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

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

  • Nat Aging. 2025 Jun;5(6):1097-1113. doi: 10.1038/s43587-025-00869-3.
Yun Zhang # 1 2,  Huaqiu Chen # 3,  Yijia Feng # 4 5,  Mingjing Liu 6,  Zhi Lu 7,  Bolang Hu 4 5,  Lifen Chen 5,  Yang Zhang 8,  Jiawen Liu 3,  Fang Cai 5,  Yifan Zhao 4 5,  Wenhao Pan 4 5,  Xinxin Liao 9,  Sipei Pan 5,  Isabel Bestard-Lorigados 10,  Yili Wu 4 5,  Weihong Song 11 12 13
Affiliations

Affiliations

  • 1 Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. zhangyun_202104@163.com.
  • 2 National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China. zhangyun_202104@163.com.
  • 3 National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China.
  • 4 The Second Affiliated Hospital and Yuying Children's Hospital, Zhejiang Key Laboratory of Alzheimer's Disease, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou Medical University, Wenzhou, China.
  • 5 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
  • 6 Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 7 Department of Nuclear Medicine, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
  • 8 National Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.
  • 9 Department of Geriatric Neurology, Xiangya Hospital, Central South University, Changsha, China.
  • 10 Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, University of British Columbia, Vancouver, British Columbia, Canada.
  • 11 The Second Affiliated Hospital and Yuying Children's Hospital, Zhejiang Key Laboratory of Alzheimer's Disease, Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou Medical University, Wenzhou, China. weihong@wmu.edu.cn.
  • 12 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Center for Geriatric Medicine and Institute of Aging, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China. weihong@wmu.edu.cn.
  • 13 Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, University of British Columbia, Vancouver, British Columbia, Canada. weihong@wmu.edu.cn.
  • # Contributed equally.
PMID: 40394225 DOI: 10.1038/s43587-025-00869-3
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.

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