Alteration of the Wnt/GSK3/-catenin signalling pathway by rapamycin ameliorates pathology in an Alzheimer's disease model
Alteration of the Wnt/GSK3/-catenin signalling pathway by rapamycin ameliorates pathology in an Alzheimer's disease model
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DOI：
10.3892/ijmm.2019.4198
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发表时间：
2019-07-01
影响因子：
5.4
通讯作者：
He, Guiqiong
中科院分区：
文献类型：
--
作者：
Chen, Jingfei;Long, Zhimin;He, Guiqiong
糖原合成酶激酶3（glycogen synthase kinase 3，GSK 3）的异常激活是阿尔茨海默病（Alzheimer's disease，AD）的发病机制之一，其导致淀粉样肽（amyloid -peptide，A）斑块过度产生、Tau蛋白过度磷酸化和神经元丢失。许多研究已经报道，雷帕霉素的哺乳动物靶蛋白（mTOR）的激活有助于A的产生和沉积，以及通过抑制自噬而形成神经元缠结（NFT）。GSK 3也参与mTOR信号通路。然而，通过调节GSK 3的功能来抑制mTOR的活化是否影响AD的病理仍不清楚。在这项研究中，我们腹腔注射淀粉样前体蛋白（APP）/早老素-1（PS1）转基因小鼠与雷帕霉素，一种已知的自噬激活剂，抑制mTOR。我们的研究结果表明，雷帕霉素治疗减少老年斑沉积，减少APP的产生，并下调-和-分泌酶活性。雷帕霉素还通过促进自噬增加A清除率，并通过上调胰岛素降解酶的水平减少Tau过度磷酸化。此外，雷帕霉素显著促进了稳定转染APPswe基因的分化SH-SY 5 Y细胞的增殖，并防止了AD模型小鼠脑中的神经元丢失。此外，雷帕霉素诱导自噬和促进自溶体降解。在这项研究中，我们提供的证据表明，雷帕霉素抑制GSK 3的激活和提高-catenin的表达，通过提高Wnt 3a的表达水平，这有利于改善AD的病理。总的来说，我们的研究结果表明，雷帕霉素抑制mTOR的激活，并改变Wnt/GSK 3/-catenin信号通路;因此，它可能作为治疗AD的治疗靶点。
The abnormal activation of glycogen synthase kinase 3 (GSK3) is one of the mechanisms involved in the pathogenesis of Alzheimer's disease (AD), which results in amyloid -peptide (A) plaque overproduction, Tau hyper-phosphorylation and neuronal loss. A number of studies have reported that the activation of the mammalian target of rapamycin (mTOR) contributes to the generation and deposition of A, as well as to the formation of neurofibrillary tangles (NFTs) by inhibiting autophagy. GSK3 is also involved in the mTOR signalling pathway. However, whether the inhibition of the activation of mTOR via the regulation of the function of GSK3 affects the pathology of AD remains unclear. In this study, we intraperitoneally injected amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice with rapamycin, a known activator of autophagy that inhibits mTOR. Our results revealed that rapamycin treatment decreased senile plaque deposition by reducing APP generation, and downregulating - and -secretase activity. Rapamycin also increased A clearance by promoting autophagy and reduced Tau hyperphosphorylation by upregulating the levels of insulin-degrading enzyme. Additionally, rapamycin markedly promoted the proliferation of differentiated SH-SY5Y cells stably transfected with the APPswe gene and prevented neuronal loss in the brains of mice in a model of AD. Moreover, rapamycin induced autophagy and promoted autolysosome degradation. In this study, we provide evidence that rapamycin inhibits GSK3 activation and elevates -catenin expression by improving the Wnt3a expression levels, which facilitates the amelioration of AD pathology. On the whole, our findings indicate that rapamycin inhibits the activation of mTOR and alters the Wnt/GSK3/-catenin signalling pathway; thus, it may serve as a therapeutic target in the treatment of AD.