Abstract

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. A chili pepper extract that activates a sensory protein helps to improve lipid metabolism in immune cells in the brain, leading to better nerve cell health in a mouse model of Alzheimer’s disease. A team led by Zhihua Yu and Hongzhuan Chen from the Shanghai Jiao Tong University School of Medicine, China, showed that mice carrying the ApoE4 risk factor gene for Alzheimer’s exhibited defects in how well their brain’s immune cells, known as microglia, processed lipids. These problems were exacerbated when the microglia lacked a working version of a sensory protein called TRPV1. Boosting the activity of this protein with capsaicin, a TRPV1-stimulating molecule found in hot chili peppers, reversed the metabolic defects, leading to improved microglial function, reduced Alzheimer’s-associated brain pathology and enhanced memory in the mice.