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BIOLOGY OF ALZHEIMER AMYLOID IN NEURONS

神经元中阿尔茨海默病淀粉样蛋白的生物学

基本信息

批准号：
7894691
负责人：
GUNNAR K GOURAS
金额：
$ 10.65万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894691
关键词：
Aging Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloidosis Axon Biological Biology Brain Cell membrane Cell physiology Data Development Disease Distal Electron Microscopy Endocytosis Functional disorder Generations Gold Hippocampus (Brain)Human Lead Lesion Link Lip structure Maintenance Membrane Multivesicular Body Mutant Strains Mice Mutation Nerve Degeneration Nerve Growth Factors Neurites Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Organelles Pathogenesis Pathology Pathway interactions Patients Perforant Pathway Physiological Play Process Proteins Recycling Reporting Role Signal Transduction Site Sorting - Cell Movement Synapses Synaptic Receptors Synaptic plasticity System Testing Transgenic Mice Ubiquitin Vesicle Wild Type Mouse abeta accumulation base early onset effective therapy extracellular fast axonal transport in vivo insight interest intraneuronal beta amyloid mouse model multicatalytic endopeptidase complex mutant neuropathology receptor research study retrograde transport therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): Beta-amyloid is a major constituent of the plaques found in the brains of patients afflicted by Alzheimer's disease and reduction in beta-amyloid is currently a major target of therapeutic strategies for the disease. We reported electron microscopy studies to better define the subcellular localization of beta-amyloid in the brain and to determine how plaques form in a well-established transgenic mouse model of beta-amyloidosis. We found that beta-amyloid localized especially to small intracellular organelles, called multivesicular bodies, and smaller vesicles, and that this beta-amyloid accumulates with aging within Alzheimer's disease vulnerable neurons within these organelles until associated morphological alterations appear, especially within distal nerve cell processes and synaptic compartments. Multivesicular bodies are currently being actively studied for their role in recycling and degradation of among others, important membrane receptors, and for their transport along axons of vital cargo proteins, including nerve growth factors and their receptors. Aberrant protein accumulation has become a common theme in neurodegenerative diseases and we propose biological and pathological studies to explore the accumulation and modulation of beta-amyloid in multivesicular bodies within neurons. Specifically, we hypothesize that accumulating beta-amyloid may cause alterations in recycling and/or degradation of important synaptic receptors, in the ubiquitin proteasome system and/or in retrograde transport within neurites. In addition, we hypothesize that our preliminary evidence on synaptic activity reducing intraneuronal beta-amyloid provides a potential explanation for an emerging paradox in the field relating to elevation of beta-amyloid secretion with synaptic activity. A better understanding of beta-amyloid accumulation in multivesicular bodies within neurons, which are associated with early beta-amyloid related changes with Alzheimer disease pathogenesis, may be important in developing more effective treatments for Alzheimer's disease.

描述（由申请人提供）：β-淀粉样蛋白是在患有阿尔茨海默病的患者的脑中发现的斑块的主要成分，并且β-淀粉样蛋白的减少是目前该疾病的治疗策略的主要目标。我们报道了电子显微镜研究，以更好地确定β-淀粉样蛋白在脑中的亚细胞定位，并确定斑块如何在一个完善的β-淀粉样变性转基因小鼠模型中形成。我们发现β-淀粉样蛋白特别定位于小的细胞内细胞器，称为多泡体和较小的囊泡，并且这种β-淀粉样蛋白随着年龄的增长在这些细胞器内的阿尔茨海默病脆弱神经元内积累，直到出现相关的形态学改变，特别是在远端神经细胞突起和突触隔室中。目前正在积极研究多泡体在其中重要的膜受体的再循环和降解中的作用，以及它们沿重要货物蛋白（包括神经生长因子及其受体）的轴突的沿着。异常蛋白质积累已成为神经退行性疾病的一个共同主题，我们提出生物学和病理学研究，以探讨β-淀粉样蛋白在神经元内的多泡体中的积累和调节。具体来说，我们假设β-淀粉样蛋白的积累可能会导致改变循环和/或降解的重要突触受体，在泛素蛋白酶体系统和/或在神经突内的逆行运输。此外，我们假设，我们的初步证据突触活动减少神经元内β-淀粉样蛋白提供了一个潜在的解释，在该领域的一个新兴的悖论与海拔β-淀粉样蛋白分泌与突触活动。更好地了解β-淀粉样蛋白在神经元内的多泡体中的积累，这与阿尔茨海默病发病机制的早期β-淀粉样蛋白相关变化有关，可能对开发更有效的阿尔茨海默病治疗方法很重要。