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Intracellular Consequences Of Amyloid In Alzheimers Disease

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Intracellular Consequences of Amyloid in Alzheimer s Disease

Intracellular Consequences of Amyloid in Alzheimer s Disease Book
Author : Michael R. D'Andrea
Publisher : Academic Press
Release : 2016-02-21
ISBN : 012804330X
Language : En, Es, Fr & De

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Book Description :

Consequences of Intracellular Amyloid in Alzheimer’s Disease addresses one of the more currently unresolved aspects confounding Alzheimer’s research, the significance of intraneuronal amyloid. It seeks to explain some of the unresolved questions concerning intracellular amyloid and its origin, entry, and toxicity. Following up on Dr. D’Andrea’s first book, Bursting Neurons and Fading Memories: An Alternative Hypothesis for the Pathogenesis of Alzheimer’s Disease, this book further examines the Inside-Out or Bursting alternative hypothesis of how amyloid escapes the circulatory system to ultimately enter neurons, also examining whether there is a relationship between intracellular amyloid, amyloid plaques, and cognitive impairment. Through a comprehensive explanation of the currently relevant scientific research on intracellular amyloid compiled in this handy reference, readers will better understand the mechanisms that lead to neuron death. Presents the latest research on the significance of intracellular amyloid as it relates to Alzheimer’s Addresses crucial questions about intracellular amyloid, including how if forms and enters neurons, its toxicity, if it triggers cell death, and how amyloid plaques are formed Examines the potential relationship between intracellular amyloid, plaques, and cognitive impairment in an effort to answer whether Alzheimer’s is initially a problem of amyloid, the neuron, or of the blood-brain barrier Seeks to help researchers generate additional alternative therapeutic opportunities to cure Alzheimer’s

The Neuron inflammatory Effects of Intracellular A beta

The Neuron inflammatory Effects of Intracellular A beta  Book
Author : Lindsay Welikovitch
Publisher : Unknown
Release : 2021
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

"AbstractDespite being the most common cause of dementia worldwide, there are still no available drugs to prevent or cure Alzheimer’s disease (AD). In addition to the deposition of amyloid-[beta] (A[beta]) plaques and tau neurofibrillary tangles (NFT) as hallmark brain lesions, the AD neuropathology comprises a significant immunological component. That inflammation is likely a contributory factor in the AD pathogenesis is evidenced by the fact that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) in cognitively healthy adults protects against disease development. It is widely presumed that dense amyloid plaques and accumulating cellular debris represent the primary inflammatory stimuli within the AD brain. However, inflammation is frequently observed in AD transgenic animal models devoid of plaques and cell death. Since the basis of this early inflammatory reaction remains unexplored, investigations characterizing these preclinical AD immune processes may reveal promising therapeutic targets for early disease intervention. Chapter 1 of this Thesis serves as a review of the fundamental characteristics of the AD neuropathology and an evaluation of the current status of the field at large. While low molecular weight soluble oligomers are the most potent amyloid species within the brain, several technical limitations have historically prevented direct inspection of the soluble amyloid pool within the human brain; thus, it is unclear exactly how it evolves before overt plaque deposits become apparent. Using exquisitely preserved post-mortem human brain material, in Chapter 2, we demonstrate that soluble amyloid peptides and oligomers accumulate within the intraneuronal compartment in brain areas that are most vulnerable to early pathology and degeneration. Our findings implicate the buildup of intraneuronal A[beta] as a potential pathogenic factor in AD, instigating cellular damage from the ‘inside-out’. Chapter 3 describes the neuroinflammatory effects of this same iA[beta] pool within a transgenic rat model of the AD-like amyloid pathology, as well as human brain. Given that inflammation is a major determinant in driving disease progression, we asked how iA[beta] might provoke a plaque-independent neuroinflammatory environment. By analyzing neuron-specific inflammatory gene and protein expression, we discovered that neurons burdened with increasing levels of soluble A[beta] engage in well-known inflammatory signaling cascades and are associated with responsive microglial cells. Together, our findings reveal the neuron as an understated suspect in triggering harmful neuroinflammation during early stages of disease. Finally, in Chapter 4, we will review the known biological mechanisms that mediate iA[beta]-toxicity and consider how they might trigger a neuronal inflammatory reaction. By discussing the processes underlying complex neuroglial interactions during health and disease, we will examine how they may similarly contribute to the development and progression of neural deficits during early AD. And lastly, we will reconcile certain aspects of the disputed amyloid cascade hypothesis with a novel ‘plaque-independent’ amyloid hypothesis, while proposing novel therapeutic avenues for combatting disease onset"--

