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Upregulation of AMPK Ameliorates Alzheimer’s Disease-Like Tau Pathology and Memory Impairment

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Abstract

The studies have shown that 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is involved in Alzheimer’s disease (AD) pathology, but the effects of AMPK on AD-like Tau abnormal phosphorylation and its underlying mechanism remains unclear. Herein, we found that the mRNA expression and activity of AMPK are significantly decreased in the brains of the aging C57 mice and 3 × Tg AD mice when compared with their respective control. Moreover, when downregulation of AMPK with AAV-siAMPK-eGFP in the hippocampus CA3 of 3-month-old C57 mice, the mice display AD-like Tau hyperphosphorylation, fear memory impairment, and glycogen synthase kinase-3β (GSK3β) activity increased. On the other hand, there are also AD-like Tau hyperphosphorylation, impairment of fear memory, and AMPK activity decreased in streptozotocin (STZ) mice. Interestingly, AMPK overexpression could efficiently rescue AD-like Tau phosphorylation and brain impairment in STZ mice. Moreover, the activity of GSK3β and the level of Tau phosphorylation (Ser396 and Thr231 sites) were significantly decreased in HEK293 Tau cells transfected by AMPK plasmid or treated with agonists salicylate (SS), but GSK3β agonists Wortmannin (Wort) could ablate AMPK-mediated Tau dephosphorylation. Taken together, the study indicated that AMPK reduces Tau phosphorylation and improves brain function and inhibits GSK3β in AD-like model. These findings proved that AMPK might be a new target for AD in the future.

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Funding

This work was supported by the National Nature Scientific Foundation of China (81671262, 81901105) and Natural Science Foundation of Anhui province (1908085QH357).

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  1. Lin Wang and Na Li contributed equally to this work.

Authors and Affiliations

  1. Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Lin Wang, Na Li, Fang-Xiao Shi, Wei-Qi Xu, Yun Cao, Ying Lei, Jian-Zhi Wang, Qing Tian & Xin-Wen Zhou

  2. Department of Pathophysiology, Wannan Medical College, Wuhu, 241001, China

    Lin Wang

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Wang, L., Li, N., Shi, FX. et al. Upregulation of AMPK Ameliorates Alzheimer’s Disease-Like Tau Pathology and Memory Impairment. Mol Neurobiol 57, 3349–3361 (2020). https://doi.org/10.1007/s12035-020-01955-w

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