Research Article: Anti-inflammatory CAR-microglia targeting A? for Alzheimer’s disease therapy
Abstract:
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-? (A?) plaques and chronic neuroinflammation, which together drive progressive neuronal loss and cognitive decline. In recent years, monoclonal antibodies targeting A? have demonstrated encouraging clinical benefits in Alzheimer’s disease (AD). However, their therapeutic efficacy remains limited by insufficient and unsustained clearance of A?, as well as treatment-associated neuroinflammatory responses. These limitations highlight the need for alternative strategies that can achieve efficient A? elimination while maintaining immune homeostasis. To overcome these challenges, we developed a novel anti-inflammatory CAR-Microglia (CAR-Mic) incorporating a construct based on the TAM receptor family (TYRO3, AXL, and MERTK), which are key regulators of efferocytosis and anti-inflammatory responses. The resulting A?-targeted CAR-Mics showed enhanced A? engulfment and reduced proinflammatory cytokines release. Among the constructs tested, AXL-CAR demonstrated the most favorable overall performance and was therefore selected for the generation of human induced pluripotent stem cell (iPSC)-derived CAR microglia-like cells (CAR-iMGLs). In an AD mouse model, AXL-CAR-iMGLs exhibited enhanced A? clearance without evidence of severe adverse effects. Collectively, these findings establish TAM receptor-based CAR-iMGLs as a promising cell therapy model for AD and potentially other neurodegenerative disorders characterized by chronic neuroinflammation and defective pathological protein clearance.
Introduction:
Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid-? (A?) plaques and neurofibrillary tangles, accompanied by chronic neuroinflammation, neuronal dysfunction, and neurodegeneration ( 1 , 2 ). In recent years, monoclonal antibodies targeting A? have achieved promising clinical outcome ( 3 – 5 ), however, these antibodies predominantly engage Fc receptors on microglia, often leading to excessive immune activation and neuroinflammation, and inducing synapse loss and cognitive…
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