Neuroprotective role of the ‘sialic acid – SIGLEC’ axis in the central nervous system

人类在小胶质细胞上表达抑制性信号Siglec-11和激活信号Siglec-16，两者可以相互抵消。缺乏抑制信号Siglec-E的小鼠在24个月大时表现出存活率降低，表现出夸大的氧化损伤迹象和非常轻微的认知改变，但对神经炎症和神经退化的影响尚不清楚。小胶质细胞的Siglec-F可以补偿Siglec-E的丢失。在这个项目中，我们将利用人源化的siglec-11转基因(TG)和siglec-16转基因小鼠来研究抑制的人siglec-11受体和激活的人siglec-16受体对神经炎症和神经变性的脑表型的影响。我们进一步研究在Siglec-e-/-x Siglec-f-/-双基因敲除小鼠中缺乏抑制性Siglec效应，以阐明免疫系统通过‘唾液酸-Siglec’轴发挥的任何神经保护作用。因此，我们将进行免疫组织化学和转录分析，以检测不同年龄段的炎症或氧化应激以及神经元或突触丢失的任何迹象。最后，我们将试图通过阻断补体级联(Siglec-16 Tg x C3-/-小鼠)或抑制小胶质细胞的自由基产生(Siglec-16 Tg x NOX2-/-小鼠)来挽救任何Siglec-16 Tg引发的中枢神经组织损伤。这些数据将有助于了解免疫细胞的抑制性和激活性信号Siglecs在衰老和其他神经炎性疾病中对大脑的保护机制，并有助于阐明免疫细胞上的Siglecs作为神经退行性疾病的潜在治疗靶点。

Humans express inhibitory-signaling SIGLEC-11 and activatory-signaling SIGLEC-16 on microglia that can counteract each other. Mice lacking the inhibitory-signaling Siglec-E exhibited reduced survival, showed exaggerated signs of oxidative damage and very mild cognitive alterations at 24 months of age, but effects on neuroinflammation and neurodegeneration are unclear. Siglec-F of microglia might compensate the loss of Siglec-E. In this project we will study the impact of the inhibitory human SIGLEC-11 and activatory human SIGLEC-16 receptors on the brain phenotype in respect to neuroinflammation and neurodegeneration using humanized SIGLEC-11 transgenic (tg) and SIGLEC-16 tg mice. We further investigate the lack of an inhibitory Siglec effect in Siglec-e-/- x Siglec-f-/- -double knockout mice to elucidate any neuroprotective role of the immune system via the ‘Sialic Acid - Siglec’ axis. Therefore, we will perform immunohistochemistry and transcriptomics analyses to detect any sign of inflammation or oxidative stress and neuronal or synaptic loss at different ages. Finally, we will try to rescue any SIGLEC-16 tg-triggered damage to the central nervous tissue by blocking the complement cascade (SIGLEC-16 tg x C3-/- mice) or inhibiting the radical production of microglia (SIGLEC-16 tg x Nox2-/- mice). Data will help to understand the protective mechanism of inhibitory- versus activatory-signaling Siglecs of the immune cells for the brain during aging and other neuroinflammatory conditions and will help to elucidate Siglecs on immune cells as potential therapy target in neurodegenerative diseases.