Department of Chemistry, University of Alberta, Edmonton, Canada.
Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Canada.
Mol Neurodegener. 2024 May 27;19(1):42. doi: 10.1186/s13024-024-00734-8.
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.
小胶质细胞在阿尔茨海默病（AD）中发挥着多种病理生理作用，遗传易感性因素使小胶质细胞功能发生倾斜，从而影响 AD 风险。CD33 是一种免疫调节受体，与 AD 易感性相关，通过单核苷酸多态性改变 mRNA 剪接，使蛋白表达从长蛋白异构体（CD33M）偏向短异构体（CD33m）。由于 CD33 在小鼠和人类之间的功能差异，了解人类 CD33 异构体如何在体内对小胶质细胞功能产生差异影响一直具有挑战性。我们通过研究表达任一种人类 CD33 异构体的转基因小鼠与淀粉样蛋白病变的 5XFAD 小鼠模型的交叉，解决了这一挑战，并发现人类 CD33 异构体对小胶质细胞对淀粉样β（Aβ）沉积的反应有相反的影响。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减少，树突状神经突变形更多。相反，CD33m 促进斑块致密化和小胶质细胞-斑块接触，并最小化神经突斑块病理，突出了这种异构体的 AD 保护作用。与 CD33M 小鼠中出现的更具侵袭性的病理相比，CD33m 驱动的保护表型在更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的影响更为显著。除了在调节吞噬作用方面的不同作用外，单细胞 RNA 测序和蛋白质组学分析表明，CD33m 小胶质细胞在斑块接触部位上调巢蛋白，这是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 的顶级遗传易感性因素如何调节小胶质细胞功能提供了新的功能见解。
