Complement C3aR depletion reverses HIF-1α-induced metabolic impairment and enhances microglial response to Aβ...

Area of Science:

• Neuroscience
• Immunology
• Metabolic disease

Background:

• Microglia, the brain's immune cells, express the complement C3a receptor (C3aR).
• Alzheimer's disease (AD) is linked to microglial dysfunction and amyloid-beta (Aβ) plaque accumulation.
• Dysregulated microglial metabolism and lipid homeostasis are implicated in AD pathogenesis.

Purpose of the Study:

• To investigate the role of C3aR in microglial subpopulations and their function in an AD mouse model.
• To elucidate the impact of C3aR signaling on microglial metabolism and lipid profiles in AD.
• To evaluate the therapeutic potential of targeting the C3aR pathway in AD.

Main Methods:

• Utilized a knockin mouse model with a Td-tomato reporter for C3aR expression.
• Performed transcriptomic analysis on C3aR-expressing microglia from wild-type and AD model (APP-KI) mice.
• Generated C3aR-deficient (C3ar1-null) microglia and crossed C3ar1-knockout mice with APP-KI mice.
• Assessed microglial metabolic signatures, lipid metabolism, Aβ phagocytosis, and cognitive function.

Main Results:

• Identified distinct microglial subpopulations based on C3aR expression, with a shift towards high C3aR expression around Aβ plaques in APP-KI mice.
• Discovered upregulated hypoxia-inducible factor 1 (HIF-1) signaling and abnormal lipid metabolism in C3aR-positive microglia from APP-KI mice.
• Demonstrated that C3aR ablation in microglia reduced HIF-1α expression, improved lipid profiles, enhanced Aβ phagocytosis, and ameliorated AD pathology and cognitive deficits.

Conclusions:

• A heightened C3aR/HIF-1α signaling axis contributes to microglial metabolic and lipid dysregulation in Alzheimer's disease.
• Targeting the C3aR pathway represents a promising therapeutic strategy for Alzheimer's disease by restoring microglial function and reducing pathology.