Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging
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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.
Keywords: Aging; Alzheimer's disease.
Reference
Propson, N. E., Roy, E. R., Litvinchuk, A., Köhl, J., & Zheng, H. (2021). Endothelial C3a receptor mediates vascular inflammation and blood-brain barrier permeability during aging. The Journal of clinical investigation, 131(1).
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