Alleviating neuronal inflammation induced by Aβ₄₂ in SH-SY5Y through interaction with polysialic...

Amyloid beta (Aβ) aggregation is one of the distinctive pathological hallmarks of Alzheimer's disease (AD). Therefore, the development of effective inhibitors against Aβ aggregate formation offers great promise for the treatment of AD. In this study, we designed a novel negatively charged functionalized conjugate aimed at inhibiting Aβ₄₂ aggregation and attenuating neurotoxicity by grafting polysialic acid with mannuronate oligosaccharide, a biocompatible glycan extracted from seaweeds, designated as polysialic acid-mannan conjugate (PSA-MOS). ThT, biological microscopy, TEM and CD confirmed the inhibition of Aβ₄₂ aggregation by PSA-MOS, as well as its ability to inhibit the conformational transition of Aβ₄₂ to β-sheet. CCK-8 assay demonstrated that PSA-MOS was not cytotoxic to SH-SY5Y (p < 0.05) and promoted cell proliferation. In the Aβ₄₂-induced SH-SY5Y injury models, PSA-MOS dose-dependently ameliorated cytotoxicity (p < 0.0001) and significantly reduced the levels of inflammatory factors of IL-1β (p < 0.0001), IL-6 (p < 0.0001) and TNF-α (p < 0.05). MD simulations demonstrated that PSA-MOS effectively impeded the α-helix to β-sheet transition of the Aβ₄₂ monomer via electrostatic interactions with its CTR and NTR regions. These findings demonstrate the therapeutic potential of PSA-MOS as promising glycoconjugate for the treatment of AD.