mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies.
mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies.
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DOI：
10.1111/acel.12057
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发表时间：
2013-06
期刊：
影响因子：
7.8
通讯作者：
Oddo S
中科院分区：
文献类型：
--
作者：
Caccamo A;Magrì A;Medina DX;Wisely EV;López-Aranda MF;Silva AJ;Oddo S
tau蛋白的积累是几种神经退行性疾病中的关键事件，统称为tau蛋白病，包括阿尔茨海默病和额颞叶痴呆。病理性tau过度磷酸化并聚集形成神经元缠结。导致tau蛋白积累的分子机制仍不清楚，需要做更多的工作来阐明它们。年龄是所有tau蛋白病的主要风险因素，这表明有助于衰老过程的分子变化可能促进tau蛋白积累，并代表不同tau蛋白病的共同机制。在这里，我们使用多种动物模型和互补的遗传和药理学方法来证明哺乳动物雷帕霉素靶蛋白（mTOR）调节tau蛋白的磷酸化和降解。具体来说，我们表明，基因增加mTOR活性提高内源性小鼠tau蛋白水平和磷酸化。作为补充，我们进一步证明，在过表达突变型人tau的小鼠模型中，用雷帕霉素减少mTOR信号转导可改善tau病理学和相关的行为缺陷。从机制上讲，我们提供了令人信服的证据表明mTOR和tau之间的关联与GSK 3 β和自噬功能有关。总之，我们表明增加mTOR信号传导促进tau病理，而减少mTOR信号传导改善tau病理。鉴于压倒性的证据表明，减少mTOR信号传导可以增加寿命和健康寿命，本文提供的数据对衰老和tau蛋白病具有深远的临床意义，并为衰老如何导致tau蛋白病提供了分子基础。此外，这些结果提供了临床前数据，表明减少mTOR信号传导可能是tau蛋白病的有效治疗方法。
Accumulation of tau is a critical event in several neurodegenerative disorders, collectively known as tauopathies, which include Alzheimer’s disease and frontotemporal dementia. Pathological tau is hyperphosphorylated and aggregates to form neurofibrillary tangles. The molecular mechanisms leading to tau accumulation remain unclear and more needs to be done to elucidate them. Age is a major risk factor for all tauopathies, suggesting that molecular changes contributing to the aging process may facilitate tau accumulation and represent common mechanisms across different tauopathies. Here, we use multiple animal models and complementary genetic and pharmacological approaches to show that the mammalian target of rapamycin (mTOR) regulates tau phosphorylation and degradation. Specifically, we show that genetically increasing mTOR activity elevates endogenous mouse tau levels and phosphorylation. Complementary to it, we further demonstrate that pharmacologically reducing mTOR signaling with rapamycin ameliorates tau pathology and the associated behavioral deficits in a mouse model overexpressing mutant human tau. Mechanistically, we provide compelling evidence that the association between mTOR and tau is linked to GSK3β and autophagy function. In summary, we show that increasing mTOR signaling facilitates tau pathology while reducing mTOR signaling ameliorates tau pathology. Given the overwhelming evidence showing that reducing mTOR signaling increases lifespan and health span, the data presented here have profound clinical implications for aging and tauopathies and provide the molecular basis for how aging may contribute to tau pathology. Additionally, these results provide pre-clinical data indicating that reducing mTOR signaling may be a valid therapeutic approach for tauopathies.
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DOI：
10.1073/pnas.1012851108
发表时间：
2010-12-28
影响因子：
11.1
作者：
Caccamo, Antonella;Maldonado, Monica A.;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
影响因子：
120.1
作者：
Cohen, P;Goedert, M
通讯作者：
Goedert, M
影响因子：
16.2
作者：
Oddo, S;Billings, L;LaFerla, FM
通讯作者：
LaFerla, FM
影响因子：
15.1
作者：
Caccamo A;Magrí A;Oddo S
通讯作者：
Oddo S
影响因子：
3.1
作者：
Gipson TT;Johnston MV
通讯作者：
Johnston MV