Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy
- Yun Chen
- Yizhou Liu
- Khai Nguyen
- Junjie Wu
- Sihui Song
- Kent Lin
- Patrick F. Rodrigues
- Siling Du
- Charles Zhou
- Kyle Xiong
- Megan Bosch
- Peter Bor-Chian Lin
- Darya Khantakova
- Shitong Wu
- May Wu
- Carla Yuede
- David M. Holtzman
- Marco Colonna
2026-03-05
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.