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Cell. 2010 Jul 23;142(2):320-32. doi: 10.1016/j.cell.2010.06.020.

SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10.

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1
Paul F. Glenn Laboratory and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Erratum in

  • Cell. 2010 Aug 6;142(3):494-5.

Abstract

A hallmark of Alzheimer's disease (AD) is the accumulation of plaques of Abeta 1-40 and 1-42 peptides, which result from the sequential cleavage of APP by the beta and gamma-secretases. The production of Abeta peptides is avoided by alternate cleavage of APP by the alpha and gamma-secretases. Here we show that production of beta-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 alpha-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor beta, 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.

PMID:
20655472
PMCID:
PMC2911635
DOI:
10.1016/j.cell.2010.06.020
[Indexed for MEDLINE]
Free PMC Article
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