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Published on: December 18, 2019
Complement C3a Receptor (C3aR) Mediates Vascular Dysfunction, Hippocampal Pathology, and Cognitive Impairment in a
Kanchan Bhatia1,2, Adam Kindelin1, Muhammad Nadeem3
1Department of Neurosurgery, Barrow Neurological Institute, SJHMC, Dignity Health, Phoenix, AZ, 85013, USA.
Insights
Blocking the complement C3a receptor (C3aR) reduces brain damage and improves cognitive function in a mouse model of vascular contributions to cognitive impairment and dementia (VCID). This suggests C3aR signaling exacerbates VCID pathology.
Area of Science:
- Neuroscience
- Immunology
- Vascular Biology
Background:
- Vascular contributions to cognitive impairment and dementia (VCID) are a major cause of dementia.
- Complement C3a receptor (C3aR) signaling has been implicated in cerebral ischemia and Alzheimer's disease models.
Purpose of the Study:
- To investigate the role of complement C3a-C3aR signaling in the development and progression of VCID.
- To evaluate the therapeutic potential of C3aR inhibition in VCID.
Main Methods:
- Utilized the bilateral common carotid artery stenosis (BCAS) model in wild-type and C3aR-knockout mice.
- Assessed cerebral blood flow (CBF), hippocampal atrophy (HA), white matter degeneration (WMD), and cognitive function (Morris water maze, novel object recognition).
- Employed laser speckle contrast analysis (LSCI) and magnetic resonance imaging (MRI) for anatomical and physiological assessments.
Main Results:
- BCAS induced decreased CBF, increased HA, WMD, and neurovascular inflammation in wild-type mice compared to C3aR-knockout mice.
- C3aR-knockout mice showed improved cognitive performance in both Morris water maze and novel object recognition tests.
- Genetic deletion of C3aR mitigated the adverse effects of BCAS on brain structure and function.
Conclusions:
- Over-activation of the C3a/C3aR axis exacerbates neuroinflammation and contributes to poor outcomes in VCID.
- C3aR deletion offers a protective effect against VCID progression.
- Targeting C3aR signaling may represent a potential therapeutic strategy for VCID.
Abstract:
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.
