Expression of anti-amyloid CARs in microglia promotes efficient and selective phagocytosis of Aβ1‒42.

Genetic engineering of microglial cells is a promising therapeutic avenue emerging with advancements in gene delivery techniques. Using a recently developed AAV capsid for efficient in vitro transduction we report the engineering of microglia with CARs (CAR-Mic) targeting phagocytosis of amyloid beta 1‒42 (Aβ42). Functional screening of seven CAR constructs in human iPSC-derived microglia revealed up to 6-fold increases in internalized Aβ relative to viral control. CAR-driven phagocytic enhancement was selective for Aβ, dependent on intracellular domain signaling, and was confirmed in primary mouse microglia. These findings highlight the potential of using this approach to target dysfunctional microglia in Alzheimer's disease and other CNS disorders.