CNS Neuroscience & Therapeutics
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2023
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IF 5.5
Tao Zhang,Yuan Tian,Xiaoqing Zheng,Ruomeng Li,Li Hu,Xindong Shui,Yingxue Mei,Quling Wang,Mi Zhang,Xiuzhi Zheng,Long Wang,Dongmei Chen,Wucheng Tao,Tae Ho Lee
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.
研究领域:
神经科学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2022
·
IF 6.656
Chang-Long He,Yong Tang,Xue Chen,Tao Long,Yan-Ni He,Jing Wei,Jian-Ming Wu,Cai Lan,Lu Yu,Fei-Hong Huang,Cong-Wei Gu,Jian Liu,Chong-Lin Yu,Vincent Kam-Wai Wong,Betty Yuen-Kwan Law,Da-Lian Qin,An-Guo Wu,Xiao-Gang Zhou
Background Protein aggregates are considered key pathological features in neurodegenerative diseases (NDs). The induction of autophagy can effectively promote the clearance of ND-related misfolded proteins. Objective In this study, we aimed to screen natural autophagy enhancers from traditional Chinese medicines (TCMs) presenting potent neuroprotective potential in multiple ND models. Methods The autophagy enhancers were broadly screened in our established herbal extract library using the transgenic Caenorhabditis elegans ( C. elegans ) DA2123 strain. The neuroprotective effects of the identified autophagy enhancers were evaluated in multiple C. elegans ND models by measuring Aβ-, Tau-, α-synuclein-, and polyQ40-induced pathologies. In addition, PC-12 cells and 3 × Tg-AD mice were employed to further validate the neuroprotective ability of the identified autophagy enhancers, both in vitro and in vivo . Furthermore, RNAi bacteria and autophagy inhibitors were used to evaluate whether the observed effects of the identified autophagy enhancers were mediated by the autophagy-activated pathway. Results The ethanol extract of Folium Hibisci Mutabilis (FHME) was found to significantly increase GFP::LGG-1-positive puncta in the DA2123 worms. FHME treatment markedly inhibited Aβ , α-synuclein, and polyQ40, as well as prolonging the lifespan and improving the behaviors of C. elegans , while siRNA targeting four key autophagy genes partly abrogated the protective roles of FHME in C. elegans . Additionally, FHME decreased the expression of AD-related proteins and restored cell viability in PC-12 cells, which were canceled by cotreatment with 3-methyladenine (3-MA) or bafilomycin A1 (Baf). Moreover, FHME ameliorated AD-like cognitive impairment and pathology, as well as activating autophagy in 3 × Tg-AD mice. Conclusion FHME was successfully screened from our natural product library as a potent autophagy enhancer that exhibits a neuroprotective effect in multiple ND models across species through the induction of autophagy. These findings offer a new and reliable strategy for screening autophagy inducers, as well as providing evidence that FHME may serve as a possible therapeutic agent for NDs.
研究领域:
神经科学
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药理学
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中药
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自噬研究
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神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）