Regulation of forkhead transcription factor FoxO3a contributes to calorie restriction-induced prevention of Alzheimer’s disease-type amyloid neuropathology and spatial memory deterioration

摘要

Forkhead transcription factor FoxO3a, also known as DAF-16 in C. Elegans nematodes, is a key regulator of the insulin receptor (IR)/IGF-1 signaling pathway mediated extension of lifespan in worms and yeast. In this study, we report that calorie restriction (CR) - mediated activation of IR signaling pathway leads to hyperphosphorylation of FoxO3a transcription factor and, consequently, its exclusion from nucleus. This inactivation of FoxO3a activity is correlated with attenuation of Alzheimer’s disease (AD)-type amyloid neuropathology and with preservation of spatial reference memory in the Tg2576 mouse model of AD. Further in vitro studies reveal that exogenous expression of viral triple mutant constitutively active (CA) FoxO3a resulting in increased nuclear FoxO3a activity in primary neuron cultures derived from Tg2576 mouse embryos, causally promotes AD amyloid-β peptide (Aβ) levels by inhibiting non-amyloidogenic α-secretase activity, indicating the existence of an inverse correlation between FoxO3a activity and cerebral Aβ amyloidosis. Moreover, we report for the first time that the exclusion of the FoxO3a transcription factor from the nucleus in combination with inhibition of nuclear FoxO3a activity by SIRT1-mediated deacetylation in response to CR is a mechanism resulting in the repression of Rho-associated protein kinase-1 (ROCK1) gene expression, thereby activating non-amyloidogenic α-secretase processing of APP and lowering Aβ generation. This study provides a novel metabolic pathway for prevention and/or treatment of AD.