Abstract Astrocytes are abundant cells in the central nervous system that provide trophic support for neurons and clear detrimental factors, such as Aβ oligomers (AβOs). However, in the brains of Alzheimer’s disease (AD) patients, astrocytes lose these physiological functions. Here, we genetically engineered astrocytes with an anti-AβO chimeric antigen receptor (CAR), constructed by replacing the antigen-binding domain of MerTK with an AβO-specific single-chain variable fragment, to direct their phagocytic activity against AβOs. CAR-engineered astrocytes (CAR-As) showed significantly enhanced phagocytosis of AβOs due to effective activation of Rac1, Cdc42 and RhoA and markedly decreased release of pro-inflammatory cytokines due to inhibition of the NF-κB and cytokine receptor signalling pathways. Consistently, in situ CAR-As markedly ameliorated the cognitive deficits of APP/PS1 transgenic mice possibly by clearing AβOs and creating a non-inflammatory microenvironment for neuronal survival and the restoration of microglia to a healthy phenotype. Our present study is the first to introduce a CAR-A-based therapy, validate its feasibility and effectiveness, and highlight its potential application for the treatment of AD and other brain disorders.

Attenuating amyloid-beta pathology in mice with in situ programmed astrocytes