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miR-431 可减轻 APPswe/PS1dE9 小鼠的突触可塑性和记忆缺陷。

MiR-431 attenuates synaptic plasticity and memory deficits in APPswe/PS1dE9 mice.

机构信息

Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School.

Department of Neurology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases; and.

出版信息

JCI Insight. 2023 Jun 22;8(12):e166270. doi: 10.1172/jci.insight.166270.

DOI:10.1172/jci.insight.166270
PMID:37192007
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10371242/
Abstract

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.

摘要

突触可塑性障碍在阿尔茨海默病（AD）的发病机制中起着关键作用，新出现的证据表明 microRNAs（miRs）是 AD 中突触功能障碍的替代生物标志物和治疗靶点。在这项研究中，我们发现 miR-431 的水平在遗忘型轻度认知障碍和 AD 患者的血浆中下调。此外，它在 APPswe/PS1dE9（APP/PS1）小鼠的海马体和血浆中也减少了。在海马体 CA1 中过表达 miR-431 的慢病毒可改善 APP/PS1 小鼠的突触可塑性和记忆缺陷，而不影响淀粉样蛋白-β水平。Smad4 被鉴定为 miR-431 的靶标，Smad4 敲低调节了突触蛋白的表达，包括 SAP102，并保护 APP/PS1 小鼠免受突触可塑性和记忆功能障碍的影响。此外，Smad4 的过表达逆转了 miR-431 的保护作用，表明 miR-431 通过抑制 Smad4 至少部分减轻了突触损伤。因此，这些结果表明 miR-431/Smad4 可能是 AD 治疗的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/fbdbe646c770/jciinsight-8-166270-g239.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/d3b74d2591b1/jciinsight-8-166270-g232.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/5223349f936b/jciinsight-8-166270-g235.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/85e824845db4/jciinsight-8-166270-g236.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/17cfbb793c77/jciinsight-8-166270-g237.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/418639640a9a/jciinsight-8-166270-g238.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/fbdbe646c770/jciinsight-8-166270-g239.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/d3b74d2591b1/jciinsight-8-166270-g232.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/dd6057fb56e7/jciinsight-8-166270-g233.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/24639737f1f2/jciinsight-8-166270-g234.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/5223349f936b/jciinsight-8-166270-g235.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/85e824845db4/jciinsight-8-166270-g236.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/17cfbb793c77/jciinsight-8-166270-g237.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/418639640a9a/jciinsight-8-166270-g238.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c5fc/10371242/fbdbe646c770/jciinsight-8-166270-g239.jpg

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