Title | SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Donmez G, Wang D, Cohen DE, Guarente L |
Journal | Cell |
Volume | 142 |
Issue | 2 |
Pagination | 320-32 |
Date Published | 2010 Jul 23 |
ISSN | 1097-4172 |
Keywords | ADAM Proteins, ADAM10 Protein, Alzheimer Disease, Amyloid beta-Peptides, Amyloid Precursor Protein Secretases, Animals, Brain, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurogenesis, Receptors, Notch, Receptors, Retinoic Acid, Sirtuin 1, Tretinoin |
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. |
DOI | 10.1016/j.cell.2010.06.020 |
Alternate Journal | Cell |
PubMed ID | 20655472 |
PubMed Central ID | PMC2911635 |
Grant List | R01 AG015339 / AG / NIA NIH HHS / United States R01 AG015339-08 / AG / NIA NIH HHS / United States |
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