Yu Bai, United States of America
Emory University Cell BiologyAuthor Of 1 Presentation
PATHOLOGICAL TAU INDUCES NEURODEGENERATION BY SEQUESTERING AND INHIBITING LSD1
Abstract
Aims
Alzheimer’s disease (AD) is characterized by the aberrant accumulation of β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau (NFTs). Surprisingly, we previously found that the histone demethylase LSD1/KDM1A is mislocalized to NFTs in AD cases. In addition, we showed that loss of LSD1 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. Based on these data, we sought to determine whether pathological tau functions through LSD1 to induce neuronal dysfunction.
Methods
If pathological tau is functioning through the sequestration of LSD1, then reducing LSD1 in PS19 Tauopathy mice should make these mice more sensitive to pathological tau, and overexpressing LSD1 should rescue neuronal dysfunction.
Results
Reducing LSD1 in PS19 Tau mice accelerates the depletion of LSD1 from the nucleus. This results in decreased survival, exacerbated paralysis, and increased neurodegeneration. Reducing LSD1 also exacerbates the genome-wide expression changes induced by pathological tau. Conversely, overexpressing LSD1 in hippocampal neurons of PS19 mice at 8.5 months, when pathological tau is already present, is sufficient to suppress tau-induced neurodegeneration and block the Tau induced immune response through 11 months. In addition, overexpressing LSD1 specifically counteracts tau-induced gene expression changes genome-wide.
Conclusions
We propose that pathological tau leads to neuronal cell death in AD by sequestering LSD1 in the cytoplasm and interfering with the continuous requirement for LSD1 to epigenetically repress transcription associated with alternative cell fates.