Neuroprotective Role and Immunomodulatory Effects of Sialylation

Abstract

Sialic acids are terminal sugars on the cellular glycocalyx, crucial for modulating immune responses in the sialylated central nervous system. Sialylation acts as an inhibitory checkpoint, regulating inflammation and tissue damage. Sialic acid-binding immunoglobulin-type lectins (SIGLECs), expressed on immune cells, bind sialylated glycoproteins and glycolipids, thereby inhibiting pro-inflammatory responses and phagocytosis. In the first part of this thesis the therapeutic effects of 6'-sialyllactose (6SL), a human milk oligosaccharide, in preventing neomycin-induced hearing loss in postnatal mice were explored. Systemic 6SL injection improved hearing, reduced macrophage activation in the cochlear spiral ganglion, and reversed the expression of the proinflammatory IL-1β and apoptotic Pik3cd gene transcripts. In vitro, 6SL demonstrated anti-inflammatory, anti-phagocytic, and neuroprotective effects on lipopolysaccharide-challenged THP1-macrophages, highlighting its therapeutic potential in inflammatory induced ototoxicity. In the second part the role of the human-specific SIGLEC-11 receptor in neurodegeneration and neuroinflammation in the aging brain was examined. Humanized Siglec-11 transgenic (tg) mice were studied at 6 and 24 months. Siglec-11 tg mice showed fewer Iba1-positive microglial cells, reduced lipid-laden microglia, and less neuronal loss compared to WT mice. Transcriptomic analysis revealed suppression of gene transcript pathways related to inflammatory and oxidative stress at 6 months, and complement and coagulation cascades at 24 months in Siglec-11 tg mice, suggesting a protective role for SIGLEC-11 in mitigating brain inflammation. In the third part the impact of age-related reduced sialylation on retinal inflammation and degeneration in Gne+/- mice with a heterozygous knock-out of the Gne gene was investigated. At 9 months, Gne+/- mice had lower polysialic and trisialic acid levels, higher CD68 expression, and at 12 months, fewer rod bipolar cells. Transcriptomic analysis revealed upregulated complement, inflammation, and apoptosis pathways, with increased pro-inflammatory and complement markers. Crossing Gne+/- mice with C3-deficient mice prevented CD68 elevation, rod bipolar cell loss, and increased C4 expression, indicating that retinal inflammation and cell loss in hyposialylation are driven by complement activation. These findings highlight the relevance of sialylation in modulating immunity and reducing inflammation, thus offering new options for treatment of neurodegenerative diseases.