SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10
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Guarente_SIRT1 suppresses.pdf
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Author(s)
Donmez Yalcin, Gizem
Cohen, Dena E.
Wang, Diana G.
Guarente, Leonard Pershing
Date Issued
July 2010
Journal
Cell
Publisher
Elsevier
Citation
Donmez, Gizem, Diana Wang, Dena E. Cohen, and Leonard Guarente. “SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10.” Cell 142, no. 2 (July 2010): 320-332. Copyright © 2010 Elsevier Inc.
Version
Final published version
Abstract
A hallmark of Alzheimer's disease (AD) is the accumulation of plaques of Aβ 1–40 and 1–42 peptides, which result from the sequential cleavage of APP by the β and γ-secretases. The production of Aβ peptides is avoided by alternate cleavage of APP by the α and γ-secretases. Here we show that production of β-amyloid and plaques in a mouse model of AD are reduced by overexpressing the NAD-dependent deacetylase SIRT1 in brain, and are increased by knocking out SIRT1 in brain. SIRT1 directly activates the transcription of the gene encoding the α-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor β, a known regulator of ADAM10 transcription. ADAM10 activation by SIRT1 also induces the Notch pathway, which is known to repair neuronal damage in the brain. Our findings indicate SIRT1 activation is a viable strategy to combat AD and perhaps other neurodegenerative diseases.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Paul F. Glenn Center for Biology of Aging Research (Massachusetts Institute of Technology)
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1016/j.cell.2010.06.020
