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

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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.

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Acknowledgements

This work was supported by the Barrow Neurological Foundation and the Arizona Alzheimer’s Research Consortium to AFD. The Arizona Alzheimer’s Consortium (AAC) is greatly acknowledged to support this work. The authors would like to thank the staff of the Neuroscience Publications at Barrow Neurological Institute for providing the schematic figure.

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  1. Kanchan Bhatia and Adam Kindelin contributed equally.

Authors and Affiliations

  1. Department of Neurosurgery, Barrow Neurological Institute, SJHMC, Dignity Health, Phoenix, AZ, 85013, USA

    Kanchan Bhatia, Adam Kindelin, Karis Miller, Mark C. Preul & Saif Ahmad

  2. School of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, USA

    Kanchan Bhatia

  3. Department of Translational Neuroscience, Barrow Neurological Institute, SJHMC, Dignity Health, Phoenix, AZ, 85013, USA

    Muhammad Nadeem, Junxiang Yin, Karis Miller, Abdullah S. Ahmad, Elliott J. Mufson, Michael F. Waters & Saif Ahmad

  4. Department of Neurology, Augusta University, Augusta, GA, 30912, USA

    Mohammad Badruzzaman Khan

  5. Department of Neurology, Barrow Neurological Institute, SJHMC, Dignity Health, Phoenix, AZ, 85013, USA

    Junxiang Yin, Abdullah S. Ahmad & Michael F. Waters

  6. Barrow Neurological Institute/Arizona State University Center for Preclinical Imaging, Barrow Neurological Institute, SJHMC, Dignity Health, Phoenix, AZ, 85013, USA

    Alberto Fuentes & Gregory H. Turner

  7. Departments of Neurosurgery & Translational Neuroscience, Barrow Neurological Institute, SJHMC, Dignity Health, Phoenix, AZ, 85086, USA

    Andrew F. Ducruet

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  1. Kanchan Bhatia
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Contributions

KB, AK, MN, JY, KM, MBK, KM and SA performed experiments, analyzed data, and drafted the manuscript; AF and GHT performed MRI imaging and analyzed data; SA, ASA, MCP, EJF, and MFW reviewed and edited the manuscript; AFD designed and oversaw the project, assisted in analyzing and interpreting the data, and edited the manuscript.

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Correspondence to Saif Ahmad or Andrew F. Ducruet.

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12975_2022_993_MOESM1_ESM.pptx

Supplementary file1 (PPTX 3700 KB) Supplemental Figure 1. Representative images showing baseline cortical CBF before surgery. We monitored CBF in each group including Sham (WT), Sham (KO), BCAS (WT) and BCAS (KO) mice. There was no statistical significance noted between group comparisons. Supplemental Figure 2. Representative Luxol fast blue (LFB) staining for white matter degeneration. The intensity of LFB staining was significantly decreased in BCAS (WT) compared with Sham (WT). However, BACS (KO) group showed significant improvement vs BCAS (WT). A, Representative images (20x) were taken from cross sections of corpus callosum of each group of mice with LFB staining and its higher magnification (40x, scale bar=20μm) at 4 months after BCAS surgery. B, Histogram representing grading score of white matter degeneration in BCAS-WT and improvement in BCAS-KO mice. Data are expressed as Mean ± SD. Data was analyzed using one-Way ANOVA with Tukey’s post-hoc, n=5 (*** p < 0.001 vs Sham, *p= 0.05 vs BCAS-KO). Supplemental Figure 3. Immunoblotting gel images. A-F, Uncropped western blot images (MBP, VCAM1, Iba1, ZO1, pSTAT3 and Occludin) are presented with maker band denoted. Supplemental Figure 4. A, mouse brain (hippocampal region) was stained with only secondary antibody conjugated with FITC-488 for negative control immunofluorescence. B, mouse brain (hippocampal region) was stained with FITC-488 and primary C3aR antibody.

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Bhatia, K., Kindelin, A., Nadeem, M. et al. Complement C3a Receptor (C3aR) Mediates Vascular Dysfunction, Hippocampal Pathology, and Cognitive Impairment in a Mouse Model of VCID. Transl. Stroke Res. 13, 816–829 (2022). https://doi.org/10.1007/s12975-022-00993-x

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