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Intracellular Consequences of Amyloid in Alzheimer's Disease

Intracellular Consequences of Amyloid in Alzheimer's Disease
A Book

by Michael R. D'Andrea

  • Publisher : Academic Press
  • Release : 2016-02-21
  • Pages : 220
  • ISBN : 012804330X
  • Language : En, Es, Fr & De
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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]
Implications for the Development of Early Alzheimer's Disease

by Lindsay Welikovitch

  • Publisher : Unknown Publisher
  • Release : 2021
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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"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
A Book

by Abraham Seung Chul Chyung

  • Publisher : Unknown Publisher
  • Release : 2000
  • Pages : 153
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Investigating the Effects of the Alzheimer's Disease-associated Amyloid Β-peptide on Intracellular Calcium Homeostasis

Investigating the Effects of the Alzheimer's Disease-associated Amyloid Β-peptide on Intracellular Calcium Homeostasis
A Book

by L. E. Allan

  • Publisher : Unknown Publisher
  • Release : 2010
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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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
A Book

by L. E. Allan

  • Publisher : Unknown Publisher
  • Release : 2010
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Intracellular Traffic and Neurodegenerative Disorders

Intracellular Traffic and Neurodegenerative Disorders
A Book

by Peter H. St.George-Hyslop,William C. Mobley

  • Publisher : Springer Science & Business Media
  • Release : 2009-02-03
  • Pages : 184
  • ISBN : 3540879412
  • Language : En, Es, Fr & De
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Many adult onset neurodegenerative diseases arise from the accumulation of misfolded peptides. This book examines the role sub-cellular trafficking pathways play in the pathological accumulation of these misfolded proteins and in attempts to clear them.

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

Uncovering a New Model of Intracellular Processing of the Amyloid Precursor Protein
Towards a Test of the Amyloid Hypothesis

by Daniel M. Skovronsky

  • Publisher : Unknown Publisher
  • Release : 2000
  • Pages : 167
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Research Progress in Alzheimer's Disease and Dementia

Research Progress in Alzheimer's Disease and Dementia
A Book

by Miao-Kun Sun

  • Publisher : Nova Publishers
  • Release : 2007
  • Pages : 438
  • ISBN : 9781600219603
  • Language : En, Es, Fr & De
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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.

Neuroprotective Signal Transduction

Neuroprotective Signal Transduction
A Book

by Mark P. Mattson

  • Publisher : Springer Science & Business Media
  • Release : 1997-10-10
  • Pages : 347
  • ISBN : 1592594751
  • Language : En, Es, Fr & De
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In Neuroprotective Signal Transduction prominent researchers and clinicians focus on how inter- and intracellular signaling mechanisms prevent the degeneration and death of neurons occurring in both acute and chronic neurodegenerative disorders. Authoritative contributions dissect the signaling pathways of an array of neuroprotective factors-ranging from neurotrophins (NGF, BDNF, NT-3, and NT-4/5), to growth factors (bFGF, IGF-1, GDNF), to cytokines (TNF, IL-1b, and TGFb), to secreted amyloid precursor proteins, to protease nexin-1. Also treated are cytoprotective signaling events that occur within injured neurons independently of intercellular signals. Neuroprotective Signal Transduction presents fundamental, cutting-edge treatment of the cellular and molecular signal transduction pathways found in human neurodegenerative conditions. The book's elucidation of the molecular cascades evolved by the nervous system to protect itself is now lead to effective strategies for preventing neuronal degeneration in such conditions as stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and will form the basis for powerful new drug discovery and gene therapy strategies.

Molecular Biology of Alzheimer's Disease

Molecular Biology of Alzheimer's Disease
Genes and Mechanisms Involved in Amyloid Generation

by Christian Haass

  • Publisher : CRC Press
  • Release : 2003-09-02
  • Pages : 330
  • ISBN : 020330361X
  • Language : En, Es, Fr & De
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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.

Structure, Aggregation, and Inhibition of Alzheimer's [Beta]-amyloid Peptide (A[Beta])

Structure, Aggregation, and Inhibition of Alzheimer's [Beta]-amyloid Peptide (A[Beta])
A Book

by Qiuming Wang

  • Publisher : Unknown Publisher
  • Release : 2013
  • Pages : 193
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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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.

