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

Zhang, L.; Lu, S.; Jia, Y.-b.; Hou, S.-j.; Zhu, J.; Liu, X.-g.; Sun, X.-y.; Huang, Y.-r.; Zhao, Y.-x.; Ren, H.; Liu, C.-y.; Cui, F.; Liu, D.-q.; Du, X.-y.; Niu, X.-y.; li, L.-j.; Wang, K.; Liang, S.-y.; Yang, J.-j.; Ji, S.-y.; Sun, L.; Zhou, W.-w.; Xie, X.-x.; Yu, X.-l.; Wang, X.; Liu, R.-t.

2023-11-02 neuroscience
10.1101/2023.10.30.564697 bioRxiv
Show abstract

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.

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