Mammalian target of rapamycin: A valid therapeutic target through the autophagy pathway for alzheimer's disease?

Autophagy plays a critical role in multiple pathological lesions of Alzheimer's disease (AD), such as the formation of amyloid plaques from amyloid-beta (A beta) production and accumulation via dysregulating amyloid precursor protein turnover and enhancing the activity of beta- and/or ?-secretases, intraneuronal neurofibrillary tangles (NFT) because of tau hyperphosphorylation, and neuronal apoptosis. Dysfunction of the autophagy-lysosome system also contributes to A beta accumulation and the formation of tau oligomers and insoluble aggregates, because induction of autophagy enhances the clearance of both soluble and aggregated forms of A beta and tau proteins. The mammalian target of rapamycin (mTOR) pathway plays a central role in controlling protein homeostasis and negatively regulates autophagy. Inhibition of mTOR by rapamycin improves cognitive deficits and rescues A beta pathology and NFTs by increasing autophagy. Several mTOR signaling components may be potential biomarkers of cognitive impairment in the clinical diagnosis of AD. Thus, mTOR-related agents through the control of autophagy-lysosome protein degradation are emerging as an important therapeutic target for AD. (c) 2012 Wiley Peridicals, Inc.