TRPV1 sustains microglial metabolic reprogramming in Alzheimer's disease

• Published in: EMBO reports 2021-06, Vol.22 (6), p.e52013-n/a
• Main Authors: Lu, Jia, Zhou, Wei, Dou, Fangfang, Wang, Chenfei, Yu, Zhihua
• Format: Article
• Language: English
• Subjects: Agonists; AKT protein; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Animal models; Animals; Autophagy; capsaicin; Capsaicin receptors; Defects; Disease Models, Animal; EMBO19; EMBO21; EMBO27; Energy metabolism; Glycolysis; Immune response; Immune system; Immunological memory; Impairment; Metabolic disorders; Metabolic rate; Metabolism; Mice; Mice, Transgenic; Microglia; Microglia - metabolism; Neurodegenerative diseases; Oxidative phosphorylation; Pathogenesis; Pathology; Phagocytes; Phagocytosis; Pharmacology; Phosphorylation; Presenilin 1; TOR protein; TRPV Cation Channels - genetics; TRPV1
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202052013

As the brain-resident innate immune cells, reactive microglia are a major pathological feature of Alzheimer's disease (AD). However, the exact role of microglia is still unclear in AD pathogenesis. Here, using metabolic profiling, we show that microglia energy metabolism is significantly suppressed during chronic Aβ-tolerant processes including oxidative phosphorylation and aerobic glycolysis via the mTOR-AKT-HIF-1α pathway. Pharmacological activation of TRPV1 rescues Aβ-tolerant microglial dysfunction, the AKT/mTOR pathway activity, and metabolic impairments and restores the immune responses including phagocytic activity and autophagy function. Amyloid pathology and memory impairment are accelerated in microglia-specific TRPV1-knockout APP/PS1 mice. Finally, we showed that metabolic boosting with TRPV1 agonist decreases amyloid pathology and reverses memory deficits in AD mice model. These results indicate that TRPV1 is an important target regulating metabolic reprogramming for microglial functions in AD treatment. SYNOPSIS This study reveals that TRPV1 activation rescues metabolic defects of microglia, thereby decreasing amyloid pathology and reversing memory deficits of Alzheimer’s mouse models. Pharmacological activation of TRPV1 rescues the defects in energy metabolism and increases the autophagy and phagocytosis function of chronic Aβ-tolerant microglia. Amyloid pathology and memory impairment are accelerated in microglia-specific TRPV1-knockout APP/PS1 mice. Metabolic boosting with TRPV1 agonist decreases amyloid pathology and reverses memory deficits in APP/PS1 mice. Graphical Abstract This study reveals that TRPV1 activation rescues metabolic defects of microglia, thereby decreasing amyloid pathology and reversing memory deficits of Alzheimer’s mouse models.