Figure 2.

Mechanisms of activity for sirtuins in Alzheimer's disease. In vitro and neuronal culture data show that SIRT1 can directly deacetylate tau protein at multiple residues^62,63,64. The mechanism proposed by these investigators is that removal of acetyl groups may expose lysine residues to ubiquitin ligases so that tau protein is marked for proteasomal degradation^62,63. This process decreases accumulation of hyperphosphorylated PHF tau, cognitive defects and early mortality in the P301L tau mouse model^62,63. Overexpression of SIRT1 has also been shown to decrease plaque burden and improve behavioral phenotypes by deacetylating retinoic acid receptor β, a transcriptional activator of ADAM10. ADAM10 is a component of the α-secretase, which processes APP along an anti-amyloidogenic pathway that decreases formation of toxic Aβ42 species⁵⁹. An independent study has also shown that SIRT1 expression may decrease levels of ROCK1, a serine/threonine Rho kinase previously shown to regulate Aβ metabolism, and this effect also promotes the non-amyloidogenic α-secretase pathway^14,58. The SIRT1 agonist resveratrol was also found to enhance proteasome-mediated clearance of Aβ⁴⁴ and reduce the plaque burden in the brains of transgenic mice overexpressing APP^45,46. Experiments using mixed cortical culture models have also shown that SIRT1 acts to reduce Aβ-stimulated NF-κB signaling in microglia⁵⁷.