期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 46, 页码 29133-29143出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2013552117
关键词
LSD1; neurodegeneration; tauopathy | Alzheimer's; Alzheimer's disease; epigenetics
资金
- Emory University Neuroscience NINDS [P30NS055077]
- Georgia Clinical and Translational Science Alliance of the NIH [UL1TR002378]
- National Center for Advancing Translational Sciences of the NIH [UL1TR000454]
- National Institute of General Medicine training grant [T32 GM008367-26]
- National Research Service Award Fellowship from NINDS [F31 NS098663-02]
- NINDS [1R01NS087142]
- NINDS Training in Translational Research in Neurology grant [5T32 NS007480-17]
- NIH [K99/R00 GM127671]
- Emory University Alzheimer's Disease Research Center [P50 AG025688]
- National Institute of Neurological Disorders and Stroke (NINDS), Emory University Neuroscience Core Facilities [P30NS055077]
July Tauopathies are a class of neurodegenerative diseases associated with pathological tau. Despite many advances in our understand-ing 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.
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