TRPV1-Mediated Microglial Autophagy Attenuates Alzheimer’s Disease-Associated Pathology and Cognitive Decline

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.

Capsaicin Inhibits Shigella flexneri Intracellular Growth by Inducing Autophagy

“…Moreover, capsaicin is known to selectively bind to the TRPV1 receptor and induce calcium influx ( Liang et al, 2018 ; Allais et al, 2020 ). TRPV1 is expressed in intestinal cells and is known to induce autophagy ( Chen et al, 2021 ; Wang et al, 2021 ). Hence, Caps-induced autophagy might be due to TRPV1 activation.…”

Microglial Endocannabinoid Signalling in AD

“…Marked increases in CB 2 levels have also been found in the microglia of the APP/PS1 model [ 148 ]. Additionally, there is evidence concerning the alteration of TRPV1: in the brain of 3xTg (APP Swedish, tau P301L, and PSEN1 M146V) the expression of the receptor was found downregulated [ 128 ].…”

“…In the hippocampus and cortex of the 3xTg mice, microglial cells showed distinctive phenotypic changes, such as more protrusions and longer branch length, suggesting a less-activated state. In this model, the activation of TRPV1 via capsaicin decreased amyloid and phosphorylated tau pathology, reversed memory deficit and promoted microglia activation, metabolism and autophagy [ 128 ]. Notably, impaired autophagic flux was correlated with ageing, characterized by immune senescence of macrophages [ 158 ].…”

Transient Receptor Potential Vanilloid 1 Function at Central Synapses in Health and Disease

“…Disrupted TRPV1-mediated synaptic plasticity and metaplasticity may be involved, but this remains a matter of debate. For instance, TRPV1 activation or reinsertion prevents the shift in excitatory/inhibitory balance and restores normal brain oscillatory activity ( Balleza-Tapia et al, 2018 ), rescues hippocampal LTP and improves memory performance ( Chen et al, 2017 ; Du et al, 2020 ; Wang et al, 2020a , 2021 ). However, a recent report suggests that the absence of TRPV1 rescues memory deficits in AD ( Kim et al, 2020 ).…”