MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice.
MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice.
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DOI：
10.1172/jci.insight.166270
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发表时间：
2023-06-22
期刊：
影响因子：
8
通讯作者：
Zhu, Xiaolei
中科院分区：
文献类型：
--
作者：
Ge, Jianwei;Xue, Zhiwei;Shu, Shu;Yu, Linjie;Qin, Ruomeng;Tao, Wenyuan;Liu, Pinyi;Dong, Xiaohong;Lan, Zhen;Bao, Xinyu;Ye, Lei;Xu, Yun;Zhu, Xiaolei
突触可塑性损伤在阿尔茨海默病（AD）的发病机制中起着关键作用，并且新的证据表明microRNA（miRs）是AD中突触功能障碍的替代生物标志物和治疗靶点。在本研究中，我们发现miR-431在遗忘型轻度认知功能障碍和AD患者的血浆中水平下调。此外，在APPswe/PS1 dE 9（APP/PS1）小鼠的海马和血浆中，它也减少。慢病毒介导的miR-431在海马CA 1区的过表达改善了APP/PS1小鼠的突触可塑性和记忆缺陷，但不影响淀粉样蛋白-β水平。Smad 4被鉴定为miR-431的靶点，Smad 4敲低可调节突触蛋白（包括SAP 102）的表达，并保护APP/PS 1小鼠免受突触可塑性和记忆功能障碍的影响。此外，Smad 4过表达逆转了miR-431的保护作用，表明miR-431至少部分地通过Smad 4抑制来减弱突触损伤。这些结果表明miR-431/Smad 4可能是AD治疗的潜在靶点。
Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and emerging evidence has shown that microRNAs (miRs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of patients with amnestic mild cognitive impairment and AD. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus-mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it did not affect amyloid-β levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins, including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.
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