Neurodegenerative disorders with prominent filamentous a-synuclein (a-syn) aggregates in CMS neurons or glia are known as ct-synucleinopathies or synuclienopathies, and those characterized by neuronal a-syn inclusions, or Lewy bodies (LBs) and neurites (LNs) D, include Parkinson's disease without dementia (PD), PD with dementia (PDD) and dementia with LBs (DLB). Most PD is sporadic, but mutations/duplications in the a-syn gene of rare kindreds cause autosomal dominant hereditary PD and PDD/DLB. Thus, filamentous a-syn inclusions are linked to the onset/progression of synucleinopathies, and this is re-enforced by studies in which we showed that transgenic (TG) mice engineered to express human a-syn develop neuronal and glial a-syn pathologies that recapitulate their human counterparts. We now propose to test hypotheses that a-syn which accumulates as insoluble aggregates cause cognitive impairments in PDD and DLB and these deficits are augmented by the presence of tau and/or p amyloid neuropathologies. To accomplish this, we will use brain samples obtained from Core C to compare the regional distribution of a-syn, tau and Ap neuropathology in clinically well defined PD, PDD/DLB and LB variant of Alzheimer's disease patients follwed in Core B and studied by Projects 1 and 2. Since existing a-syn TG mouse models we and others generated are inadequate to evaluate the contributions of these filamentous protein lesions to cognitive impairments, new TG mouse models with regulated overexpression of wild type (WT) or mutant a-syn in forebrain neurons will be developed to specifically address this issue. Finally, the role of regulated overexpression of tau tangles and Ap plaques in enhancing cognitive decline in the new a-syn TG mouse models will be evaluated, and comparisons of these TG mice with human disease samples from Core C will be performed in Aims 1-4 to establish verisimilitude of our models to human synucleinopathies. Taken together, our work will lead to more informative models of synucleinopathies and address important questions on mechanisms leading to a-syn pathologies and their contribution to brain degeneration in synucleinopathies.

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National Institute of Neurological Disorders and Stroke (NINDS)
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