PgmNr M296: The function of the histone demethylase KDM1A (LSD1) in Tau mediated neurodegeneration.

Authors:
David Katz; Michael Christopher; Dexter Myrick; Amanda Engstrom; Rohitha Moudgal


Institutes
Dept. of Cell Biology, Emory University, Atlanta, GA.


Abstract:

Alzheimer’s disease (AD) is the most common form of dementia that occurs during aging. AD is associated with the pathological aggregation of Ab and pTau. Nevertheless, it remains unclear how these protein aggregates lead to neuronal cell death in AD. Here we implicate a potential epigenetic step in AD. Data from our lab demonstrates that the histone demethylase KDM1A/LSD1 is mislocalized with aggregated pTau in AD cases. In addition, we find that loss of KDM1A systemically in adult mice is sufficient to recapitulate many aspects of AD, including widespread neuronal cell death in the hippocampus and cortex, learning and memory defects, and global gene expression changes that match AD cases. Surprisingly, in degenerating hippocampal neurons, we also detect the inappropriate re-expression of stem cell genes. These data raise the possibility that aggregated pTau leads to neuronal cell death in AD by interfering with the continuous requirement for KDM1A to epigenetically repress transcription associated with alternative cell fates. To further investigate the potential involvement of KDM1A in the AD pathway, we also removed one copy of Kdm1a from Tg(Prnp-MAPT*P301S)PS19Vle (P301S Tau) mice, which contain a transgene overexpressing an aggregation prone form of MTAP (Tau). If pTau leads to neurodegeneration by interfering with KDM1A, we would expect these mice to exhibit a faster, more severe neurodegeneration phenotype. Remarkably, our preliminary results indicate that partial loss of KDM1A enhances the Tau-mediated neurodegeneration in this mouse model. These results indicate that it may be possible to target KDM1A therapeutically to block the progression of AD in patients.