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

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.

Unraveling the enigma: housekeeping gene Ugt1a7c as a universal biomarker for microglia

“…CX3CR1 plays a crucial role in regulating the inflammatory response and synapse maturation in CNS microglia ( 122 , 172 , 173 ). During postnatal brain development, the brain participates in synaptic pruning, a natural process in which brain microglia eliminate extra synapses ( 122 , 123 , 133 , 174 , 175 ). Interestingly, despite the relative stability of both Csf1r and Cx3cr1 expression, the fluctuation of their expression levels around 10-fold makes the two genes more suitable for distinguishing microglial subtypes rather than serving as housekeeping biomarkers for microglia ( 62 ).…”

The Intersection of cerebral cholesterol metabolism and Alzheimer's disease: Mechanisms and therapeutic prospects

“…Studies indicate that the use of the LXR agonist GW3965 can promote the uptake of myelin debris by microglia, reduce lipid droplet formation, and enhance the expression of the cholesterol transporter ABCA1, thereby slowing the progression of Tau protein pathology [ 173 ]. Additionally, the use of capsaicin can rescue lipid metabolism disturbances in ApoE4 neurons, restoring autophagy defects caused by AKT-mTOR pathway disruption [ 174 , 175 ]. Furthermore, research has shown that modulating CYP46A1 with efavirenz enhances cholesterol elimination and circulation in the brain [ 176 ].…”

Capsaicin: A Potential Treatment to Improve Cerebrovascular Function and Cognition in Obesity and Ageing

“…Jamornwan et al [ 140 ] found that nitro-capsaicin, in both vascular damaged and control microglial cell cultures, suppressed microglial activation, decreasing proinflammatory cytokines, such as TNF-α and IL-6, and enhanced anti-inflammatory factors, such as IL-4 and IL-10. Further, when mice with aberrant e4 apolipoprotein E (ApoE4) genes were given 1 mg/kg/day intraperitoneal capsaicin for 1 month, it reversed impaired lipid metabolism, microglial dysfunction, and other neuronal impairments induced by mutant ApoE4 [ 141 ]. This demonstrates the potential of capsaicin and capsaicin analogues to reduce chronic microglial activation, a risk factor of neurodegenerative disease and cognitive decline.…”