期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 131, 期 1, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI140966
关键词
-
资金
- NIH [R01 NS093652, R01 AG020670, R01 AG057509, RF1 AG054111, RF1 AG062257]
- [NCI-CA125123]
Dysfunction of the immune and vascular systems has been implicated in aging and Alzheimer's disease. The complement pathway is a key regulator of innate immunity in the brain. Enhanced C3a/C3aR signaling through endothelial cells can lead to vascular inflammation and blood-brain barrier dysfunction, contributing to neuroinflammation in aging and neurodegenerative disease.
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.
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