BIOLOGY OF ALZHEIMER AMYLOID IN NEURONS

描述（由申请人提供）：β -淀粉样蛋白是在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，以更好地定义β -淀粉样蛋白在大脑中的亚细胞定位，并确定斑块是如何在一个完善的β -淀粉样变性转基因小鼠模型中形成的。我们发现-淀粉样蛋白特别定位于小的细胞内细胞器，称为多泡体和更小的囊泡，并且这种-淀粉样蛋白随着衰老在阿尔茨海默病易损的神经元内这些细胞器中积累，直到相关的形态学改变出现，特别是在远端神经细胞过程和突触区室中。目前，人们正在积极研究多泡体在回收和降解重要膜受体等方面的作用，以及它们沿着重要货物蛋白（包括神经生长因子及其受体）轴突运输的作用。异常蛋白积累已成为神经退行性疾病的共同主题，我们建议通过生物学和病理学研究来探索神经元内多泡体中β -淀粉样蛋白的积累和调节。具体来说，我们假设β -淀粉样蛋白的积累可能导致重要突触受体的循环和/或降解、泛素蛋白酶体系统和/或神经突内逆行运输的改变。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，为与突触活性升高β -淀粉样蛋白分泌有关的领域中新出现的悖论提供了潜在的解释。更好地了解神经元内多泡体中β -淀粉样蛋白的积累，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具有重要意义。

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.