Developing Therapeutics for Alzheimer's Disease

Developing Therapeutics for Alzheimer's Disease
Progress and Challenges

by Michael S. Wolfe

  • Publisher : Academic Press
  • Release : 2016-05-27
  • Pages : 676
  • ISBN : 0128021640
  • Language : En, Es, Fr & De
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Developing Therapeutics for Alzheimer's Disease: Progress and Challenges provides a thorough overview of the latest advances toward the development of therapeutics for Alzheimer’s disease, along with the major hurdles that still must be overcome and potential solutions to these problems. Despite the lack of progress toward developing therapeutics that can slow or stop the progression of this disease, important discoveries have been made and many promising approaches are advancing in preclinical studies and clinical trials. This book outlines the special challenges related to specific targets and approaches, while presenting a realistic, comprehensive and balanced view of drug discovery and development in this area. Written by international leaders in the field, the book assesses prospects for the emergence of effective agents and allows readers to better understand the challenges, failures, and future potential for research in Alzheimer’s disease. This book is a valuable resource to academic scientists carrying out translational research in Alzheimer’s disease, industrial scientists engaged in Alzheimer's drug discovery, executives in biopharmaceutical companies making strategic decisions regarding the direction of internal research and potential outside partnerships, and graduate-level students pursuing courses on Alzheimer's therapeutics. Provides a realistic but promising assessment of the potential of various therapeutic approaches to Alzheimer’s disease Focuses primarily on neuroprotective agents and cognitive enhancers, as well as approaches to targeting the amyloid B-peptide, tau and Apolipoprotein E Discusses alternative approaches, preclinical and clinical development issues, related biomarkers and diagnostics, and prevention and nonpharmacological approaches

New Intracellular Mechanisms Involved in Alzheimer's Disease and Frontotemporal Dementia

New Intracellular Mechanisms Involved in Alzheimer's Disease and Frontotemporal Dementia
A Book

by Eva Borger,Frank Gunn-Moore,University of St. Andrews. School of Biology

  • Publisher : Unknown Publisher
  • Release : 2012
  • Pages : 322
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Dementia causes an increasing social and economic burden worldwide, demanding action regarding its diagnosis, treatment and everyday management. Recent years have seen many advances in neurodegeneration research, but the search for new truly disease modifying therapies for Alzheimer's disease (AD) and frontotemporal dementia (FTD) has so far not been successful. This is mainly due to a lack of understanding of the precise intracellular events that lead up to neuronal dysfunction in early and in late stages of the disease. This thesis describes the approaches taken to extend the current knowledge about the intracellular effects of neuronal amyloid-beta and the signalling pathways causing neuronal death or disturbed synaptic function in dementia. Endophilin-1(Ep-1), amyloid-binding alcohol dehydrogenase (ABAD), peroxiredoxin-2 (Prx-2) and the EF-hand domain family, member D2 (EFHD2) have been found to be elevated in the human brain with dementia and in mouse models for frontotemporal lobar degeneration (FTLD) or AD. The expression of these proteins as well as the expression of c-Jun N-terminal kinase (JNK), c-Jun and APP were analysed by western blotting and real-time PCR in human brains affected by AD or FTLD as well as in mouse models for AD. This provided a new insight into the regulation of these proteins in relation to each other in the ageing brain and uncovered a new potential link between elevated levels of EFHD2, Prx-2 and APP in FTLD. By studying the effects of the overexpression of Ep-1 in neurons, this research has led to a better understanding of its role in JNK-activation. It furthermore verified a protective role for Prx-2 against neurotoxicity and pointed towards a new function for Prx-2 in the regulation of JNK-signalling. The analysis of the effect of increased levels of EFHD2 uncovered for the first time its involvement in the PI3K-signalling cascade in neuronal cells. The current work has therefore contributed to the knowledge about the cellular processes that are affected by Ep-1, Prx-2 and EFHD2 in different types of dementia and will greatly benefit future research into their actions in the neuronal network.