Intracellular Amyloid Precursor Protein Processing in NT2N Cells

Intracellular Amyloid Precursor Protein Processing in NT2N Cells Book
Author : Abraham Seung Chul Chyung
Publisher : Unknown
Release : 2000
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Download Intracellular Amyloid Precursor Protein Processing in NT2N Cells book written by Abraham Seung Chul Chyung, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.

Investigating the Effects of the Alzheimer s Disease associated Amyloid peptide on Intracellular Calcium Homeostasis

Investigating the Effects of the Alzheimer s Disease associated Amyloid    peptide on Intracellular Calcium Homeostasis Book
Author : L. E. Allan
Publisher : Unknown
Release : 2010
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Download Investigating the Effects of the Alzheimer s Disease associated Amyloid peptide on Intracellular Calcium Homeostasis book written by L. E. Allan, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.

Investigating the Effects of the Alzheimer s Disease associated Amyloid beta peptide on Intracellular Calcium Homeostasis

Investigating the Effects of the Alzheimer s Disease associated Amyloid  beta  peptide on Intracellular Calcium Homeostasis Book
Author : L. E. Allan
Publisher : Unknown
Release : 2010
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Download Investigating the Effects of the Alzheimer s Disease associated Amyloid beta peptide on Intracellular Calcium Homeostasis book written by L. E. Allan, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.

Mechanistic Studies of the Amyloid Precursor Protein Intracellular Domain AICD with Implications for Alzheimer s Disease

Mechanistic Studies of the Amyloid Precursor Protein Intracellular Domain  AICD  with Implications for Alzheimer s Disease Book
Author : Caroline Beckett
Publisher : Unknown
Release : 2013
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Download Mechanistic Studies of the Amyloid Precursor Protein Intracellular Domain AICD with Implications for Alzheimer s Disease book written by Caroline Beckett, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.

Research Progress in Alzheimer s Disease and Dementia

Research Progress in Alzheimer s Disease and Dementia Book
Author : Miao-Kun Sun
Publisher : Nova Publishers
Release : 2007
ISBN : 9781600219603
Language : En, Es, Fr & De

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Book Description :

Alzheimer's disease (AD), the most common form of neurodegenerative disorder in the elderly, is characterised pathologically by extracellular amyloid plaques and intracellular neurofibrillary tangles, pathophysiologically by synaptic dysfunction, and clinically by a progressive decline in cognition. Currently, AD has no cure and its prevalence is predicted to triple by 2050 with the rapid increase in the ageing population, unless more effective treatments are developed. Since the publication of the second book volume, the rapid progress in the research fields of AD and dementia continues through the intensive efforts of research scientists worldwide. This third book volume contains 15 chapters, bringing together a presentation of research frontiers in current AD/dementia research. The topics include molecular genetics of AD, gene expression abnormalities in AD progression, presenilins, taupathy in AD, single -induced(neuron gene expression abnormalities in AD, intracellular A neurodegeneration, roles of lipoprotein receptors in AD onset and progression, cholesterol and tau hyperphosphorylation, AD diagnostics and therapeutic strategies, in vivo visualisation of amyloid-like structures, cathepsin B, antiamyloidogenesis and neuroprotection, environmental enrichment, Fragile X mental retardation gene and dementia, category learning in Parkinson's disease, cerebrovascular disease and dementia, and dementia and hypertension. These chapters cover current advances in our understanding of the pathogenic mechanisms underlying AD and dementia, in the diagnosis of early AD and dementia, and in the development of therapeutic agents that target memory-relevant AD pathogenesis. The book will be highly valuable to students and scientists worldwide who are interested in the scientific research progress in AD and dementia.

