PROJECT II: Pathologic Alpha-synuclein Strains & Diverse Synucleinopathies Project II Leader: J.Q. Trojanowski; Co-Investigators: V.M.-Y. Lee & K. Luk Project II Summary/Abstract Project II (formerly Project IV and renumbered II to improve the flow of the research) in this new U19 “Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias” at the University of Pennsylvania (Penn) Perelman School of Medicine (PSOM) tests the hypothesis that heterogeneity and progression of alpha-synuclein (aSyn) pathology in Lewy bodies (LBs) and neurites (LNs) of Parkinson's disease without (PD) or with dementia (PDD) and dementia with LBs (DLB), as well as Alzheimer's disease (AD) with aSyn (AD+aSyn) LBs and LNs co-pathologies represent the spread of different neuronal aSyn strains.1 We compare these strains to each other and with aSyn strains from multiple system atrophy (MSA) glial cytoplasmic inclusions (GCI) which rarely appear in AD or in combination with LBs/LNs. This will advance insights into how distinct aSyn strains in AD+aSyn vs PD vs PDD vs DLB vs MSA drive clinical and pathological heterogeneity of these disorders. Since dementia in PDD and DLB, referred to as LB dementia (LBD), frequently is accompanied by AD co-pathologies, including Aβ amyloid plaques and neurofibrillary tau inclusions, and 50% of AD patients have LBs, we also test the hypothesis that aSyn strains in PDD vs DLB vs AD+aSyn brains induce Aβ and tau pathologies whereas aSyn strains in PD vs MSA brains lacking AD pathology might not. Project II collaborates with Project I, which performs in vitro aSyn strain studies and provides Project II with highly characterized and validated aSyn strains from postmortem AD+aSyn, PD, LBD and MSA brains as well as in vitro amplified LB and GCI aSyn strains. For these studies, living subjects are studied in Core B and Projects III/IV and their brains are obtained through Core C while Core D provides data management, biostatistics and bioinformatics support. The extent to which the models of synucleinopathies induced by intracerebral injections of LB and GCI aSyn strains in Project II correspond to authentic human AD+aSyn vs PD vs LBD vs MSA will be assessed. Thus, Project II works closely with all U19 Center Cores/Projects to determine if the LB aSyn strain (aSyn-LB) from PD vs AD+aSyn vs LBD brains compared to the MSA GCI aSyn strain (aSyn-GCI) differentially induce pathological aSyn in neurons versus glia as well as recruit AD-like Aβ and tau deposits or other neurodegenerative disease co-pathologies such as TDP-43. This will be done following intracerebral injections of these aSyn strains into wild type (WT) mice, human WT aSyn transgenic (Tg) mice (line 61) on a mouse aSyn knock out (KO) background (KO61) and CNP-aSyn (M2) Tg mice with an aSyn KO background (KOM2) that model GCIs compared to Tg mouse models of AD-like Aβ plaques (5xFAD, Tg2576, APP knock in mice) and a Tg mouse model of AD-like tau pathologies (PS19 line). The ...