Alzheimer's Disease: Cellular and Molecular Aspects of Amyloid beta

Alzheimer's Disease: Cellular and Molecular Aspects of Amyloid beta
A Book

by J. Robin Harris,Falk Fahrenholz

  • Publisher : Springer Science & Business Media
  • Release : 2006-11-22
  • Pages : 409
  • ISBN : 0387232265
  • Language : En, Es, Fr & De
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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.

Amyloid-? and lysozyme proteotoxicity in Drosophila

Amyloid-? and lysozyme proteotoxicity in Drosophila
Beneficial effects of lysozyme and serum amyloid P component in models of Alzheimer’s disease and lysozyme amyloidosis

by Liza Bergkvist

  • Publisher : Linköping University Electronic Press
  • Release : 2017-05-16
  • Pages : 91
  • ISBN : 9176855066
  • Language : En, Es, Fr & De
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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.

Alzheimer's Disease

Alzheimer's Disease
Advances for a New Century

by George Perry

  • Publisher : IOS Press
  • Release : 2013
  • Pages : 474
  • ISBN : 1614991537
  • Language : En, Es, Fr & De
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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

Murine Embryonal Carcinoma (P19) Cells as a Model System to Explore the Biology of the Amyloid Precursor Protein

Murine Embryonal Carcinoma (P19) Cells as a Model System to Explore the Biology of the Amyloid Precursor Protein
A Book

by Anonim

  • Publisher : Unknown Publisher
  • Release : 1999
  • Pages : 129
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Dependence of Synaptic Plasticity and Memory Facilitation Upon Amyloid Precusor Protein Intracellular Domain

Dependence of Synaptic Plasticity and Memory Facilitation Upon Amyloid Precusor Protein Intracellular Domain
A Book

by Huifang Ma

  • Publisher : Unknown Publisher
  • Release : 2006
  • Pages : 362
  • ISBN : 9876543210XXX
  • Language : En, Es, Fr & De
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Preclinical and clinical issues in Alzheimer’s disease drug research and development

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

by Cesare Mancuso,Silvana Gaetani

  • Publisher : Frontiers Media SA
  • Release : 2015-03-03
  • Pages : 129
  • ISBN : 2889194337
  • Language : En, Es, Fr & De
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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.

Molecular and Cellular Mechanisms of Neuronal Plasticity

Molecular and Cellular Mechanisms of Neuronal Plasticity
Basic and Clinical Implications

by Yigal H. Ehrlich

  • Publisher : Springer Science & Business Media
  • Release : 2012-12-06
  • Pages : 229
  • ISBN : 1461548691
  • Language : En, Es, Fr & De
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Numerous studies have proven the biological basis of memory formation and have begun to identify the biochemical traces and cellular circuits that are formed by experience, and which participate int the storage of information in the brain, its retention for long durations, and its retrieval upon demand. Cells in the nervous system have the capability of undergoing extremely long-lasting alterations in response to hormonal, pharmacological, and environmental stimulations. The mechanisms underlying this neuronal plasticity are activated by experiential inputs and operate in the process of learning and the formation of memories in the brain. This volume presents research areas which have not been highlighted in the past. In addition to studies on the involement of functional proteins in neuronal adaptation, this volume presents recent developments on the critical roles of bioactive lipids and nucleotides in these processes. In addition to the widely studied role of second messengers, a review of studies on extracellular phosphorylation systems operating on the surface of brain neurons is presented.The first section of the volume presents studies of basic mechanisms operating in a wide range of adaptive processes. The second section presents recent advances in investigations that have demonstrated the clinical implications of this research. These include: state of the art use of transgenic models in studies of molecular and cellular mechanisms implicated in familial Alzheimer's disease and Amyotrophic Lateral Sclerosis; studies of specific proteins implicated in Alzheimer's disease, including an adapter that binds to the beta-amyloid precurser protein (beta-APP) and the microtubular protein Tau and its membrane-bound counterpart. The advantages of using cell culture models for elucidating the causes of neuronal degeneration and for identifying mechanisms of neuroprotection are also presented among the chapters in the section on clinical implications.