Attenuating amyloid-beta pathology in mice with in situ programmed astrocytes
Astrocytes are abundant cells in the central nervous system that provide trophic support for neurons and clear detrimental factors, such as A{beta} oligomers (A{beta}Os). However, in the brains of Alzheimers disease (AD) patients, astrocytes lose these physiological functions. Here, we genetically engineered astrocytes with an anti-A{beta}O chimeric antigen receptor (CAR), constructed by replacing the antigen-binding domain of MerTK with an A{beta}O-specific single-chain variable fragment, to direct their phagocytic activity against A{beta}Os. CAR-engineered astrocytes (CAR-As) showed significantly enhanced phagocytosis of A{beta}Os due to effective activation of Rac1, Cdc42 and RhoA and markedly decreased release of pro-inflammatory cytokines due to inhibition of the NF-{kappa}B and cytokine receptor signalling pathways. Consistently, in situ CAR-As markedly ameliorated the cognitive deficits of APP/PS1 transgenic mice possibly by clearing A{beta}Os 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.