新型miR-4536-3p抑制通过减少β淀粉样蛋白积累和tau蛋白磷酸化改善阿尔茨海默病。

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

作者信息

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

机构信息

Department of Physiology, Chonnam National University Medical School, Jeollanamdo, 58128, Republic of Korea.

Healthcare Advanced Chemical Research Institute, Korea Testing and Research Institute, Jeollanamdo, 58141, Republic of Korea.

出版信息

Alzheimers Res Ther. 2025 Aug 12;17(1):189. doi: 10.1186/s13195-025-01834-3.

DOI:10.1186/s13195-025-01834-3

PMID:40796907

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.

摘要

背景

阿尔茨海默病（AD）的特征是认知功能下降、β-淀粉样蛋白（Aβ）积累和tau蛋白过度磷酸化。有效的治疗方法仍然有限；因此，最近的研究探索了微小RNA作为潜在的治疗靶点。

方法

使用体外（SH-SY5Y细胞）和体内（5xFAD小鼠）AD模型研究miR-4536-3p抑制作用。通过功能测定评估细胞凋亡、神经元标志物和信号通路。通过莫里斯水迷宫评估认知效应。

结果

抑制miR-4536-3p可增加突触可塑性关键调节因子 drebrin1（DBN1）的表达，但可减少Aβ沉积、tau蛋白磷酸化和细胞凋亡。该治疗提高了神经元标志物水平，并显著增强了5xFAD小鼠的空间学习和记忆能力。机制上，抑制miR-4536-3p可激活PI3K/Akt/GSK3β信号通路，抑制细胞凋亡并减轻AD病理。