Chimeric Antigen Receptor Macrophages Target and Resorb Amyloid Plaques in a Mouse Model of Alzheimer's Disease.
Chimeric Antigen Receptor Macrophages Target and Resorb Amyloid Plaques in a Mouse Model of Alzheimer's Disease.
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嵌合抗原受体巨噬细胞在阿尔茨海默病小鼠模型中靶向并吸收淀粉样斑块。
DOI：
10.1101/2023.04.28.538637
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
DeSelm,CarlJ
中科院分区：
文献类型：
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作者：
Pan,Qiuyun;Yan,Ping;Kim,AlexanderB;Xiao,Qingli;Pandey,Gaurav;Haecker,Hans;Epelman,Slava;Diwan,Abhinav;Lee,Jin-Moo;DeSelm,CarlJ
大量证据表明免疫疗法在治疗阿尔茨海默病 (AD) 中发挥着重要作用。几种针对聚集形式的 β 淀粉样蛋白 (Aβ) 的单克隆抗体已被证明可以减少淀粉样蛋白斑块，并且在某些情况下可以减轻早期 AD 患者的认知能力下降。我们试图确定基因工程巨噬细胞是否可以改善淀粉样斑块的靶向和降解。嵌合抗原受体巨噬细胞 (CAR-Ms) 有望成为一种癌症治疗方法，是增强 AD 中淀粉样蛋白斑块的靶标识别和吞噬作用的一种有吸引力的策略。我们对巨噬细胞进行基因工程改造，使其表达含有抗淀粉样蛋白抗体 aducanumab 作为外部结构域和内部 Fc 受体信号结构域的 CAR。 CAR-Ms 在体外和离体 APP/PS1 脑切片上识别并降解 Aβ；然而，当海马内注射时，这些第一代 CAR-M 的持久性有限，并且无法减少斑块负荷。我们通过创建能够分泌 M-CSF 并无需外源细胞因子即可自我维持的 CAR-M 克服了这一限制。这些 CAR-M 在大脑微环境中具有更高的存活率，并显着减少体内局部斑块负荷。这些原理验证研究表明，以前仅应用于癌症的 CAR-M 可以用于靶向和降解不需要的物质，例如 AD 小鼠大脑中的淀粉样斑块。
Substantial evidence suggests a role for immunotherapy in treating Alzheimer’s disease (AD). Several monoclonal antibodies targeting aggregated forms of beta amyloid (Aβ), have been shown to reduce amyloid plaques and in some cases, mitigate cognitive decline in early-stage AD patients. We sought to determine if genetically engineered macrophages could improve the targeting and degradation of amyloid plaques. Chimeric antigen receptor macrophages (CAR-Ms), which show promise as a cancer treatment, are an appealing strategy to enhance target recognition and phagocytosis of amyloid plaques in AD. We genetically engineered macrophages to express a CAR containing the anti-amyloid antibody aducanumab as the external domain and the Fc receptor signaling domain internally. CAR-Ms recognize and degrade Aβ in vitro and on APP/PS1 brain slices ex vivo; however, when injected intrahippocampally, these first-generation CAR-Ms have limited persistence and fail to reduce plaque load. We overcame this limitation by creating CAR-Ms that secrete M-CSF and self-maintain without exogenous cytokines. These CAR-Ms have greater survival in the brain niche, and significantly reduce plaque load locally in vivo. These proof-of-principle studies demonstrate that CAR-Ms, previously only applied to cancer, may be utilized to target and degrade unwanted materials, such as amyloid plaques in the brains of AD mice.