Alzheimer’s disease (AD) is characterized by the appearance of amyloid‐β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK‐p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec‐F which was upregulated on a subset of reactive microglia. The human paralog Siglec‐8 was also upregulated on microglia in AD. Siglec‐F and Siglec‐8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV‐2 cell line and human stem cell‐derived microglia models. Siglec‐F overexpression activates an endocytic and pyroptotic inflammatory response in BV‐2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine‐based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV‐2 cells. Collectively, our results point to an important role for mouse Siglec‐F and human Siglec‐8 in regulating microglial activation during neurodegeneration.

中文翻译：

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磷酸蛋白质组学鉴定神经退行性变过程中小胶质细胞 Siglec-F 炎症反应


阿尔茨海默病 (AD) 的特点是出现β-淀粉样蛋白斑块、神经原纤维缠结以及涉及记忆的大脑区域出现炎症。使用质谱法，我们定量了 CK-p25、5XFAD 和 Tau P301S 神经退行性疾病小鼠模型的磷酸蛋白质组。我们发现了一个涉及 Siglec-F 的共同反应，该反应在反应性小胶质细胞的子集上上调。人类旁系同源物 Siglec-8 在 AD 中的小胶质细胞上也表达上调。在 BV-2 细胞系和人类干细胞衍生的小胶质细胞模型中，用干扰素 γ (IFNγ) 激活小胶质细胞后，Siglec-F 和 Siglec-8 上调。 Siglec-F 过表达可激活 BV-2 细胞中的内吞和焦亡炎症反应，这取决于其唾液酸底物和免疫受体酪氨酸抑制基序 (ITIM) 磷酸化位点。相关的人类 Siglecs 在 BV-2 细胞中诱导了类似的反应。总的来说，我们的结果表明小鼠 Siglec-F 和人类 Siglec-8 在神经退行性变过程中调节小胶质细胞激活方面发挥着重要作用。