[p3–083]: phenotypic screening for novel inhibitors of tau aggregation in human ipsc‐derived neurons

Tauopathies are neurodegenerative diseases characterized by the presence of aggregates of abnormally hyperphosphorylated tau. Due to the intrinsic differences in clearance mechanisms between neuronal and non-neuronal cells, we used human iPSC-derived neurons to develop a biologically relevant cellular model that recapitulates the disease. AAV8-mediated overexpression of both wild type (hu tau WT) and an aggregation-prone construct of tau (hu Tau-mod) in iPSC-neurons resulted in disease-relevant phenotypes such as tau phosphorylation, misfolding, aggregation and subsequently neuronal death. Phenotypic screening of a selected library of annotated compounds in the in vitro model of human iPSC-derived neurons resulted in ∼7% hit rate with targets spanning across different functional classes such as autophagy, kinase inhibition, inflammation etc. Dose-response evaluation of the hits and confirmatory screening assays resulted in identification of select leads. Efforts are ongoing to identify the mechanism of action of selected leads and to support target identification efforts. In addition, we have established the translation of this model in vivo. Overexpression of both WT and aggregation-prone construct of tau in rat hippocampus showed increased tau phosphorylation, misfolding and neurodegeneration at 6 weeks post AAV infusion. Behavioral analyses at 6-weeks post infusion of wild-type tau showed partial deficit in passive avoidance task as well as novel object recognition. Biochemical and immunohistochemical analyses are ongoing to further characterize the in vivo model of tauopathy. Our goal is to uncover key targets involved in the clearance of tau aggregates that could become potential strategies to cure neurodegenerative disorders associated with tau.