Alzheimer s Disease Cellular and Molecular Aspects of Amyloid beta

Alzheimer s Disease  Cellular and Molecular Aspects of Amyloid beta Book
Author : J. Robin Harris,Falk Fahrenholz
Publisher : Springer Science & Business Media
Release : 2006-11-22
ISBN : 0387232265
Language : En, Es, Fr & De

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Book Description :

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.

Abeta Peptide and Alzheimer s Disease

Abeta Peptide and Alzheimer s Disease Book
Author : Colin J. Barrow,David H. Small
Publisher : Springer Science & Business Media
Release : 2006-12-22
ISBN : 1846284406
Language : En, Es, Fr & De

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Book Description :

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.

Amyloid and lysozyme proteotoxicity in Drosophila

Amyloid   and lysozyme proteotoxicity in Drosophila Book
Author : Liza Bergkvist
Publisher : Linköping University Electronic Press
Release : 2017-05-16
ISBN : 9176855066
Language : En, Es, Fr & De

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Book Description :

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-? (A?) peptide, a small peptide of around 42 amino acids which is cleaved from the larger, membrane-bound, protein A?PP by two different enzymes, BACE1 and ?-secretase. In the first part of this thesis, two different fly models for Alzheimer’s disease were used: the A? fly model, which directly expresses the A? peptide, and the A?PP-BACE1 fly model, in which all the components necessary to produce the A? 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 A? peptide is needed to achieve the same, or an even greater, toxic effect in the A?PP-BACE1 model compared to the A? 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 A? generated in the fly models. And indeed, lysozyme is able to save the flies from A?-induced toxicity. A? 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) A? generated from A?PP processing in the fly CNS results in higher proteotoxicity compared with direct expression of A? from the transgene, ii) lysozyme can prevent A? 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.

Investigation of the intercellular transmission of synuclein amyloid and TDP 43

Investigation of the intercellular transmission of   synuclein  amyloid   and TDP 43 Book
Author : Christopher Sackmann
Publisher : Linköping University Electronic Press
Release : 2019-10-14
ISBN : 917519015X
Language : En, Es, Fr & De

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Book Description :

