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

• 批准号: 7475061
• 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
• 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/7475061
• 关键词: Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloidosis; Axon; Biological; Biology; Brain; Cell membrane; Cell physiology; Chromosome Pairing; Data; Development; Disease; Distal; Electron Microscopy; Elevation; Endocytosis; Functional disorder; Generations; Gold; Hippocampus (Brain); Human; Lead; Lesion; Link; Lip structure; Localized; 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; Transgenic Organisms; Ubiquitin; Vesicle; Wild Type Mouse; abeta accumulation; base; early onset; 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

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(申请人提供)：β-淀粉样蛋白是阿尔茨海默病患者大脑中发现的斑块的主要成分，减少β-淀粉样蛋白目前是该疾病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-淀粉样蛋白在大脑中的亚细胞定位，并确定在已建立的β-淀粉样变性转基因小鼠模型中斑块是如何形成的。我们发现，β-淀粉样蛋白特别定位于细胞内的小细胞器，称为多泡小体和较小的小泡，并且随着年龄的增长，这种β-淀粉样蛋白在阿尔茨海默病患者这些细胞器中的脆弱神经元中积累，直到出现相关的形态变化，特别是在远端神经细胞突起和突触间隔内。目前，人们正在积极研究多囊泡小体在重要的膜受体的循环和降解中的作用，以及它们沿着重要货物蛋白轴突的运输，包括神经生长因子及其受体。异常蛋白积聚已成为神经退行性疾病的共同主题，我们建议进行生物学和病理学研究，以探索β-淀粉样蛋白在神经元内多囊体内的积聚和调节。具体地说，我们假设积累的β-淀粉样蛋白可能导致泛素蛋白酶体系统中重要突触受体的循环和/或降解的改变，和/或轴突内的逆行运输。此外，我们假设，我们关于突触活性降低神经元内β-淀粉样蛋白的初步证据为该领域中出现的与突触活性相关的β-淀粉样蛋白分泌增加的悖论提供了潜在的解释。更好地了解神经元内多泡体内的β-淀粉样蛋白积聚与阿尔茨海默病发病机制中早期β-淀粉样蛋白相关的变化有关，这可能对开发更有效的阿尔茨海默病治疗方法具有重要意义。