Activation of AMPK by GLP-1R agonists mitigates Alzheimer-related phenotypes in transgenic mice.

IF 17 Q1 CELL BIOLOGY
Nature aging Pub Date : 2025-06-01 Epub Date: 2025-05-20 DOI:10.1038/s43587-025-00869-3
Yun Zhang, Huaqiu Chen, Yijia Feng, Mingjing Liu, Zhi Lu, Bolang Hu, Lifen Chen, Yang Zhang, Jiawen Liu, Fang Cai, Yifan Zhao, Wenhao Pan, Xinxin Liao, Sipei Pan, Isabel Bestard-Lorigados, Yili Wu, Weihong Song
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Abstract

Individuals with type 2 diabetes mellitus have an increased risk of developing Alzheimer's disease (AD). GLP-1 receptor agonists (GLP-1RAs) are used for glycemic control in diabetes and show potential neuroprotective properties, but their effects on AD and the underlying mechanisms are not well understood. Here we demonstrate that GLP-1RAs can alleviate AD-related phenotypes by activating 5' AMP-activated protein kinase (AMPK) signaling. We found that plasma GLP-1 levels were decreased in AD model mice and negatively correlated with amyloid-beta (Aβ) load in patients with AD. Enhancing GLP-1 signaling through GLP-1RAs increased CaMKK2-AMPK signaling, which subsequently reduced BACE1-mediated cleavage of amyloid precursor protein (APP) and Aβ generation. GLP-1RAs also increased AMPK activity in microglia, inhibiting neuroinflammation and promoting Aβ phagocytosis. Consequently, GLP-1RAs inhibited plaque formation and improved memory deficits in AD model mice. Our findings indicate that AMPK activation mediates the effects of GLP-1RAs on AD, highlighting the therapeutic potential of GLP-1RAs for the treatment of AD.

GLP-1R激动剂激活AMPK可减轻转基因小鼠的阿尔茨海默病相关表型。
2型糖尿病患者患阿尔茨海默病(AD)的风险增加。GLP-1受体激动剂(GLP-1RAs)用于糖尿病患者的血糖控制,并显示出潜在的神经保护特性,但其对AD的作用及其潜在机制尚不清楚。在这里,我们证明GLP-1RAs可以通过激活5' amp激活的蛋白激酶(AMPK)信号来缓解ad相关表型。我们发现,AD模型小鼠血浆GLP-1水平降低,并与AD患者β淀粉样蛋白(Aβ)负荷负相关。通过GLP-1RAs增强GLP-1信号,增加CaMKK2-AMPK信号,随后减少bace1介导的淀粉样蛋白前体蛋白(APP)的裂解和Aβ的产生。GLP-1RAs还能提高小胶质细胞AMPK活性,抑制神经炎症,促进Aβ吞噬。因此,GLP-1RAs抑制斑块形成,改善AD模型小鼠的记忆缺陷。我们的研究结果表明,AMPK激活介导GLP-1RAs对AD的作用,突出了GLP-1RAs治疗AD的治疗潜力。
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
CiteScore
14.70
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0.00%
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