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Deletion of Type-2 Cannabinoid Receptor Induces Alzheimer’s Disease-Like Tau Pathology and Memory Impairment Through AMPK/GSK3β Pathway

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Abstract

Although several studies have shown that type-2 cannabinoid receptor (CB2R) is involved in Alzheimer’s disease (AD) pathology, the effects of CB2R on AD-like tau abnormal phosphorylation and its underlying mechanism remain unclear. Herein, we employed the CB2R−/− mice as the animal model to explore roles of CB2R in regulating tau phosphorylation and brain function. We found that CB2R−/− mice display AD-like tau hyperphosphorylation, hippocampus-dependent memory impairment, increase of GSK3β activity, decrease of AMPK and Sirt1 activity and mitochondria dysfunction. Interestingly, AICAR or resveratrol (AMPK agonist) could efficiently rescue most alternations caused by solo deletion of CB2R in CB2R−/− mice. Moreover, JWH133, a selective agonist of CB2R, reduces phosphorylation of tau and GSK3β activity in HEK293 tau cells, but the effects of JWH133 on phosphorylation of tau and GSK3β disappeared while blocking AMPK activity with compound C or Prkaa2-RNAi. Taken together, our study indicated that deletion of CB2R induces behavior damage and AD-like pathological alternation via AMPK/GSK3β pathway. These findings proved that CB2R/AMPK/GSK3β pathway can be a promising new drug target for AD.

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Acknowledgements

This work was supported by the National Nature Scientific Fund of China (81671262 and 81171196) and Self-innovation fund of HUST and Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, HUST. The authors would like to thank Dr. Nancy E. Buckley for providing CB2R KO mice.

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  1. Lin Wang and Bing-Jin Liu contributed equally to this work.

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  1. Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Lin Wang, Bing-Jin Liu, Yun Cao, Wei-Qi Xu, Dong-Sheng Sun, Meng-Zhu Li, Fang-Xiao Shi, Qing Tian, Jian-Zhi Wang & Xin-Wen Zhou

  2. Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China

    Lin Wang, Bing-Jin Liu, Yun Cao, Wei-Qi Xu, Dong-Sheng Sun, Meng-Zhu Li, Fang-Xiao Shi, Man Li, Qing Tian, Jian-Zhi Wang & Xin-Wen Zhou

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Fig. S1

Inhibition of AMPK or CB2R causes tau hyperphosphorylation in HEK 293 tau cells. HEK293 tau cells were transfected with AMPK shRNA or scramble shRNA for 48 h, and then given AM630 for 24 h, the cell lysates were prepared for western blot. (a) The expression level of total tau (Tau5), phosphorylated tau (pT231, pS396), phosphorylated AMPK (pT172-AMPK) and CB2R. (b) Quantitation of the immunoreactivities to the antibodies shown in (a) respectively. The experiments were independently performed at least three times (n = 3), one-way ANOVA with a post hoc Tukey’s test, *p < 0.05, **p < 0.01 versus Scr; #P < 0.05, ##P < 0.01 versus Scr + AM630. Data were expressed as mean ± SEM (JPEG 332 kb)

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Wang, L., Liu, BJ., Cao, Y. et al. Deletion of Type-2 Cannabinoid Receptor Induces Alzheimer’s Disease-Like Tau Pathology and Memory Impairment Through AMPK/GSK3β Pathway. Mol Neurobiol 55, 4731–4744 (2018). https://doi.org/10.1007/s12035-017-0676-2

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