Microglia play diverse pathophysiological roles in Alzheimer’s disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-β (Aβ) deposition. Mice expressing CD33M have increased Aβ levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function.

中文翻译：

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阿尔茨海默病相关的人 CD33 亚型独特地调节 5XFAD 小鼠的小胶质细胞反应


小胶质细胞在阿尔茨海默病 (AD) 中发挥着多种病理生理学作用，遗传易感性因素会影响小胶质细胞的功能，从而影响 AD 风险。 CD33 是一种与 AD 易感性相关的免疫调节受体，通过单核苷酸多态性调节 mRNA 剪接，使蛋白质表达从长蛋白质亚型 (CD33M) 偏向短亚型 (CD33m)。由于小鼠和人类之间 CD33 的功能差异，了解人类 CD33 亚型如何对体内小胶质细胞功能产生差异性影响一直具有挑战性。我们通过研究表达人类 CD33 亚型的转基因小鼠与 5XFAD 淀粉样变性小鼠模型杂交来应对这一挑战，并发现人类 CD33 亚型对小胶质细胞对淀粉样蛋白-β (Aβ) 沉积的反应具有相反的影响。与 5XFAD 对照小鼠相比，表达 CD33M 的小鼠 Aβ 水平升高、斑块更弥散、疾病相关小胶质细胞更少、营养不良的神经突更多。相反，CD33m 促进斑块压实和小胶质细胞斑块接触，并最大限度地减少神经炎斑块病理，突出了该亚型的 AD 保护作用。与在较晚的时间点出现的 CD33M 小鼠中更具侵袭性的病理学相比，由 CD33m 驱动的保护性表型在较早的时间点被检测到，这表明 CD33m 在疾病进展的早期阶段对小胶质细胞功能具有更显着的影响。除了在调节吞噬作用方面的不同作用外，scRNAseq 和蛋白质组学分析还表明，CD33m+ 小胶质细胞在斑块接触位点上调巢蛋白（一种参与细胞迁移的中间丝）。 总的来说，我们的工作为 CD33 作为 AD 的首要遗传易感因子如何调节小胶质细胞功能提供了新的功能见解。