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

Abstract

Alzheimer's disease (AD) is characterized by cognitive impairment in clinical presentation, and by β-amyloid (Aβ) production and the hyper-phosphorylation of tau in basic research. More highlights demonstrate that the activation of the mammalian target of rapamycin (mTOR) enhances Aβ generation and deposition by modulating amyloid precursor protein (APP) metabolism and upregulating β- and γ-secretases. mTOR, an inhibitor of autophagy, decreases Aβ clearance by scissoring autophagy function. mTOR regulates Aβ generation or Aβ 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.

Keywords: Alzheimer’s disease; mammalian target of rapamycin; neurofibrillary tangles; rapamycin; signaling; β-amyloid.

Figure 1

Schematic diagram of the potential mechanism by which the activation of mTOR regulates Aβ. Notes: Aβ is generated from APP by the sequential cleavage of β-secretase and γ-secretase. The activation of mTOR could upregulate β- and γ-secretases in the process of Aβ generation. Additionally, the activation of mTOR contributes to the dysfunction of autophagy, which leads to accumulations of immature forms of AVs, enhancing the failure of Aβ clearance and the Aβ deposition and formation of Aβ plaques. Abbreviations: Akt, protein kinase B; AMPK, AMP-activated protein kinase; APP, amyloid precursor protein; AVs, autophagic vacuoles; GSK-3, glycogen synthase kinase 3; IGF-1, insulin-like growth factor 1; mTOR, mammalian target of rapamycin; PI3-K, phosphoinositide 3-kinase.