Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging.

Nicholas E Propson, Ethan R Roy, Alexandra Litvinchuk, Jörg Köhl, Hui Zheng

The Journal of clinical investigation 2021 Jan 04

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Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial cell-specific ablation of C3ar1. Using an in vitro model of the BBB, we identified intracellular Ca2+ as a downstream effector of C3a/C3aR signaling and a functional mediator of vascular endothelial cadherin junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation was also observed in a tau-transgenic mouse model. Our studies suggest that heightened C3a/C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contributes to overall neuroinflammation in aging and neurodegenerative disease.

Citation

Nicholas E Propson, Ethan R Roy, Alexandra Litvinchuk, Jörg Köhl, Hui Zheng. Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging. The Journal of clinical investigation. 2021 Jan 04;131(1)