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are disorders characterized by the progressive deposition of proteinaceous inclusions throughout the brain in a predictable manner. Each disease is described by the involvement of different misfolded and aggregated proteins (AD, amyloid-? and tau; PD, ?-synuclein; ALS and FTLD, TDP-43) that spread between anatomically connected brain regions, causing cell death in previously healthy regions. Disease progresses as these aggregated proteins spread throughout the brain in a prion-like fashion. Oligomeric forms of these proteins (aggregates comprising of ?3-30 individual proteins) are thought to be the most relevant to disease, as they are capable of prion-like propagation and can cause cellular toxicity. The work in this thesis aims to elucidate the mechanisms by which different neurodegenerative disease related proteins (amyloid-?, ?-synuclein and TDP-43) are taken up and transferred between cells, and the effects exerted by these proteins on downstream cells. Paper I examined the uptake and cell to cell transmission of oligomeric ?-synuclein (?-syn). Using a 3D co-culture model, we determined that ?-syn (monomeric, oligomeric and fibrillar assemblies) were readily taken up and transferred between neuron-like cells, and that this transfer was mediated by an endosomal/lysosomal mechanism. It was also determined that larger ?-syn assemblies (oligomers and fibrils) were found in donor and acceptor cells more frequently than monomeric ?-syn, which we speculate is a due to the larger aggregates’ resistance to cellular proteases. In Paper II, we identified a novel mechanism for the uptake of oligomeric proteins, in the discovery that the gap junction channel protein connexin 32 mediates the uptake of ?-syn oligomers in a preferential manner. Gap junction proteins act as a means of communication between adjacent cells, forming a transmembrane pore to facilitate the passage of small molecules. Here, we determined that connexin 32 drives the preferential uptake of oligomeric ?-syn relative to monomeric and fibrillar ?-syn. This system was not exclusive to ?-syn however, as the preferential uptake of oligomeric amyloid-? (A?) was also observed. In addition to the uptake of oligomers, we observed that increased ?-syn expression elicited the increased expression of connexin 32, in a positive feedback mechanism. When connexin 32 was inhibited pharmacologically or knocked out using CRISPR/Cas9, the preferential uptake of oligomers was abolished. These phenomena were also observed in oligodendrocytes (the accumulation of oligomeric ?-syn in oligodendrocytes is a hallmark of Multiple Systems Atrophy), three different mouse models of ?-syn overexpression, as well as in post-mortem human tissues. Paper III undertook the investigation of cell to cell transfer of TDP-43. Although it was recently confirmed that TDP-43 propagates throughout the brain in a prion-like fashion, it remains unclear how post-translational modifications of TDP-43 affect its propensity to be transferred between cells. This leaves a gap in the understanding of how TDP-43 proteinopathies progress, as post-translationally modified TDP-43 is understood to be critical to pathogenesis. To study this, we generated several TDP-43 cell lines, expressing full-length TDP-43 or C-/N-terminally truncated fragments, known contributors to TDP-43 proteinopathies. Using the 3D co-culture model, we determined that preservation of the N-terminus of TDP-43 enhanced its ability to transmit between cells, whereas an intact the C-terminus reduced transfer. Additionally, since we have previously shown that both oligomeric A? and ?-syn are incorporated into extracellular vesicles (EVs) such as exosomes, and that these EVs can sufficiently mediate the transfer of protein oligomers to downstream cells, we investigated whether this was also true for TDP-43. We demonstrated that full-length TDP-43 and TDP-43 fragments could be found within EVs generated by these cells, but that these EVs were unable to propagate the protein to downstream cells. Instead, the transmission of TDP-43 occurs in a manner dependent upon physical proximity between cells, possibly across the synaptic cleft itself. Next, we studied the acute effects exerted by oligomeric A? upon healthy neurons in order to understand the earliest effects of oligomeric A? challenge. In Paper IV, we used iPSC-derived neurons generated from human donors expressing different amyloid-? precursor protein (APP) genes, one harbouring the familial AD-causing V717I London mutation, the other expressing WT APP. After differentiating these cells into functional neurons in vitro, the neurons were challenged with acute exposure to exogenous oligomeric A? and analyzed by LC-MS/MS to observe the early effects. By analyzing the proteome and phosphoproteome of these cells, we identified many proteins and phosphoproteins that were up- or down-regulated in response to oligomeric A? at this early timepoint. Among these changes, oligomeric A? caused the downregulation of TDP-43, heterogeneous nuclear ribonucleoproteins, and coatomer complex I proteins. Conversely, increases were observed in 20S proteasome subunits and vesicle associated proteins VAMP1/2. We also observed the differential phosphorylation of tau at serine 208, indicating that phosphorylation at this residue might be an important early event in tauopathy. Altogether, the work described in this thesis has provided new understanding as to how different neurodegenerative disease related proteins are taken up and transferred between cells. In doing so, we have identified some of the mechanisms by which this spreading occurs, and that the changes elicited by these toxic oligomeric proteins are rapid and widespread. By learning about these processes, we have identified novel targets that could be used in the development of disease modifying therapeutics.

