Genetic Reduction of Mammalian Target of Rapamycin Ameliorates Alzheimer's Disease-Like Cognitive and Pathological Deficits by Restoring Hippocampal Gene Expression Signature
Genetic Reduction of Mammalian Target of Rapamycin Ameliorates Alzheimer's Disease-Like Cognitive and Pathological Deficits by Restoring Hippocampal Gene Expression Signature
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DOI：
10.1523/jneurosci.0777-14.2014
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发表时间：
2014-06-04
影响因子：
5.3
通讯作者：
Oddo, Salvatore
中科院分区：
文献类型：
--
作者：
Caccamo, Antonella;De Pinto, Vito;Oddo, Salvatore
在阿尔茨海默病（AD）患者中发现了雷帕霉素（mTOR）信号转导的哺乳动物靶标升高，并与糖尿病和衰老（AD的两个已知风险因素）有关。然而，过度活跃的mTOR是否在与AD相关的认知缺陷中起作用仍然是难以捉摸的。在这里，我们在遗传上减少了Tg2576小鼠大脑中的mTOR信号传导，Tg2576小鼠是一种广泛使用的AD动物模型。我们发现，抑制mTOR信号减少了淀粉样蛋白β沉积并挽救了记忆缺陷。从机制上讲，mTOR信号的减少导致自噬诱导增加，并将Tg2576小鼠的海马基因表达特征恢复到野生型水平。我们的研究结果暗示过度活跃的mTOR信号传导是AD中基因表达失调和认知缺陷的潜在信号传导途径。此外，过度活跃的mTOR信号传导可能代表了衰老促进AD发展的分子途径。
Elevated mammalian target of rapamycin (mTOR) signaling has been found in Alzheimer's disease (AD) patients and is linked to diabetes and aging, two known risk factors for AD. However, whether hyperactive mTOR plays a role in the cognitive deficits associated with AD remains elusive. Here, we genetically reduced mTOR signaling in the brains of Tg2576 mice, a widely used animal model of AD. We found that suppression of mTOR signaling reduced amyloid-beta deposits and rescued memory deficits. Mechanistically, the reduction in mTOR signaling led to an increase in autophagy induction and restored the hippocampal gene expression signature of the Tg2576 mice to wild-type levels. Our results implicate hyperactive mTOR signaling as a previous unidentified signaling pathway underlying gene-expression dysregulation and cognitive deficits in AD. Furthermore, hyperactive mTOR signaling may represent a molecular pathway by which aging contributes to the development of AD.