TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia

Wang Chenfei; Lu Jia; Sha Xudong; Qiu Yu; Chen Hongzhuan; Yu Zhihua

doi:10.1038/s12276-023-00935-z

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자료유형: 학술저널

저자정보: Wang Chenfei (Shanghai Jiao Tong University School of Medicine) Lu Jia (Shanghai Jiao Tong University School of Medicine) Sha Xudong (Shanghai Jiao Tong University School of Medicine) Qiu Yu (Shanghai Jiao Tong University School of Medicine) Chen Hongzhuan (Shanghai Jiao Tong University School of Medicine) Yu Zhihua (Shanghai Jiao Tong University School of Medicine)

저널정보: 대한생화학·분자생물학회 Experimental and Molecular Medicine Experimental and Molecular Medicine 제55권

발행연도: 2023.2

수록면: 347 - 363 (17page)

DOI: 10.1038/s12276-023-00935-z

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Although the ε4 allele of the apolipoprotein E (ApoE4) gene has been established as a genetic risk factor for many neurodegenerative diseases, including Alzheimer’s disease, the mechanism of action remains poorly understood. Transient receptor potential vanilloid 1 (TRPV1) was reported to regulate autophagy to protect against foam cell formation in atherosclerosis. Here, we show that ApoE4 leads to lipid metabolism dysregulation in microglia, resulting in enhanced MHC-II-dependent antigen presentation and T-cell activation. Lipid accumulation and inflammatory reactions were accelerated in microglia isolated from TRPV1flox/flox; Cx3cr1cre-ApoE4 mice. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued lipid metabolic impairments in ApoE4 neurons and defects in autophagy caused by disruption of the AKT-mTOR pathway. TRPV1 activation with capsaicin reversed ApoE4-induced microglial immune dysfunction and neuronal autophagy impairment. Capsaicin rescued memory impairment, tau pathology, and neuronal autophagy in ApoE4 mice. Activation of TRPV1 decreased microglial phagocytosis of synapses in ApoE4 mice. TRPV1 gene deficiency exacerbated recognition memory impairment and tau pathology in ApoE4 mice. Our study suggests that TRPV1 regulation of lipid metabolism could be a therapeutic approach to alleviate the consequences of the ApoE4 allele.

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