P4‐025: MULTIPLICATION OF THE SNCA LOCUS EXACERBATES NEURONAL NUCLEAR AGING IN HIPSC‐DERIVED NEURONAL MODELS OF PARKINSON'S AND DEMENTIA WITH LEWY BODIES

Background: The pathological hallmark of synucleinopathies, including Parkinson’s disease, is the deposition of insoluble aggregates of misfolded a-synuclein. However, it is now accepted that soluble aggregates, termed oligomers, are a key causal agent in synucleinopathies. An emerging concept in neurodegenerative disease research and diagnosis is that disease pathologies overlap or even form a continuum. For example, a-synuclein and tau pathology often coexist in Parkinson’s disease and dementia with Lewy bodies. We posit that while a-synuclein is the primary trigger for synucleiopathies, tau likely contributes to secondary symptoms and clinical heterogeneity in these dementia disorders. We further hypothesize that a-synuclein and tau interaction is essential for the development of full neurotoxicity. Methods:To test our hypothesis, we used either a preventative (immunpotherapy initiated at 4months of age) or a treatment (immunotherapy initiated at 9 months of age) experimental design using A53T a-synuclein transgenic mice. Monotherapy with either F8H7 anti-a-synuclein oligomers antibody or TOMA anti-tau oligomers antibody as well as combination therapies were performed. Immunotherapy effectiveness was tested with neurobehavioral testing and post mortem analysis of a-synuclein and tau pathology. Neurobehavioral testing included elevated plus maze, SHIRPA, open field, rotarod, grip strength, tail suspension, gait analysis, novel object recognition, fear conditioning, acoustic startle, and pre-pulse inhibition. Immunohistochemical and biochemical assays for a-synuclein and tau pathology were performed on fixed and fresh tissue samples, respectively. Results:Preliminary studies indicate that monotherapy and combination therapy alleviated motor deficits in A53T a-synuclein transgenic mice as measured with rotarod, grip strength, and gait analysis. We revealed a depression-like phenotype in A53T mice with tail suspension that was not affected by immunotherapy. Conclusions: The effectiveness of monotherapy targeting a-synuclein versus tau with a prevention versus treatment design reveals novel disease mechanisms. Combination therapy in a treatment design appears to be as effective, and possibly more effective, than F8H7monotherapy targeting a-synuclein oligomers. The effectiveness of tau monotherapy supports the notion that targeting a component of secondary clinical pathology may have translational value.