding of molecular basis for amyloid fibril polymorphism and provides a preliminary characterization of the potential toxic amyloid oligomer cylindrin. In addition, the new crystallization methodology described in this work has the potential to improve the chances of crystallizing longer amyloid segments and additional proteins of unknown structure. Greater comprehension of the structural details of amyloid proteins not only can shed light into amyloid-aggregation mechanisms, but can also offer insight into the mechanisms of toxicity and aid in the development of therapeutics that target amyloid fibrillization and block aggregation.
Amyloid Proteins
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Author : Einar M. Sigurdsson
language : en
Publisher: Springer Science & Business Media
Release Date : 2008-02-02
Amyloid Proteins written by Einar M. Sigurdsson 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 2008-02-02 with Science categories.
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.
Pathobiology Of Alzheimer S Disease
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Author :
language : en
Publisher: Elsevier
Release Date : 1995-10-17
Pathobiology Of Alzheimer S Disease written by and has been published by Elsevier this book supported file pdf, txt, epub, kindle and other format this book has been release on 1995-10-17 with Medical categories.
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
Amyloid Fibril Formation In Alzheimer S Disease
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Author : Joseph Timothy Jarrett
language : en
Publisher:
Release Date : 1993
Amyloid Fibril Formation In Alzheimer S Disease written by Joseph Timothy Jarrett and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 1993 with Alzheimer's disease categories.
Amyloid diseases are characterized by the presence of highly insoluble protein deposits in specific tissues or throughout the body. The amyloid protein in Alzheimer's disease is the beta protein, a ca 4 kDa protein which derives from a 110-135 kDa precursor protein. The beta protein is produced as an excreted protein in cell culture, and has been detected in the CSF and blood of healthy individuals. AD amyloid contains several variants of this protein, differing at their N- and C-termini. The variants differing at the C-terminus have been reported to have different properties: beta1-39 and beta1-40 are more soluble than beta1-42 and beta1-43. We have studied peptides derived from a bacterial protein which are similar to the C-terminus of the beta protein, and have shown that amyloid fibril formation is a nucleation-dependent assembly process. The kinetics are characterized by a lag phase, during which the peptide is apparently soluble, followed by a growth phase, during which fibrils are rapidly formed. Seeding with fragmented fibrils results in new fibril formation, bypassing the rate-limiting nucleation step. Fibril formation requires highly specific hydrophobic interactions, as demonstrated by the sequence specificity of seeding. In peptides which model the C-terminus of the beta protein, the longer variants beta26-43 and beta26-42 form fibrils immediately while the shorter variants beta26-40 and beta26-39 have lag times of hours to days before fibril formation occurs. Addition of fibrils derived from any of the beta proteins results in seeding of the slower nucleating variants. We have also studied the affect of the C-terminus on the structure. Using 13C labeled peptides and solid-state NMR, we have shown that beta26-40 and beta26-43 have a cis amide between Gly37 and Gly38. Using isotope-edited FTIR, we show that there is considerable structural variation between beta26-40 and beta26-43 in the vicinity of this cis amide. Beta26-43 appears highly ordered while the slower nucleating beta26-40 appears disordered. Finally we show that hydrophobic effects in solution may stabilize the cis amide, and this may play a critical role in the mechanism of amyloid formation.
Protein Misfolding Aggregation And Conformational Diseases
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Author : Vladimir N. Uversky
language : en
Publisher: Springer Science & Business Media
Release Date : 2007-05-26
Protein Misfolding Aggregation And Conformational Diseases written by Vladimir N. Uversky 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 2007-05-26 with Medical categories.
The second volume continues to fill the gap in protein review and protocol literature. It does this while summarizing recent achievements in the understanding of the relationships between protein misfoldings, aggregation, and development of protein deposition disorders. The focus of Part B is the molecular basis of differential disorders.