Activation of transient receptor potential vanilloid 1 ameliorates tau accumulation-induced synaptic damage and cognitive dysfunction via autophagy enhancement
© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
CNS neuroscience & therapeutics - 30(2024), 3 vom: 18. März, Seite e14432 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Tao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.03.2024 Date Revised 18.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/cns.14432 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM361398972 |
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| 100 | 1 | |a Zhang, Tao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Activation of transient receptor potential vanilloid 1 ameliorates tau accumulation-induced synaptic damage and cognitive dysfunction via autophagy enhancement |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Completed 07.03.2024 | ||
| 500 | |a Date Revised 18.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a autophagy | |
| 650 | 4 | |a capsaicin | |
| 650 | 4 | |a cognition | |
| 650 | 4 | |a tau | |
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| 650 | 4 | |a transient receptor potential vanilloid 1 | |
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| 650 | 7 | |a Capsaicin |2 NLM | |
| 650 | 7 | |a S07O44R1ZM |2 NLM | |
| 650 | 7 | |a tau Proteins |2 NLM | |
| 650 | 7 | |a TRPV Cation Channels |2 NLM | |
| 650 | 7 | |a TRPV1 protein, mouse |2 NLM | |
| 700 | 1 | |a Tian, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Xiaoqing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ruomeng |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Shui, Xindong |e verfasserin |4 aut | |
| 700 | 1 | |a Mei, Yingxue |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Quling |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Mi |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Xiuzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Long |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Dongmei |e verfasserin |4 aut | |
| 700 | 1 | |a Tao, Wucheng |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Tae Ho |e verfasserin |4 aut | |
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