miR-132/ PTEN轴调控tau蛋白过度磷酸化的机制研究

Tau hyperphosphorylation is an important pathological feature of Alzheimer’s disease (AD). As a new potential biomarker of AD, miR-132 dysregulation has been reported correlates closely with tau hyperphosphorylation. However, the mechanism of miR-132 regulates tau phosphorylation remains elusive. Our previous studies have demonstrated that escitalopram attenuates tau hyperphosphorylation through the Akt/GSK-3β pathway in vitro and in vivo. Pre-experiment suggests that miR-132 expression is markedly downregulated under the environment of tau hyperphosphorylation, and Pten is a potential target gene of miR-132. So we hypothesized that miR-132 targeting Pten gene to inhibit PTEN expression, activating downstream Akt/GSK-3β signaling pathway, leading to the inhibition of tau phosphrylation. This project will use primary hippocampus neurons, P301L-tau transgenetic mice and the plasma of AD patients to study the effect and the mechanism of miR-132 on tau phosphortylation, and then to verify that escitalopram attenuates tau protein hyperphosphorylation via miR-132/PTEN/Akt/GSK-3β signaling axis. This project will reveal new mechanism for tau hyperphosphortylation from a new perspective of miR-132-PTEN-Akt/GSK-3β signaling, providing a new intervention target for the treatment of AD, also supporting theoretically for escitalopram used in prevention or treatment for AD.

tau蛋白过度磷酸化是AD的主要病理机制之一。作为AD潜在的生物标志物，miR-132与tau蛋白磷酸化密切相关，但miR-132调控tau蛋白磷酸化的机制不明。我们前期研究证实抗抑郁剂艾司西酞普兰通过Akt/GSK-3β减少tau蛋白过度磷酸化，预实验提示tau蛋白过度磷酸化时miR-132下调，PTEN是miR-132的靶基因。故提出假说：miR-132靶向PTEN，激活Akt/GSK-3β，抑制tau蛋白磷酸化。本项目拟采用原代海马神经元、P301L-tau转基因小鼠、AD患者血浆探究miR-132对tau蛋白磷酸化的调控作用及机制，验证艾司西酞普兰通过miR-132/PTEN/Akt/GSK-3β轴抑制tau蛋白过度磷酸化。本项目将从miR-132/PTEN/Akt/GSK-3β轴这一新视角揭示tau蛋白磷酸化的新机制，为AD提供新干预靶点，也为艾司西酞普兰用于治疗AD提供新证据。

tau蛋白过度磷酸化是AD的主要病理机制之一。作为AD潜在的生物标志物，miR-132与tau蛋白磷酸化密切相关，但miR-132调控tau蛋白磷酸化的机制不明。本项目采用原代海马神经元、P301L-tau转基因小鼠、AD患者血浆探究miR-132对tau蛋白磷酸化的调控作用及机制，验证了艾司西酞普兰通过miR-132/PTEN/Akt/GSK-3β轴抑制tau蛋白过度磷酸化。本项目从miR-132/PTEN/Akt/GSK-3β轴这一新视角揭示tau蛋白磷酸化的新机制，为AD提供新干预靶点，也为艾司西酞普兰用于治疗AD提供新证据。

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