Activation of mTOR: a culprit of Alzheimer's disease?
Activation of mTOR: a culprit of Alzheimer's disease?
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DOI：
10.2147/ndt.s75717
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发表时间：
2015
影响因子：
3.2
通讯作者：
Yan LJ
中科院分区：
文献类型：
--
作者：
Cai Z;Chen G;He W;Xiao M;Yan LJ
阿尔茨海默病(AD)的临床表现以认知功能障碍为特征，基础研究以β-淀粉样蛋白(A-β)的产生和tau的过度磷酸化为特征。更多的亮点表明，哺乳动物雷帕霉素靶标(MTOR)的激活通过调节淀粉样前体蛋白(APP)的代谢和上调β-和β-分泌酶来促进Aγ的生成和沉积。MTOR是一种自噬的抑制剂，通过剪裁自噬功能来减少Aβ的清除。MTOR通过调节几个关键信号通路来调节Aβ的生成或Aβ的清除，这些信号通路包括磷脂酰肌醇3-K/蛋白激酶B、糖原合成酶-3、腺苷活化蛋白激酶和胰岛素/胰岛素样生长因子-1。MTOR的激活也是tau异常过度磷酸化的原因之一。MTOR的抑制剂雷帕霉素可能通过促进自噬来减轻认知损害，抑制与淀粉样斑块和神经原纤维缠结相关的病理改变。此外，mTOR信号的上游和下游成分参与了AD的发生和发展。因此，抑制mTOR的激活可能是AD治疗的一个重要靶点。
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.