Genetically reducing mTOR signaling rescues central insulin dysregulation in a mouse model of Alzheimer's disease.
Genetically reducing mTOR signaling rescues central insulin dysregulation in a mouse model of Alzheimer's disease.
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DOI：
10.1016/j.neurobiolaging.2018.03.032
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发表时间：
2018-08
影响因子：
4.2
通讯作者：
Oddo S
中科院分区：
文献类型：
--
作者：
Caccamo A;Belfiore R;Oddo S
阿尔茨海默病（AD）是最常见的神经退行性疾病。散发性 AD 占 AD 病例的 95% 以上，其原因尚不清楚。已经确定了一些 AD 危险因素，其中，二型糖尿病使患 AD 的风险增加两倍。然而，糖尿病导致 AD 发病的机制仍不清楚。哺乳动物雷帕霉素靶蛋白 (mTOR) 是一种蛋白激酶，在胰岛素信号通路中发挥着至关重要的作用，并与 AD 相关。我们使用杂交策略从 Tg2576 小鼠（AD 小鼠模型）的前脑中去除 mTOR 基因的一个拷贝。我们使用 20 个月大的小鼠来评估中枢胰岛素信号传导的变化，发现 Tg2576 小鼠的胰岛素信号传导受损。这些损伤与 mTOR 相关，因为我们发现大脑 mTOR 活性较低的小鼠的中枢胰岛素信号传导有所改善。此外，从 Tg2576 小鼠中去除一份 mTOR 可以改善认知能力并降低 Aβ、tau 和细胞因子的水平。我们的研究结果表明，mTOR 信号传导是 Tg2576 中枢胰岛素功能障碍的关键介质。这些数据进一步强调了 mTOR 信号传导在 AD 发病机制中的可能作用，并增加了证据表明降低 mTOR 活性可能是 AD 的有效治疗方法。
Alzheimer’s disease (AD) is the most common neurodegenerative disease. The causes of sporadic AD, which represents more than 95% of AD cases, are unknown. Several AD risk factors have been identified and among these, type two diabetes increases the risk of developing AD by two-fold. However, the mechanisms by which diabetes contributes to AD pathogenesis remain elusive. The mammalian target of rapamycin (mTOR) is a protein kinase that plays a crucial role in the insulin signaling pathway and has been linked to AD. We used a crossbreeding strategy to remove one copy of the mTOR gene from the forebrain of Tg2576 mice, a mouse model of AD. We used 20-month-old mice to assess changes in central insulin signaling and found that Tg2576 mice had impaired insulin signaling. These impairments were mTOR dependent as we found an improvement in central insulin signaling in mice with lower brain mTOR activity. Further, removing one copy of mTOR from Tg2576 mice improved cognition and reduced levels of Aβ, tau, and cytokines. Our findings indicate that mTOR signaling is a key mediator of central insulin dysfunction in Tg2576. These data further highlight a possible role for mTOR signaling in AD pathogenesis and add to the body of evidence indicating that reducing mTOR activity could be a valid therapeutic approach for AD.
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影响因子：
4.8
作者：
Llorens-Martín M;Jurado J;Hernández F;Avila J
通讯作者：
Avila J
影响因子：
7.8
作者：
Caccamo A;Magrì A;Medina DX;Wisely EV;López-Aranda MF;Silva AJ;Oddo S
通讯作者：
Oddo S
影响因子：
4.3
作者：
King, George L.
通讯作者：
King, George L.
影响因子：
5.3
作者：
Caccamo, Antonella;De Pinto, Vito;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
影响因子：
16.2
作者：
HSIAO, KK;BORCHELT, DR;CARLSON, G
通讯作者：
CARLSON, G