Mechanisms of spreading proteinopathy in Lewy Body Dementia

项目总结 一 充分地 α-突触核蛋白 诊断， AS 病理学 路易体痴呆神经退行性变的主要障碍是缺乏能够 显示人类疾病中发现的神经病理变化的范围。尽管聚合了 发生在大脑皮层特定神经元内的路易病理I S要求做到这一点 在绝大多数病例中，同一区域存在共存的β-淀粉样斑块病变。 路易病理学。多种蛋白病变与路易氏病形成和扩散的关系 整个神经系统目前尚不清楚。这个 H Unni实验室已经工作了很多年 了解皮质α-突触核蛋白病理在突触核病中的作用，包括体内的先驱研究 多光子成像方法可以测量路易氏病变的形成和扩散 有和没有路易包涵体的单个神经元在多个月的时间内的纵向细胞命运。 最近，我们和我们的合作者兰德尔·沃尔特杰发现，β-淀粉样蛋白的存在 病理极大地增加了小鼠大脑皮质路易氏病变的形成和/或扩散 α-突触核蛋白预成纤维。在这项提案中，我们的团队将了解β-淀粉样蛋白的存在是如何 斑块和tau神经原纤维缠结加速α-突触核蛋白路易氏病变的形成和扩散 整个神经系统，以及大脑驻留免疫细胞发挥的潜在关键作用， 小胶质细胞，在这个过程中。这项工作的成果将推动我们理解和开发新的 路易体痴呆的治疗。

PROJECT SUMMARY One adequately alpha-synuclein diagnosis, as pathology major obstacle to alting neurodegeneration i n Lewy body dementias is a lack of mammalian models that display the range of neuropathological changes found in the human disease. Although aggregated Lewy pathology occurring within specific neurons in the cortex i s required to make this in the vast majority of cases, there is coexistent beta-amyloid plaque pathology in the same regions Lewy pathology. The relevance these multiple proteinopathies to the formation and spread of Lewy throughout the nervous system is currently unknown. The h Unni lab has been working for many years to understand the role of cortical alpha-synuclein pathology in synucleinopathies, including pioneering in vivo multiphoton imaging approaches that can measure the formation and spread of Lewy pathology and the longitudinal cell fates of individual neurons with and without Lewy inclusions over a period of many months. Recently, we and our collaborator Randall Woltjer have discovered that the presence of beta-amyloid pathology greatly increases the formation and/or spread of Lewy pathology in mouse cortex after seeding with alpha-synuclein preformed fibrils. In this proposal, our team will understand how the presence of beta-amyloid plaques and tau neurofibrillary tangles accelerate the formation and spread of alpha-synuclein Lewy pathology throughout the nervous system, and the potentially critical role played by brain-resident immune cells, microglia, in this process. The results of this work will push forward our ability to understand and develop new treatments for Lewy body dementias.