Back to Search
Start Over
Complement C3aR depletion reverses HIF-1[alpha]-induced metabolic impairment and enhances microglial response to A[beta] pathology
- Source :
- Journal of Clinical Investigation. June 15, 2023, Vol. 133 Issue 12
- Publication Year :
- 2023
-
Abstract
- Microglia are the major cell type expressing complement C3a receptor (C3aR) in the brain. Using a knockin mouse line in which a Td-tomato reporter is incorporated into the endogenous C3ar1 locus, we identified 2 major subpopulations of microglia with differential C3aR expression. Expressing the Td-tomato reporter on the [APP.sup.NL-G-F]-knockin (APP-KI) background revealed a significant shift of microglia to a high-C3aR-expressing subpopulation and they were enriched around amyloid [beta] (A[beta]) plaques. Transcriptomic analysis of C3aR-positive microglia documented dysfunctional metabolic signatures, including upregulation of hypoxia-inducible factor 1 (HIF-1) signaling and abnormal lipid metabolism in APP-KI mice compared with wild-type controls. Using primary microglial cultures, we found that C3ar1-null microglia had lower HIF-1[alpha] expression and were resistant to hypoxia mimetic-induced metabolic changes and lipid droplet accumulation. These were associated with improved receptor recycling and A[beta] phagocytosis. Crossing C3ar1-knockout mice with the APP-KI mice showed that C3aR ablation rescued the dysregulated lipid profiles and improved microglial phagocytic and clustering abilities. These were associated with ameliorated A[beta] pathology and restored synaptic and cognitive function. Our studies identify a heightened C3aR/HIF-1[alpha] signaling axis that influences microglial metabolic and lipid homeostasis in Alzheimer disease, suggesting that targeting this pathway may offer therapeutic benefit.<br />Introduction Alzheimer disease (AD), the leading cause of dementia in the elderly, is pathologically characterized by the accumulation of amyloid [beta] (A[beta]) plaques and intracellular tau tangles and accompanying neuroinflammation [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 133
- Issue :
- 12
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.754812467
- Full Text :
- https://doi.org/10.1172/JCI167501