The role of mTOR signaling in Alzheimer s disease

The majority (>95%) of Alzheimer s disease (AD) cases are sporadic and of unknown causes. The single major risk factor for AD is aging and molecular changes that occur in the brain as a function of age may facilitate the development of AD. However, little is known as to how the aging process facilitates the development of AD. Overwhelming evidence shows that reducing the activity of the mammalian target of rapamycin (mTOR) increases lifespan and health-span in several genetically different species. mTOR is a ubiquitously expressed protein kinase that plays a key role in regulating protein synthesis and cell growth. mTOR also is a negative regulator of autophagy induction. By simultaneously regulating protein synthesis and degradation, mTOR is key in controlling protein homeostasis, a process that is altered in AD and other proteinopathies. Another known function of mTOR signaling is the regulation of synaptic plasticity and function. Using two widely used animal models of AD, known as Tg2576 and 3xTg-AD mice, we employed multidisciplinary approaches to dissect the role of mTOR signaling in AD. We found that genetic reduction of mTOR signaling reduced amyloid-â deposits and tau pathology and rescued memory deficits in Tg2576 mice. Mechanistically, the reduction in mTOR signaling led to an increase in autophagy induction and restored the hippocampal gene expression signature of the Tg2576 mice to wild type levels. Consistent with these findings, we also found that that genetic reduction of the ribosomal protein S6 kinase 1 (S6K1), a protein kinase directly downstream of mTOR, improved synaptic plasticity and spatial memory deficits, and reduced the accumulation of amyloid-â and tau, in 3xTg-AD mice. Mechanistically, these changes were linked to reduced translation of tau and the beta-site APP cleaving enzyme 1 (BACE-1), a key enzyme in the generation of amyloid-â. Given the overwhelming evidence showing that reducing mTOR signaling increases lifespan and health span, the data presented here have profound clinical implications for aging and AD and provide the molecular basis for how aging may contribute to AD pathology. Our results implicate hyperactive mTOR/S6K1 signaling as a previous unidentified signaling pathway underlying gene-expression dysregulation, synaptic and cognitive deficits in Alzheimer s disease.