Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy

• 成果类型: Article
• 署名作者: Chen, Yun; Liu, Yizhou; Nguyen, Khai; Wu, Junjie; Song, Sihui; Lin, Kent; Rodrigues, Patrick F.; Du, Siling; Zhou, Charles; Xiong, Kyle; Bosch, Megan; Lin, Peter Bor-Chian; Khantakova, Darya; Wu, Shitong; Wu, May; Yuede, Carla; Holtzman, David M.; Colonna, Marco
• 署名单位: Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.ads3972
• 发表日期: 2026-03-05
• 页码: eads3972
• 关键词: 5XFAD MOUSE MODEL; reactive astrocytes; alzheimers; microglia; diffusion; STATES

摘要

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.