| Title: |
Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy. |
| Authors: |
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 |
| Source: |
Science; 3/5/2026, Vol. 391 Issue 6789, p1-19, 19p |
| Subject Terms: |
AMYLOID beta-protein; ASTROCYTES; NEURODEGENERATION; PHAGOCYTOSIS; IMMUNOTHERAPY; CHIMERIC antigen receptors; ALZHEIMER'S disease; MICROGLIA |
| 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. Editor's summary: Immunotherapies targeting amyloid-β (Aβ) hold promise for the treatment of Alzheimer's disease. Chen et al. developed an anti-Aβ strategy based on a chimeric antigen receptor (CAR) system called CAR-A, in which astrocytes are genetically engineered through adeno-associated viruses to express single-chain variable fragments of anti-Aβ antibodies conjugated to the intracellular domains of phagocytic receptors (see the Perspective by Boles and Gate). In vitro and mouse in vivo testing demonstrated the efficacy of CAR-A in reducing Aβ plaque formation through the coordinated activity of astrocytes and microglia. These results suggest that CAR-A could be effective in reducing disease progression in Alzheimer's disease. —Mattia Maroso INTRODUCTION: Alzheimer's disease (AD) is the most common cause of age-related dementia worldwide. Its pathology progresses from the accumulation of extracellular amyloid-β (Aβ) to the development of intraneuronal tauopathy, ultimately resulting in neurodegeneration. Currently, the most effective strategy for slowing AD progression involves anti-Aβ monoclonal antibodies, three of which have recently received clinical approval. However, these therapies share several limitations, including the need for high doses and repeated administration, a narrow therapeutic window, risks such as amyloid-related imaging abnormalities, and dependence on Fc receptor gamma subunit (FcRγ) signaling. These challenges underscore the need for new therapeutic approaches. RATIONALE: Chimeric antigen receptors (CARs) can be engineered by fusing an anti-Aβ single-chain variable fragment (scFv) to the intracellular domain of selected phagocytic receptors, creating a self-sustaining system that enables brain glia to recognize and clear Aβ aggregates. This approach avoids repeated dosing and allows intracellular signaling to be precisely tuned, a capability not offered by conventional antibody therapies. Because replacing endogenous microglia with CAR-expressing myeloid cells remains challenging for achieving durable, brain-wide coverage, we instead targeted an alternative phagocytic glial population—astrocytes. We therefore generated CAR-expressing astrocytes (CAR-A) and tested their ability to clear amyloid pathology in a mouse model of amyloid plaques using systemic AAV-PHP.eB delivery to achieve central nervous system (CNS)–wide expression. RESULTS: We present a framework for engineering CAR systems in which anti-Aβ scFv are fused to the intracellular domains of phagocytic receptors. We designed four FcRγ-independent anti-Aβ CARs that function robustly in immortalized and primary astrocytes, enhancing phagocytosis and promoting degradation of Aβ42 oligomers in vitro. On the basis of these data, we selected two CARs for in vivo delivery to CNS astrocytes through peripheral, noninvasive AAV-PHP.eB-GFAP administration. One construct links crenezumab to the phagocytic domain of MEGF10 (Cre-Megf10), and the other links aducanumab to the phagocytic domain of Dectin1 (Adu-Dectin1). A single administration of either CAR-A after plaque formation significantly reduced amyloid burden and neuritic dystrophy within 3 months, whereas early delivery prevented Aβ accumulation and associated pathology for 2.5 months. Single-nucleus RNA sequencing and immunostaining showed that both CARs induced disease-associated astrocytes and shifted microglia toward a more homeostatic state with reduced exhaustion signatures. Notably, the constructs diverged in part in their downstream effects, with Cre-Megf10 acting mainly on astrocytic states and Adu-Dectin1 additionally engaging microglial activation through astrocyte-microglia communication. CONCLUSION: Beyond the success of CAR-based therapies in oncology, this work establishes the potential of adapting phagocytic CAR technology to the CNS. By targeting astrocytes, we reveal a new therapeutic axis for AD that complements the phagocytic functions classically attributed to microglia and expands the repertoire of cellular targets for neuroimmune intervention. The observation that distinct CAR designs drive partially divergent glial programs highlights the flexibility of this platform and the opportunity to tailor CAR signaling to achieve specific therapeutic goals. Looking ahead, continued optimization will be critical to maximize amyloid clearance while preserving neuronal integrity, minimize off-target effects, and extend this approach to additional cell types. Together, these findings position CAR engineering as a scalable and tunable strategy for treating neurodegenerative disease. CAR-A treatment of amyloid pathology in an AD-related model.: (Left) Study pipeline for developing CAR-A therapies to reduce amyloid pathology from in vitro to in vivo models. (Top right) CAR-A treatment improves astrocytic phagocytosis and response to amyloid pathology, which reduces microglial burden and neuronal dystrophy. (Bottom right) Cre-Megf10 and Adu-Dectin1 treatments induced shared glial signatures, including disease-associated astrocytes and CSF1Rhigh/CD68high microglia. Additionally, CAR-Megf10 treatment induced MyoC+ astrocytes, whereas CAR-Dectin1 treatment expanded MHC-II+ microglia. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |