To develop a novel anti-inflammatory CAR-Microglia (CAR-Mic) targeting amyloid-β (Aβ) for enhanced clearance and reduced neuroinflammation in Alzheimer’s disease (AD).
Approach:
Development of CAR-Microglia: A novel CAR-Mic was engineered using constructs based on the TAM receptor family to enhance Aβ engulfment and reduce proinflammatory cytokine release.
Selection of AXL-CAR: Among the constructs tested, AXL-CAR showed the most favorable performance and was selected for generating human induced pluripotent stem cell (iPSC)-derived CAR microglia-like cells (CAR-iMGLs).
In vivo Testing: AXL-CAR-iMGLs were tested in an AD mouse model, demonstrating enhanced Aβ clearance without severe adverse effects.
Key Findings:
Monoclonal antibodies targeting Aβ have limited therapeutic efficacy due to insufficient clearance and treatment-associated neuroinflammation.
The AXL-CAR-Mic exhibited enhanced Aβ uptake and lysosomal degradation while attenuating pro-inflammatory cytokines.
Adoptive transfer of AXL-CAR-iMGLs into AD mouse brains resulted in significant reduction of Aβ plaque burden.
Interpretation:
The findings suggest that TAM receptor-based CAR-iMGLs may serve as a promising cell therapy model for AD and other neurodegenerative disorders characterized by chronic neuroinflammation.
Limitations:
The study primarily focuses on preclinical models; further research is needed to evaluate long-term efficacy and safety in humans.
The potential for immune response or other adverse effects in human subjects remains to be fully assessed.
Conclusion:
The study establishes a CAR-microglia strategy that integrates antigen-specific Aβ clearance and anti-inflammatory functions.
A regional UK audit found wide variation in imaging intervals among patients referred for mechanical thrombectomy and identified potentially modifiable barriers to timely vascular imaging.
