Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction

J Biol Chem. 2006 Aug 4;281(31):21745-54. doi: 10.1074/jbc.M602909200. Epub 2006 Jun 2.

Abstract

Nicotinamide adenine dinucleotide (NAD)+-dependent sirtuins have been identified to be key regulators in the lifespan extending effects of calorie restriction (CR) in a number of species. In this study we report for the first time that promotion of the NAD+-dependent sirtuin, SIRT1-mediated deacetylase activity, may be a mechanism by which CR influences Alzheimer disease (AD)-type amyloid neuropathology. Most importantly, we report that the predicted attenuation of beta-amyloid content in the brain during CR can be reproduced in mouse neurons in vitro by manipulating cellular SIRT1 expression/activity through mechanisms involving the regulation of the serine/threonine Rho kinase ROCK1, known in part for its role in the inhibition of the non-amyloidogenic alpha-secretase processing of the amyloid precursor protein. Conversely, we found that the expression of constitutively active ROCK1 in vitro cultures significantly prevented SIRT1-mediated response, suggesting that alpha-secretase activity is required for SIRT1-mediated prevention of AD-type amyloid neuropathology. Consistently we found that the expression of exogenous human (h) SIRT1 in the brain of hSIRT1 transgenics also resulted in decreased ROCK1 expression and elevated alpha-secretase activity in vivo. These results demonstrate for the first time a role for SIRT1 activation in the brain as a novel mechanism through which CR may influence AD amyloid neuropathology. The study provides a potentially novel pharmacological strategy for AD prevention and/or treatment.

MeSH terms

  • Alzheimer Disease / diet therapy*
  • Alzheimer Disease / prevention & control
  • Amyloid / analysis
  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Caloric Restriction*
  • Endopeptidases / metabolism
  • Enzyme Activation
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Neurons / enzymology*
  • Neurons / pathology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology
  • Sirtuin 1
  • Sirtuins / metabolism*
  • rho-Associated Kinases

Substances

  • Amyloid
  • Intracellular Signaling Peptides and Proteins
  • Protein-Serine-Threonine Kinases
  • ROCK1 protein, human
  • Rock1 protein, mouse
  • rho-Associated Kinases
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Sirtuins