Complement C3a Receptor (C3aR) Mediates Vascular Dysfunction, Hippocampal Pathology, and Cognitive Impairment in a Mouse Model of VCID

Transl Stroke Res. 2022 Oct;13(5):816-829. doi: 10.1007/s12975-022-00993-x. Epub 2022 Mar 8.


Vascular contributions to cognitive impairment and dementia (VCID) secondary to chronic mild-moderate cerebral ischemia underlie a significant percentage of cases of dementia. We previously reported that either genetic deficiency of the complement C3a receptor (C3aR) or its pharmacological inhibition protects against cerebral ischemia in rodents, while others have implicated C3aR in the pathogenesis seen in rodent transgenic models of Alzheimer's disease. In the present study, we evaluated the role of complement C3a-C3aR signaling in the onset and progression of VCID. We utilized the bilateral common carotid artery stenosis (BCAS) model to induce VCID in male C57BL/6 wild-type and C3aR-knockout (C3aR-/-) mice. Cerebral blood flow (CBF) changes, hippocampal atrophy (HA), white matter degeneration (WMD), and ventricular size were assessed at 4 months post-BCAS using laser speckle contrast analysis (LSCI) and magnetic resonance imaging (MRI). Cognitive function was evaluated using the Morris water maze (MWM), and novel object recognition (NOR), immunostaining, and western blot were performed to assess the effect of genetic C3aR deletion on post-VCID outcomes. BCAS resulted in decreased CBF and increased HA, WMD, and neurovascular inflammation in WT (C57BL/6) compared to C3aR-/- (C3aR-KO) mice. Moreover, C3aR-/- mice exhibited improved cognitive function on NOR and MWM relative to WT controls. We conclude that over-activation of the C3a/C3aR axis exacerbates neurovascular inflammation leading to poor VCID outcomes which are mitigated by C3aR deletion. Future studies are warranted to dissect the role of cell-specific C3aR in VCID.

Keywords: Cerebral blood flow (CBF), White matter degeneration (WMD); Complement C3a receptor (C3aR); Inflammation; Vascular contributions to cognitive impairment and dementia (VCID).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia* / complications
  • Cognitive Dysfunction* / pathology
  • Dementia, Vascular* / complications
  • Disease Models, Animal
  • Hippocampus / pathology
  • Inflammation / complications
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Complement* / genetics


  • Receptors, Complement
  • complement C3a receptor