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TRPV1 sustains microglial metabolic reprogramming in Alzheimer's disease
Jia Lu1, Wei Zhou2,3,4,5,6, Fangfang Dou7
1Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
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.
Insights
Targeting TRPV1 channels in microglia shows promise for Alzheimer's disease (AD) treatment by restoring their metabolic function and immune responses, reducing amyloid pathology and improving memory.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Microglia, the brain's immune cells, are implicated in Alzheimer's disease (AD) pathology.
- The precise role of microglia in AD pathogenesis remains incompletely understood.
Purpose of the Study:
- To investigate the role of microglial energy metabolism in AD.
- To explore TRPV1 (transient receptor potential cation channel subfamily V member 1) as a therapeutic target for AD.
Main Methods:
- Metabolic profiling of microglia in an AD mouse model.
- Pharmacological activation and genetic knockout of TRPV1 in microglia.
- Assessment of amyloid pathology and cognitive function in AD mice.
Main Results:
- Microglial energy metabolism, including oxidative phosphorylation and glycolysis, is suppressed in AD via the mTOR-AKT-HIF-1α pathway.
- TRPV1 activation restored microglial metabolic function, immune responses (phagocytosis, autophagy), and ameliorated AD pathology and memory deficits.
- Loss of TRPV1 in microglia accelerated amyloid pathology and cognitive decline.
Conclusions:
- TRPV1 plays a critical role in regulating microglial metabolic reprogramming and function in AD.
- Targeting TRPV1 offers a potential therapeutic strategy for Alzheimer's disease by modulating microglial metabolism.
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