| Proteolytic processing of the beta-amyloid precursor protein (APP) by alpha-, beta-and gamma-secretase enzymes generating the amyloid-beta (Abeta) peptide and the APP intracellular domain (AICD) is a central event in Alzheimer's disease (AD). Herewe show that in vitro CR decreases Abeta, AICD and full-length APP levels in human cell lines without affecting APP transcription and that some of these effects can be recapitulated by over-expressing the NAD+ dependent deacetylase SirT1 in our cell lines. Resveratrol, a SirT1 agonist, also has similar effects on APP metabolism. SirT1 and resveratrol however, do not affect full-length APP levels. In our cell lines, SirT1 and resveratrol reduces secreted Abeta levels by increasing the alpha-secretase cleavage of APP and also possibly by affecting gamma-secretase activity. Extending these studies to an in vivo setting, an AICD reporter Drosophila model of AD, shows that caloric restriction, Sir2 gain-of-function and resveratrol treatment suppress AD-like rough-eye phenotype in the fly eyes. Finally to study the mechanism of CR and SirT1 mediated effects on APP metabolism in entire central nervous system, we created and characterized a novel Drosophila model of AD. We have shown that our model displays neuroanatomical and behavioral features that are characteristic of AD patients. |
