The Inhibition of LSD1 VIA Sequestration Contributes to Tau-Mediated Neurodegeneration

Alzheimer’s disease (AD) is characterized by the abnormal aggregation of β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau (NFTs). However, the molecular mechanism underlying the neuronal cell death is not well understood. The H3K4me1/2 demethylase, LSD1 functions in nucleus to repress genes. Surprisingly, our lab found that LSD1 is mis-localized with cytoplasmic pathological tau in human AD cases, that suggests LSD1 may be inhibited by tau. To study the function of LSD1, our lab showed that the inducible deletion of LSD1 in adult mice induces cortical and hippocampal neurodegeneration, learning and memory deficits, and transcription alternations that match human AD cases. Therefore, we hypothesized that pathological tau contributes to neuronal cell death by sequestering LSD1 into the cytoplasm.

To address this hypothesis, we utilized the PS19 tauopathy mouse model to examine the functional consequences of changing LSD1 expression and to examine the interaction between pathological tau and LSD1. We found that LSD1 is depleted from the nucleus and mis-localized with cytoplasmic NFTs in adult PS19 Tau mice, supporting the hypothesis that NFTs sequester LSD1. In addition, we found that changing LSD1 expression can specifically modulate tau-mediated neurodegeneration in PS19 mice. This suggests that pathological tau is functioning in part through LSD1. Finally, we found that LSD1 interacts with pathological tau through its N-terminus.

We conclude that pathological tau functions in part by sequestering LSD1 in the cytoplasm and preventing it from continually blocking inappropriate gene expression. A model for the pathological interaction between LSD1 and tau will be presented.