Complement C3aR depletion reverses HIF-1α–induced metabolic impairment and enhances microglial response to Aβ pathology
Manasee Gedam, … , Meng C. Wang, Hui Zheng
Manasee Gedam, … , Meng C. Wang, Hui Zheng
Published June 15, 2023
Citation Information: J Clin Invest. 2023;133(12):e167501. https://doi.org/10.1172/JCI167501.
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Complement C3aR depletion reverses HIF-1α–induced metabolic impairment and enhances microglial response to Aβ pathology

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 APPNL-G-F–knockin (APP-KI) background revealed a significant shift of microglia to a high-C3aR-expressing subpopulation and they were enriched around amyloid β (Aβ) 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-1α expression and were resistant to hypoxia mimetic–induced metabolic changes and lipid droplet accumulation. These were associated with improved receptor recycling and Aβ 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 Aβ pathology and restored synaptic and cognitive function. Our studies identify a heightened C3aR/HIF-1α signaling axis that influences microglial metabolic and lipid homeostasis in Alzheimer disease, suggesting that targeting this pathway may offer therapeutic benefit.

Authors

Manasee Gedam, Michele M. Comerota, Nicholas E. Propson, Tao Chen, Feng Jin, Meng C. Wang, Hui Zheng

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Figure 1

Plaque-associated microglia express C3aR and display a compromised metabolic profile.

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Plaque-associated microglia express C3aR and display a compromised metab...
(A) Representative images of human tissues from AD patients stained for C3aR (magenta), Iba-1 (green), and plaques (gray) showing higher C3aR expression in microglia proximal to the plaque (solid yellow arrowheads) compared with microglia distal from the plaque (hollow yellow arrowheads). Scale bar: 10 μm. (B) Representative images from 9-month-old APP-KI mice crossed with C3aR Td-tomato reporter (magenta) stained for Iba-1 (green) and plaques (gray). Solid arrowheads mark higher-C3aR-expressing microglia proximal to the plaque compared with microglia distal from the plaque (hollow yellow arrowheads) Scale bar: 10 μm. (C) Left: Flow cytometry plot displaying the distribution of microglia from 9-month-old WT and APP-KI mice based on C3aR expression. Right: Histogram depicting the distribution of microglia based on C3aR expression. (D) Bar graph showing the percentage of C3aR expression in WT and APP-KI mice. Data presented as mean ± SEM. NS, nonsignificant. **P < 0.01 by 2-sided Student’s t test. (E) Volcano plot from RNA-seq of C3aR+ cells showing upregulated genes (red) and downregulated genes (blue) in 9-month-old APP-KI compared with WT mice. (F) Pathway analysis using KEGG revealing significantly altered metabolic and HIF-1 signaling pathways in APP-KI mice compared with WT (P-value cutoff: 0.05). (G) Heatmap showing altered lipid and hypoxia modules in C3aR+ microglia from APP-KI mice compared with WT.