Mechanisms of spreading proteinopathy in Lewy Body Dementia

项目摘要 一 充分 阿尔法synuclein 诊断， 作为 病理 改变路易体痴呆神经变性的主要障碍是缺乏哺乳动物模型， 显示在人类疾病中发现的神经病理学变化的范围。虽然聚合 路易病理发生在特定的神经元在皮层是必要的， 在绝大多数情况下，在相同区域中存在共存的β-淀粉样斑块病理学， 路易病理学这些多种蛋白质病与路易氏病的形成和扩散的相关性 神经系统中的神经元是目前未知的。的 H Unni实验室已经工作了很多年 了解皮质α-突触核蛋白病理学在突触核蛋白病中的作用，包括开创性的体内 多光子成像方法，可以测量路易病理的形成和传播， 纵向细胞命运的个别神经元与路易夹杂物和不超过一段时间的许多个月。 最近，我们和我们的合作者Randall Woltjer发现β-淀粉样蛋白的存在 病理学极大地增加了接种后小鼠皮质中Lewy病理学的形成和/或扩散 α-突触核蛋白形成的纤维。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神经元缠结加速α-突触核蛋白Lewy病理学的形成和扩散 在整个神经系统中，以及大脑驻留的免疫细胞所扮演的潜在关键角色， 小胶质细胞在这个过程中这项工作的结果将推动我们理解和开发新的 路易体痴呆症的治疗方法

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.