Abstract DP317: Endothelial C3aR regulates cerebrovascular transmigration of myeloid cells in VCID

Background: Vascular Contributions to Cognitive Impairment and Dementia (VCID) comprise 50% of the cases of dementia; however, there remain no effective treatments for VCID. We have shown that the central complement component C3 potentiates age-related and neurodegenerative changes in the CNS via C3a anaphylatoxin which, through interaction with its cognate receptor C3aR on endothelial cells, exacerbates vascular injury and cognitive decline in VCID. C3aR promotes chronic vascular injury, immune cell infiltration in the brains of Alzheimer disease patients, and peripheral myeloid populations are associated with onset and progression in Parkinson’s and AD. Hypothesis: Our central hypothesis is that endothelial C3a/C3aR signaling mediates transmigration of myeloid cells which promotes white matter injury, BBB injury and impaired cognitive function in VCID. Methods: Male/female endothelial C3aR knockout (C3aR Endo-/- ) and wild-type (C3aR Endo+/+ ) mice (Age:12 weeks; N=6-8/gp) were subjected to either VCID with bilateral common carotid artery stenosis (BCAS) or sham surgery. At 2-mo post-BCAS, changes in cerebral blood flow (CBF), hippocampal atrophy (HA), white matter degeneration (WMD) and ventricular size were determined using laser speckle contrast analysis and magnetic resonance imaging. Cognitive outcome was evaluated using novel object recognition (NOR). We used western blotting, ELISA and immunofluorescence techniques for protein expression and Luxol-Fast Blue (LFB) staining was performed for WMD analysis. Flowcytometery experiment was performed to analyze myeloid cells expression. Results: We found that BCAS leads to reduced CBF and white matter degeneration (WMD) along with reduced expression of myelin basic protein and tight junction proteins (ZO-1). Endothelial C3aR deletion (C3aR Endo-/- ) attenuates CBF and WMD, improves cognitive outcomes, suppresses deleterious myeloid cell infiltration, and pro-inflammatory cytokine expression relative to C3aR Endo+/+ mice. Furthermore, C3aR Endo-/- -BCAS mice showed improvement of BBB function. Conclusion: Our findings suggest that C3aR activation contributes to poor histologic and cognitive outcomes in VCID. Furthermore, Endothelial C3aR deletion suppresses microglial activation, the production of cytokines and chemokines, and protects BBB integrity.