A novel miR-4536-3p inhibition ameliorates Alzheimer's disease by reducing Aβ accumulation and tau phosphorylation.

IF 7.6 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's Research & Therapy Pub Date : 2025-08-12 DOI:10.1186/s13195-025-01834-3

Jiyun Choi, Dohee Kim, Haewon Jeong, Jinsu Hwang, Mahesh Ramalingam, Sujin Han, Hyong-Ho Cho, Byeong C Kim, Han-Seong Jeong, Sujeong Jang

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引用次数: 0

Abstract

Background: Alzheimer's disease (AD) is characterized by cognitive decline, amyloid-beta (Aβ) accumulation, and tau hyperphosphorylation. Effective therapies remain limited; therefore, recent studies have explored microRNAs as potential therapeutic targets.

Methods: miR-4536-3p inhibition was investigated using in vitro (SH-SY5Y cells) and in vivo (5xFAD mouse) AD models. Apoptosis, neuronal markers, and signaling pathways were assessed through functional assays. Cognitive effects were evaluated via the Morris water maze.

Results: miR-4536-3p inhibition increased an expression of Drebrin1 (DBN1), a key regulator of synaptic plasticity, but it reduced Aβ deposition, tau phosphorylation, and apoptosis. The treatment improved neuronal marker levels and significantly enhanced the spatial learning and memory of 5xFAD mice. Mechanistically, miR-4536-3p inhibition activated the PI3K/Akt/GSK3β signaling pathway, suppressing apoptosis and mitigating AD pathology.

Conclusion: miR-4536-3p inhibition offers a promising therapeutic strategy for AD by restoring the DBN1 expression, reducing neurodegeneration, and improving cognitive outcomes through PI3K/Akt pathway modulation.

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一种新的miR-4536-3p抑制通过减少Aβ积累和tau磷酸化来改善阿尔茨海默病。

背景：阿尔茨海默病（AD）以认知能力下降、β淀粉样蛋白（Aβ）积累和tau蛋白过度磷酸化为特征。有效的治疗仍然有限；因此，最近的研究已经探索了microrna作为潜在的治疗靶点。方法：采用体外（SH-SY5Y细胞）和体内（5xFAD小鼠）AD模型研究miR-4536-3p抑制作用。细胞凋亡、神经元标志物和信号通路通过功能测定进行评估。通过Morris水迷宫评估认知效果。结果：miR-4536-3p抑制增加了Drebrin1 （DBN1）的表达，DBN1是突触可塑性的关键调节因子，但它减少了a β沉积、tau磷酸化和细胞凋亡。治疗后5xFAD小鼠的神经元标记物水平明显提高，空间学习记忆能力明显增强。在机制上，miR-4536-3p抑制激活PI3K/Akt/GSK3β信号通路，抑制细胞凋亡，减轻AD病理。结论：miR-4536-3p抑制通过PI3K/Akt通路调节恢复DBN1表达，减少神经退行性变，改善认知结果，为AD提供了一种有希望的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's Research & Therapy 医学-神经病学

CiteScore

13.10

自引率

3.30%

发文量

172

审稿时长

>12 weeks

期刊介绍： Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.