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hippocampus and cortex in an APP/PSEN1 mouse. Methods:We utilize a cell-specific inducible system to express human TDP-43 and nuclear localization signal defective TDP-43DNLS 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. Results: 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. Conclusions: 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.