P3-072: Identification and Validation of TAU-Modifiers, Identified by Unbiased Genome Wide Approaches, Using AAV-Based Approaches in TAU Transgenic Mice

Abstract

Background: Identification of Tau mutations linked to neurodegen-erative Tauopathies have indicated that Tau-dysfunction is causally linked to neurodegenerative processes. Accumulating evidence furthermore corroborates a crucial executive role for Tau in the pathogenesis of AD, designating Tau as an important therapeutic target. Identification of modifiers of Tau that can modulate Tau-pathology and Tau-related phenotypic features and neurodegenerative processes observed in preclinical models has become an important research objective. Methods: A Tau-interactome mapping has been performed to identify proteins binding to Tau in an unbiased way. To further identify Tau-modifying potential of the identified interacting proteins, an AAV-based approach was used. AAV injections, driving neuronal expression of the protein of interest, were performed at P0 in previously characterized Tau transgenic mice, and in primary neuronal cultures. Biochemical and IHC analysis was performed to analyze the modifying potential of the protein of interest on Tau and Tau-pathology in vitro and in vivo. Results: Using this approach we demonstrate Tau-modifying potential for several novel proteins involved in protein degradation, more particularly in the ubiquitin proteasome degradation. Background: Although tau pathology, behavioral deficits, and neuronal loss are each observed in patients with tauopathies, the relationship between these endpoints has not been clearly established. Methods: Here we found that rTg4510 mice, overexpressing human mutant tau in the forebrain, develop progressive age-dependent increases in locomotor activity, which correlates with neurofi-brillary tangle (NFT) pathology, hyperphosphorylated tau levels, and brain atrophy. To investigate whether attenuating the tau pathology in this animal model can prevent the progression of the behavioral deficits, we treated the rTg4510 mice with either doxy