PPAR Gamma Coactivator 1 Beta (PGC-1β) Reduces Mammalian Target of Rapamycin (mTOR) Expression via a SIRT1-Dependent Mechanism in Neurons

Abstract

Mammalian target of rapamycin (mTOR) is a key regulator of metabolism, cell growth, and protein synthesis. Since decreased mTOR activity has been found to slowaginginmany species, the aim of this study was to examine the activity of mTOR and its phosphorylated form in in vitro and in vivo models mimicking Alzheimer's disease (AD), and investigate the potential pathway of PGC-1β in regulating mTOR expression. Primary neurons and N2a cells were treated with Aβ25-35, while untreated cells served as controls. The expression of mTOR, p-mTOR (Ser2448), and PGC-1β was determined with Western blotting and RT-PCR assay, and the translocation of mTOR was detected using confocal microscopy. Aβ25-35 treatment stimulated the translocation of mTOR from cytoplasm to nucleus, and resulted in elevated expression of mTOR and p-mTOR (Ser2448) and reduced PGC-1β expression. In addition, overexpression of PGC-1β was found to decrease mTOR expression. The results of this study demonstrate that Aβ increases the expression of mTOR and p-mTOR at the site of Ser2448, and the stimulation of Aβ is likely to depend on sirtuin 1, PPARγ, and PGC-1β pathway in regulating mTOR expression.