Activation of mTOR: a culprit of Alzheimer's disease?

Alzheimer's disease (AD) is characterized by cognitive impairment in clinical presentation, and by beta-amyloid (A beta) production and the hyper-phosphorylation of tau in basic research. More highlights demonstrate that the activation of the mammalian target of rapamycin (mTOR) enhances A beta generation and deposition by modulating amyloid precursor protein (APP) metabolism and upregulating beta- and gamma-secretases. mTOR, an inhibitor of autophagy, decreases A beta clearance by scissoring autophagy function. mTOR regulates A beta generation or A beta clearance by regulating several key signaling pathways, including phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt), glycogen synthase kinase 3 [GSK-3], AMP-activated protein kinase (AMPK), and insulin/insulin-like growth factor 1 (IGF-1). The activation of mTOR is also a contributor to aberrant hyperphosphorylated tau. Rapamycin, the inhibitor of mTOR, may mitigate cognitive impairment and inhibit the pathologies associated with amyloid plaques and neurofibrillary tangles by promoting autophagy. Furthermore, the upstream and downstream components of mTOR signaling are involved in the pathogenesis and progression of AD. Hence, inhibiting the activation of mTOR may be an important therapeutic target for AD.