Uncovering a New Model of Intracellular Processing of the Amyloid Precursor Protein

Uncovering a New Model of Intracellular Processing of the Amyloid Precursor Protein Book
Author : Daniel M. Skovronsky
Publisher : Unknown
Release : 2000
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Download Uncovering a New Model of Intracellular Processing of the Amyloid Precursor Protein book written by Daniel M. Skovronsky, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.

Amyloid beta clearance in Alzheimer s disease

Amyloid beta clearance in Alzheimer   s disease Book
Author : Robert Marr,Eliezer Masliah
Publisher : Frontiers Media SA
Release : 2015-03-24
ISBN : 2889194434
Language : En, Es, Fr & De

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Book Description :

Strong evidence continues to accumulate indicating that amyloid-beta (Aß) is a central part of Alzheimer’s disease (AD) pathogenesis in spite of the negative evidence coming from failed clinical trials. Therefore, mechanisms of clearance of Aß are of great interest in understanding AD pathogenesis and the development of effective treatments. This topic focuses on the issues related to Aß clearance in AD. The topics covered include proteases that degrade Aß and their localization, regulation, and functions. This topic also covers issues related to clearance through uptake by glia and through low-density lipoprotein (LDL) receptor mediated mechanisms. Signal transduction related to AD pathology and clearance is also addressed. Finally, immunotherapy and other novel therapeutic approaches are discussed.

Neurobiology of Alzheimer s Disease

Neurobiology of Alzheimer s Disease Book
Author : David Dawbarn,Shelley J. Allen
Publisher : Oxford University Press, USA
Release : 2007
ISBN : 9780198566618
Language : En, Es, Fr & De

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Book Description :

Alzheimer's disease is the most common form of dementia in the elderly; 450,000 people in the UK and 4.5 million people in the USA suffer with this disease. This 3rd edition of Neurobiology of Alzheimer's Disease gives a comprehensive and readable introduction to the disease, from molecular pathology to clinical practice. The book is intended for readers new to the field, and it also covers an extensive range of themes for those with in-depth knowledge of Alzheimer's disease. It will therefore act either as an introduction to the whole field of neurodegeneration or it will help experienced researchers to access the latest research in specialist topics. Each chapter is written by eminent scientists leading their fields in neuropathology, clinical practice and molecular neurobiology; appendices detail disease-associate proteins, their sequences, familial mutations and known structures. It will be essential reading for students interested in neurodegeneration and for researchers and clinicians, giving a coherent and cohesive approach to the whole area of research, and allowing access at different levels. For those in the pharmaceutical industry it describes the underlying molecular mechanisms involved in the pathogenesis of Alzheimer's disease and explains how current and potential therapeutics may work.

Molecular Biology of Alzheimer s Disease

Molecular Biology of Alzheimer s Disease Book
Author : Christian Haass
Publisher : CRC Press
Release : 2003-09-02
ISBN : 020330361X
Language : En, Es, Fr & De

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Book Description :

Highlighting the latest and the most timely aspects of Alzheimer's disease research, this text will enable scientists in related research fields, as well as physicians working with Alzheimer's disease patients, to obtain a quick and complete overview of the current state of the art in one of the most exciting fields in neuroscience research. Leading scientists have contributed articles focusing on key developments in this field. This includes an overview about the pathology, the genetics of familial Alzheimer's disease, proteolytic generation and aggregation of amyloid -peptide, presenilins, risk factors such as ApoE, and transgenic animal models. Some of the latest developments in Alzheimer's disease research, including the effect of presenilin knock outs on amyloid -peptide generation, are also included.

