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

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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.