Abstract
Tauopathies are a class of neurodegenerative diseases associated with pathological tau. However, the mechanism through which tau contributes to neurodegeneration remains unknown. Previously, our lab implicated the histone demethylase LSD1 in tau-induced neurodegeneration by showing that LSD1 localizes to pathological tau aggregates in Alzheimer’s Disease cases, and that it is continuously required for the survival of hippocampal and cortical neurons in mice. Here, we utilize the P301S tauopathy mouse model to demonstrate that pathological tau can exclude LSD1 from the nucleus in neurons. In addition, we show that reducing LSD1 in these mice is sufficient to highly exacerbate tau-mediated neurodegeneration. Finally, we find that overexpressing LSD1 in the hippocampus of tauopathy mice, even after pathology has formed, is sufficient to significantly delay neurodegeneration. These results suggest that inhibition of LSD1 is a downstream mediator of pathological tau. Thus, LSD1 is a promising therapeutic target for tauopathies such as Alzheimer’s Disease.