PMID- 37641913 OWN - NLM STAT- MEDLINE DCOM- 20240307 LR - 20240418 IS - 1755-5949 (Electronic) IS - 1755-5930 (Print) IS - 1755-5930 (Linking) VI - 30 IP - 3 DP - 2024 Mar TI - Activation of transient receptor potential vanilloid 1 ameliorates tau accumulation-induced synaptic damage and cognitive dysfunction via autophagy enhancement. PG - e14432 LID - 10.1111/cns.14432 [doi] LID - e14432 AB - AIMS: The autophagy-lysosomal pathway is important for maintaining cellular proteostasis, while dysfunction of this pathway has been suggested to drive the aberrant intraneuronal accumulation of tau protein, leading to synaptic damage and cognitive impairment. Previous studies have demonstrated that the activation of transient receptor potential vanilloid 1 (TRPV1) by capsaicin has a positive impact on cognition and AD-related biomarkers. However, the effect and mechanism of TPRV1 activation on neuronal tau homeostasis remain elusive. METHODS: A mouse model of tauopathy was established by overexpressing full-length human tau in the CA3 area. Mice were fed capsaicin diet (0.0125%) or normal diet for 9 weeks. The cognitive ability, synaptic function, tau phosphorylation levels, and autophagy markers were detected. In vitro, capsaicin-induced alterations in cellular autophagy and tau degradation were characterized using two cell models. Besides, various inhibitors were applied to validate the role of TRPV1-mediated autophagy enhancement in tau clearance. RESULTS: We observed that TRPV1 activation by capsaicin effectively mitigates hippocampal tau accumulation-induced synaptic damages, gliosis, and cognitive impairment in vivo. Capsaicin promotes the degradation of abnormally accumulated tau through enhancing autophagic function in neurons, which is dependent on TRPV1-mediated activation of AMP-activated protein kinase (AMPK) and subsequent inhibition of the mammalian target of rapamycin (mTOR). Blocking AMPK activation abolishes capsaicin-induced autophagy enhancement and tau degradation in neurons. CONCLUSION: Our findings reveal that capsaicin-induced TRPV1 activation confers neuroprotection by restoring neuronal tau homeostasis via modulating cellular autophagy and provides additional evidence to support the potential of TRPV1 as a therapeutic target for tauopathies. CI - (c) 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd. FAU - Zhang, Tao AU - Zhang T AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Tian, Yuan AU - Tian Y AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Zheng, Xiaoqing AU - Zheng X AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Li, Ruomeng AU - Li R AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Hu, Li AU - Hu L AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Shui, Xindong AU - Shui X AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Mei, Yingxue AU - Mei Y AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Wang, Quling AU - Wang Q AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Zhang, Mi AU - Zhang M AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Zheng, Xiuzhi AU - Zheng X AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Wang, Long AU - Wang L AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Chen, Dongmei AU - Chen D AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Tao, Wucheng AU - Tao W AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. AD - Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. FAU - Lee, Tae Ho AU - Lee TH AUID- ORCID: 0000-0001-5968-1478 AD - Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China. LA - eng GR - XRCZX2019039/Fujian Medical University/ GR - 82001128/National Natural Science Foundation of China/ GR - 82271449/National Natural Science Foundation of China/ GR - 81970993/National Natural Science Foundation of China/ GR - 2021J01672/Natural Science Foundation of Fujian Province/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230829 PL - England TA - CNS Neurosci Ther JT - CNS neuroscience & therapeutics JID - 101473265 RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - 0 (Antineoplastic Agents) RN - S07O44R1ZM (Capsaicin) RN - 0 (tau Proteins) RN - 0 (TRPV Cation Channels) RN - 0 (TRPV1 protein, mouse) SB - IM MH - Animals MH - Humans MH - Mice MH - AMP-Activated Protein Kinases/metabolism MH - *Antineoplastic Agents MH - Autophagy MH - Capsaicin/pharmacology MH - *Cognitive Dysfunction/drug therapy MH - Mammals/metabolism MH - tau Proteins/metabolism MH - TRPV Cation Channels/metabolism PMC - PMC10916438 OTO - NOTNLM OT - autophagy OT - capsaicin OT - cognition OT - tau OT - tauopathy OT - transient receptor potential vanilloid 1 COIS- The authors declare no competing interests. EDAT- 2023/08/29 06:42 MHDA- 2024/03/07 06:43 PMCR- 2023/08/29 CRDT- 2023/08/29 04:33 PHST- 2023/06/27 00:00 [revised] PHST- 2023/05/02 00:00 [received] PHST- 2023/08/14 00:00 [accepted] PHST- 2024/03/07 06:43 [medline] PHST- 2023/08/29 06:42 [pubmed] PHST- 2023/08/29 04:33 [entrez] PHST- 2023/08/29 00:00 [pmc-release] AID - CNS14432 [pii] AID - 10.1111/cns.14432 [doi] PST - ppublish SO - CNS Neurosci Ther. 2024 Mar;30(3):e14432. doi: 10.1111/cns.14432. Epub 2023 Aug 29.