FUNCTIONAL CHANGES IN MEMORY ASSOCIATED WITH TDP-43 EXPRESSION IN AN APP/PSEN1 MOUSE MODEL

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Recent studies have shown that phosphorylated TDP-43 pathology is present in up to 50% of sporadic Alzheimer's disease (AD) cases. Although mislocalized and phosphorylated TDP-43 has been observed in several neurodegenerative diseases, little is known about the role TDP-43 plays in AD pathology. We describe a mouse model of selective human TDP-43 and TDP-43ΔNLS (defective nuclear localization signal) expression in the hippocampus and cortex in an APP/PSEN1 mouse. We utilize a cell-specific inducible system to express human TDP-43 and nuclear localization signal defective TDP-43ΔNLS in hippocampal and cortical neuronal populations using the Camk2a tetracycline transactivator (Camk2a-tTA) in an APP/PSEN1 background. The effect of TDP-43 on cognition and neurotoxicity was evaluated through novel object recognition, Y-maze, pathology, electron microscopy, immunofluorescence, primary cortical neuronal cultures, proteomics, and Western blotting. We describe functional changes in short and long-term memory associated with TDP-43 expression. In addition, we describe pathological changes in AB plaques, tau aggregation, and phosphorylated TDP-43. Collectively, our data lead us to conclude that TDP-43 contributes to functional changes in memory, Ab plaque formation, tau aggregation, and accumulation of phosphorylated TDP-43. Our current data suggest that TDP-43 could be a putative target of therapeutic intervention in AD affecting both AB plaques and tauopathy.