Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau EFFECTS ON COGNITIVE IMPAIRMENTS
Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau EFFECTS ON COGNITIVE IMPAIRMENTS
复制标题
DOI：
10.1074/jbc.m110.100420
复制
发表时间：
2010-04-23
影响因子：
4.8
通讯作者：
Oddo, Salvatore
中科院分区：
文献类型：
--
作者：
Caccamo, Antonella;Majumder, Smita;Oddo, Salvatore
淀粉样蛋白-β（A β）和Tau的积累是阿尔茨海默病（AD）的不变特征。A β积累在疾病发病机制中的上游作用被广泛接受，并且有强有力的证据表明A β积累导致认知障碍。然而，将A β与认知能力下降联系起来的分子机制仍有待阐明。在这里，我们发现A β的积累增加了哺乳动物雷帕霉素靶蛋白（mTOR）信号传导，而降低mTOR信号传导降低了A β水平，从而突出了mTOR信号传导和A β之间的相互关系。mTOR通路在控制蛋白质稳态和神经元功能中起着核心作用;实际上，mTOR信号传导调节不同形式的学习和记忆。使用AD的动物模型，我们表明，用雷帕霉素恢复mTOR信号传导可以挽救认知缺陷，并通过增加自噬来改善A β和Tau病理。事实上，我们进一步表明自噬诱导对于雷帕霉素介导的A β水平降低是必要的。本文提供的结果为A β诱导的认知缺陷提供了分子基础，此外，还表明FDA批准的药物雷帕霉素可改善学习和记忆，并减少A β和Tau病理。
Accumulation of amyloid-beta (A beta) and Tau is an invariant feature of Alzheimer disease (AD). The upstream role of A beta accumulation in the disease pathogenesis is widely accepted, and there is strong evidence showing that A beta accumulation causes cognitive impairments. However, the molecular mechanisms linking A beta to cognitive decline remain to be elucidated. Here we show that the buildup of A beta increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing mTOR signaling reduces A beta levels, thereby highlighting an interrelation between mTOR signaling and A beta. The mTOR pathway plays a central role in controlling protein homeostasis and hence, neuronal functions; indeed mTOR signaling regulates different forms of learning and memory. Using an animal model of AD, we show that pharmacologically restoring mTOR signaling with rapamycin rescues cognitive deficits and ameliorates A beta and Tau pathology by increasing autophagy. Indeed, we further show that autophagy induction is necessary for the rapamycin mediated reduction in A beta levels. The results presented here provide a molecular basis for the A beta-induced cognitive deficits and, moreover, show that rapamycin, an FDA approved drug, improves learning and memory and reduces A beta and Tau pathology.