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

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.

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Publication Details

Journal
Science
Published
2026-03-05
DOI
https://doi.org/10.1126/science.ads3972
Primary Topic
Alzheimer's disease research and treatments
Type
article
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0.00
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article

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

Khai M. Nguyen, Megan E. Bosch, Carla M. Yuede, Charles Zhou et al.
Science
Alzheimer's disease research and treatments
article

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

Khai M. Nguyen, Megan E. Bosch, Carla M. Yuede, Charles Zhou, May Wu, Peter Bor‐Chian Lin, Patrick Fernandes Rodrigues, Kyle Xiong, Siling Du, Kent Lin, Darya Khantakova, Yizhou Liu, Yun Chen, Junjie Wu, David M. Holtzman, Marco Colonna, Shitong Wu, Sihui Song
article en

Abstract

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.

ScienceVol. 391(6789)
Washington University in St. Louis (US), Hope Center for Neurological Disorders (US)
Good health and well-being
Openalex Percentile: Top 32%
Alzheimer's disease research and treatments
DOISourceOpenAlex
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