Regulation of Forkhead Transcription Factor FoxO3a Contributes to Calorie Restriction‐induced Prevention of Alzheimer's Disease‐type Amyloid Neuropathology and Spatial Memory Deterioration

• DOI: 10.1196/annals.1427.024
• Publication Date: 2010-07-29T12:46:19Z
• Authors: Weiping Qin; Wei Zhao; Lap Ho; Jun Wang; Kenneth Walsh; Sam Gandy; Giulio Maria Pasi...
• Keywords: Forkhead Transcription Factors

Forkhead transcription factor FoxO3a, also known as DAF‐16 in Caenorhabditis elegans , is a key regulator of the insulin receptor (IR)/insulin‐like growth factor‐I signaling pathway mediated extension life span worms and yeast. In this study, we report that calorie restriction (CR)‐mediated activation IR leads to hyperphosphorylation FoxO3a and, consequently, its exclusion from nucleus. This inactivation activity correlated with attenuation Alzheimer's disease (AD)‐type amyloid neuropathology preservation spatial reference memory Tg2576 mouse model AD. Further, vitro studies reveal exogenous expression viral, triple‐mutant, constitutively active resulting increased nuclear primary neuron cultures derived embryos, causally promotes AD amyloid‐β peptide (Aβ) levels by inhibiting nonamyloidogenic α‐secretase activity, indicating existence an inverse correlation between cerebral Aβ amyloidosis. Moreover, for first time nucleus combination inhibition SIRT1‐mediated deacetylation response CR mechanism repression Rho‐associated protein kinase‐1 gene expression, thereby activating processing precursor lowering generation. study provides novel metabolic prevention and/or treatment