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

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.

authors

Engstrom AK,Walker AC,Moudgal RA,Myrick DA,Kyle SM,Bai Y,Rowley MJ,Katz DJ

doi

10.1073/pnas.2013552117

subject

Has Abstract

pub_date

2020-11-17 00:00:00

pages

29133-29143

issue

46

eissn

0027-8424

issn

1091-6490

pii

2013552117

journal_volume

117

pub_type

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