Rapamycin Ameliorates Cognitive Impairments and Alzheimer's Disease-Like Pathology with Restoring Mitochondrial Abnormality in the Hippocampus of Streptozotocin-Induced Diabetic Mice
Rapamycin Ameliorates Cognitive Impairments and Alzheimer's Disease-Like Pathology with Restoring Mitochondrial Abnormality in the Hippocampus of Streptozotocin-Induced Diabetic Mice
复制标题
雷帕霉素通过恢复链脲佐菌素诱导的糖尿病小鼠海马线粒体异常改善认知障碍和阿尔茨海默病样病理
DOI：
10.1007/s11064-020-03160-6
复制
发表时间：
2020-11-02
影响因子：
4.4
通讯作者：
Tang, Zhi
中科院分区：
文献类型：
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作者：
Ding, Yuanting;Liu, Heng;Tang, Zhi
阿尔茨海默病 (AD) 和糖尿病 (DM) 有共同的病理生理学发现，特别是哺乳动物雷帕霉素靶点 (mTOR) 被强烈暗示与 AD 相关，同时它也在胰岛素信号通路中发挥着关键作用。然而，DM 和 AD 耦合的机制仍然难以捉摸。在本研究中，我们发现链脲佐菌素（STZ）诱导的DM小鼠的P-mTOR Ser2448、P-p70S6K Thr389、P-tau Ser356和A beta（A beta寡聚体/单体）水平显着升高，并且Drp1和p-Drp1 S616（线粒体裂变蛋白）水平升高，而在Opa1、Mfn1 和 Mfn2（线粒体融合蛋白）与对照小鼠相比。此外，STZ 诱导的 DM 小鼠海马体中 4-HNE 和 8-OHdG 的表达异常增加，这与空间记忆能力下降和突触丧失有关。雷帕霉素是一种 mTOR 抑制剂，可以挽救 STZ 诱导的小鼠 mTOR/p70S6K 活性、tau 磷酸化和 Aβ 水平的增加，以及线粒体异常和认知障碍。这些发现表明雷帕霉素可以预防认知障碍并保护海马神经元免受 AD 样病理和线粒体异常的影响，并且雷帕霉素治疗可以通过减少海马 mTOR/p70S6K 过度活跃来使这些 STZ 诱导的改变正常化。
Alzheimer's disease (AD) and diabetes mellitus (DM) share common pathophysiological findings, in particular, the mammalian target of rapamycin (mTOR) has been strongly implied to link to AD, while it also plays a key role in the insulin signaling pathway. However, the mechanism of how DM and AD is coupled remains elusive. In the present study, we found that streptozotocin (STZ)-induced DM mice significantly increased the levels P-mTOR Ser2448, P-p70S6K Thr389, P-tau Ser356 and A beta levels (A beta oligomer/monomer), as well as the levels of Drp1 and p-Drp1 S616 (mitochondrial fission proteins) are increased, whereas no change was found in the expression of Opa1, Mfn1 and Mfn2 (mitochondrial fusion proteins) compared with control mice. Moreover, the expression of 4-HNE and 8-OHdG showed an aberrant increase in the hippocampus of STZ-induced DM mice that is associated with a decreased capacity of spatial memory and a loss of synapses. Rapamycin, an inhibitor of mTOR, rescued the STZ-induced increases in mTOR/p70S6K activities, tau phosphorylation and A beta levels, as well as mitochondria abnormality and cognitive impairment in mice. These findings imply that rapamycin prevents cognitive impairment and protects hippocampus neurons from AD-like pathology and mitochondrial abnormality, and also that rapamycin treatment could normalize these STZ-induced alterations by decreasing hippocampus mTOR/p70S6K hyperactivity.