Yun Chen, Yizhou Liu, Khai M. Nguyen, Junjie Wu, Sihui Song, Kent Lin, Patrick Fernandes Rodrigues, Siling Du, Charles Zhou, Kyle Xiong, Megan E. Bosch, Peter Bor‐Chian Lin, Darya Khantakova, Shitong Wu, May Wu, Carla M. Yuede, David M. Holtzman, Marco Colonna
Alzheimer's disease (AD) is the leading cause of dementia and is characterized by progressive amyloid accumulation followed by tau-mediated neurodegeneration. Despite advances in anti-amyloid immunotherapies, important limitations remain, highlighting the need for new therapeutic strategies. Here, we introduce anti-amyloid chimeric antigen receptors expressed in astrocytes (CAR-A) and validate their function in vitro. We show that two CAR-A designs reduce amyloid and associated pathology after plaque formation and prevent early plaque deposition in vivo. Single-nucleus RNA sequencing shows that CAR-A treatment induces a distinct glial response to amyloid pathology involving coordinated activity of astrocytes and microglia. Each construct additionally elicits distinctive, receptor-specific effects in astrocytes or microglia. Together, these findings support the therapeutic potential of CAR-A as a disease-modifying strategy for AD.