The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration

Amanda K. Engstrom, Alicia C. Walker, Rohitha A. Moudgal, Dexter A. Myrick, Stephanie M. Kyle, Yu Bai, M. Jordan Rowley, David J. Katz

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Tauopathies are a class of neurodegenerative diseases associated with pathological tau. Despite many advances in our understanding of these diseases, the direct mechanism through which tau contributes to neurodegeneration remains poorly understood. Previously, our laboratory 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 and tau-induced gene expression changes. Finally, we find that overexpressing LSD1 in the hippocampus of tauopathy mice, even after pathology has formed, is sufficient to significantly delay neurodegeneration and counteract tau-induced expression changes. These results suggest that inhibiting LSD1 via sequestration contributes to tau-mediated neurodegeneration. Thus, LSD1 is a promising therapeutic target for tauopathies such as Alzheimer’s disease.

Original languageEnglish (US)
Pages (from-to)29133-29143
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number46
DOIs
StatePublished - Nov 17 2020

Keywords

  • LSD1 | neurodegeneration | tauopathy | Alzheimer’s disease | epigenetics

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'The inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration'. Together they form a unique fingerprint.

Cite this