Abstract
Autophagy is a major regulator of the ageing process of the central nervous system and neurodegeneration. Autophagy dysfunction has been implicated in the pathogenesis of Alzheimer’s disease (AD). TRPV1 was reported to regulate autophagy to protect against foam cell formation and reduce the release of inflammatory factors in atherosclerosis. In this study, pharmacological activation of TRPV1 with the TRPV1 agonist capsaicin induced autophagy in a TRPV1-dependent manner in both primary microglia and BV2 cells. TRPV1-mediated autophagy regulated glycolysis and oxidative phosphorylation by controlling the expression of genes required for aerobic glycolysis and mitochondrial respiration in primary microglia. TRPV1 agonist capsaicin decreased amyloid and phosphorylated tau pathology and reversed memory deficits by promoting microglia activation, metabolism, and autophagy in 3xTg mice. These results indicate that TRPV1 was a potential therapeutic target for AD, which suggests that capsaicin should be further assessed as a possible treatment for AD.
Highlights
Autophagy is a major regulator of the ageing process of the central nervous system and neurodegeneration, during which toxic molecules and organelles aggregate in intracellular autophagosomes and are degraded in lysosomes (Menzies et al, 2015)
We found that upon Earle’s balanced salts solution (EBSS)-stimulation induced autophagy, transcripts of Myc, Irf4, and Hif1a were strongly induced in WT cells but not in transient receptor potential vanilloid type 1 (TRPV1)−/−-deficient or chloroquine-treated microglia (Figures 3B,C)
The results of the present study provide both in vitro and in vivo evidence that TRPV1-mediated autophagy reduced amyloid and phosphorylated tau pathology and attenuated cognitive decline in a murine model
Summary
Autophagy is a major regulator of the ageing process of the central nervous system and neurodegeneration, during which toxic molecules and organelles aggregate in intracellular autophagosomes and are degraded in lysosomes (Menzies et al, 2015). In the peripheral immune system, autophagy was shown to involve innate and adaptive responses (Hanisch and Kettenmann, 2007), antigen presentation process, and phagocytosis (Münz, 2016). Both immune tolerance and chronic inflammation during aging have shown to correlate with autophagy flux impairment in macrophages (Stranks et al, 2015). While few studies have evaluated the role of autophagy on microglia immune function including phagocytosis and inflammation, as well as the possible impact of autophagy dysregulation of these brain-resident macrophages during the pathological condition such as AD. To explain the potential beneficial effect of a TRPV1 agonist in AD, the use of 3xTg mice models demonstrated that TRPV1 was a potential therapeutic target for AD and TRPV1-mediated microglial autophagy
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