Preclinical and clinical issues in Alzheimer s disease drug research and development

Preclinical and clinical issues in Alzheimer   s disease drug research and development Book
Author : Cesare Mancuso,Silvana Gaetani
Publisher : Frontiers Media SA
Release : 2015-03-03
ISBN : 2889194337
Language : En, Es, Fr & De

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Book Description :

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive dysfunction and memory loss, inability to perform the activities of daily living and mood disorders. According to the so-called “amyloid cascade hypothesis”, amyloid-ß- peptide (Aß), produced by beta- and gamma- secretase-mediated cleavages of the amyloid precursor protein (APP), plays a pivotal role in the pathogenesis of AD. Aß was also shown to contribute to AD pathology by stimulating the hyperphosphorylation of tau which is responsible for the formation of neurofibrillary tangles. However, the “amyloid cascade hypothesis” was challenged by other theories which lend support to the idea that Aß is not causative but can be considered as an “innocent bystander” in AD. Although preclinical research generated impressive lines of evidence about the several intracellular mechanism(s) whose impairment leads to the onset and progression of AD, clinical research aimed at the development of new drugs capable of preventing or delaying the onset of neuronal damage in AD patients has produced limited results. The drugs currently available for the treatment of AD are acetylcholinesterase inhibitors (AChEI) and the NMDA glutamate receptor antagonist memantine. The AChEI increase acetylcholine levels in the synaptic cleft, which are reduced because of the progressive damage of cholinergic neurons in cognitive brain areas (e.g. amygdala, hippocampus, and frontal cortex), whereas memantine is used to prevent/reduce calcium-dependent excitotoxic neuronal cell death. Both classes of drugs have been shown to improve symptoms related to cognitive decline, but their effects are confined largely to patients with mild to moderate AD, in particular during the first year or so of treatment. An alternative to this symptomatic treatments involves the use of drugs that intervene in the pathogenesis of the disease. Recently, monoclonal antibodies against Aß were proposed as novel agents capable to remove Aß from the brain thus preventing neuronal damage. The research topic focuses on the preclinical and clinical evidence about the several factors that contribute to the pathogenesis of AD as well as the potential therapeutic role of new classes of drugs still under preclinical or clinical development.

Alzheimer s Disease

Alzheimer s Disease Book
Author : Sangram S. Sisodia,Rudolph E. Tanzi
Publisher : Springer Science & Business Media
Release : 2007-02-16
ISBN : 0387351353
Language : En, Es, Fr & De

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Book Description :

This book examines every major aspect of Alzheimer disease at a time when there has been no scholarly research volume on the subject published in the last 3-5 years. This edition includes expanded coverage of the cellular-level exploration of related dementing disorders, with in-depth presentation of prion diseases, Pick's disease, fronto-temporal disorders, transgenic models, and biochemistry of presenilins.

Structure Aggregation and Inhibition of Alzheimer s Beta amyloid Peptide A Beta

Structure  Aggregation  and Inhibition of Alzheimer s  Beta  amyloid Peptide  A Beta   Book
Author : Qiuming Wang
Publisher : Unknown
Release : 2013
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

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.

Effects of Intra Or Extracellular Amyloid beta on Tau Pathology in Transgenic Mice Modelling Alzheimer s Disease

Effects of Intra  Or Extracellular Amyloid  beta  on Tau Pathology in Transgenic Mice Modelling Alzheimer s Disease Book
Author : Sandro Ernst
Publisher : Unknown
Release : 2015
ISBN : 0987650XXX
Language : En, Es, Fr & De

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Book Description :

Download Effects of Intra Or Extracellular Amyloid beta on Tau Pathology in Transgenic Mice Modelling Alzheimer s Disease book written by Sandro Ernst, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.

Alzheimer s Disease

Alzheimer s Disease Book
Author : George Perry
Publisher : IOS Press
Release : 2013
ISBN : 1614991537
Language : En, Es, Fr & De

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Book Description :

This volume is a companion to the highly successful book published in association with the Journal of Alzheimers Disease JAD on the centennial of Alzheimers discovery Alzheimers Disease A Century of Scientific and Clinical Research. Instead of looking back, this collection, Alzheimers Disease Advances for a New Century, will look forward. Using scientometric analysis the most promising developments since the Alzheimer Centennial in 2006 have been substantiated. While prior trends and advances in genetics, amyloid-, tau, neuropathology, and oxidative stress continue as active areas, emergent areas impacting the transition