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.