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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • ADAM Proteins / metabolism*
  • ADAM10 Protein
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurogenesis
  • Receptors, Notch / metabolism
  • Receptors, Retinoic Acid / metabolism
  • Sirtuin 1 / metabolism*
  • Tretinoin / metabolism


  • Amyloid beta-Peptides
  • Membrane Proteins
  • Receptors, Notch
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta
  • Tretinoin
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • Adam10 protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1