This study explores a novel approach to target and degrade amyloid plaques in Alzheimer's disease (AD) by genetically engineering macrophages to express a chimeric antigen receptor (CAR) that targets aggregated forms of β-amyloid (Aβ). The researchers first developed first-generation CAR macrophages (CAR-Ms) that were injected intrahippocampally, but these CAR-Ms had limited persistence and failed to significantly reduce plaque load. To address this issue, they engineered next-generation "reinforced CAR-Ms" that secrete macrophage colony-stimulating factor (M-CSF) and self-maintain without exogenous cytokines. These reinforced CAR-Ms showed greater survival in the brain niche and significantly reduced plaque load in aged APP/PS1 mice. The findings suggest that CAR-Ms, when rationally engineered to produce cytokines, can be effective in targeting and degrading pathogenic material that accumulates with age, such as Aβ in AD. This approach may provide a new therapeutic strategy for treating AD by enhancing the resorption and degradation of amyloid plaques.This study explores a novel approach to target and degrade amyloid plaques in Alzheimer's disease (AD) by genetically engineering macrophages to express a chimeric antigen receptor (CAR) that targets aggregated forms of β-amyloid (Aβ). The researchers first developed first-generation CAR macrophages (CAR-Ms) that were injected intrahippocampally, but these CAR-Ms had limited persistence and failed to significantly reduce plaque load. To address this issue, they engineered next-generation "reinforced CAR-Ms" that secrete macrophage colony-stimulating factor (M-CSF) and self-maintain without exogenous cytokines. These reinforced CAR-Ms showed greater survival in the brain niche and significantly reduced plaque load in aged APP/PS1 mice. The findings suggest that CAR-Ms, when rationally engineered to produce cytokines, can be effective in targeting and degrading pathogenic material that accumulates with age, such as Aβ in AD. This approach may provide a new therapeutic strategy for treating AD by enhancing the resorption and degradation of amyloid plaques.