CD33 is an immunomodulatory receptor linked to Alzheimer's disease (AD) susceptibility via regulation of phagocytosis in microglia. Divergent features between human CD33 (hCD33) and murine CD33 (mCD33) include a unique transmembrane lysine in mCD33 and cytoplasmic tyrosine in hCD33. The functional consequences of these differences in restraining phagocytosis remains poorly understood. Using a new αmCD33 monoclonal antibody, we show that mCD33 is expressed at high levels on neutrophils and low levels on microglia. Notably, cell surface expression of mCD33 is entirely dependent on Dap12 due to an interaction with the transmembrane lysine in mCD33. In RAW264.7 cultured macrophages, BV-2 cultured microglia, primary neonatal and adult microglia, uptake of cargo - including aggregated Aβ1-42 - is not altered upon genetic ablation of mCD33. Alternatively, deletion of hCD33 in monocytic cell lines increased cargo uptake. Moreover, transgenic mice expressing hCD33 in the microglial cell lineage showed repressed cargo uptake in primary microglia. Therefore, mCD33 and hCD33 have divergent roles in regulating phagocytosis, highlighting the importance of studying hCD33 in AD susceptibility.

中文翻译：

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人 CD33 对吞噬作用的抑制在小鼠 CD33 中并不保守。

CD33 是一种免疫调节受体，通过调节小胶质细胞的吞噬作用与阿尔茨海默病 (AD) 易感性相关。人 CD33 (hCD33) 和鼠 CD33 (mCD33) 之间的不同特征包括 mCD33 中独特的跨膜赖氨酸和 hCD33 中的细胞质酪氨酸。这些差异在抑制吞噬作用方面的功能后果仍知之甚少。使用新的 αmCD33 单克隆抗体，我们发现 mCD33 在中性粒细胞上高水平表达，在小胶质细胞上低水平表达。值得注意的是，由于与 mCD33 中的跨膜赖氨酸相互作用，mCD33 的细胞表面表达完全依赖于 Dap12。在 RAW264.7 培养的巨噬细胞、BV-2 培养的小胶质细胞、原代新生儿和成人小胶质细胞中，对物质（包括聚集的 Aβ1-42）的摄取不会因 mCD33 的基因消融而改变。或者，单核细胞系中 hCD33 的缺失增加了货物的摄取。此外，在小胶质细胞谱系中表达 hCD33 的转基因小鼠显示原代小胶质细胞中的货物摄取受到抑制。因此，mCD33和hCD33在调节吞噬作用方面具有不同的作用，凸显了研究hCD33在AD易感性中的重要性。