Complement C3a Receptor (C3aR) Mediates Vascular Dysfunction, Hippocampal Pathology, and Cognitive Impairment in a...

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.