In this work, a mannan-oligosaccharide conjugate with sialic acid capable of perturbing Aβ42 aggregation was designed and synthesized. Mannan oligosaccharides with degree polymerization of 3–13 were obtained by stepwise hydrolysis of locust bean gum using β-mannanase and α-galactosidase, named as LBOS. The activated LBOS was further chemically conjugated with sialic acid (Sia, N-acetylneuraminic acid) by fluoro-mercapto chemical coupling to synthesize a conjugate LBOS-Sia, and then phosphorylated to obtain pLBOS-Sia. The successful synthesis of pLBOS-Sia was confirmed by infrared1 chromatography, mass spectrometry, and 1 H NMR. The soluble protein analysis, microscopic observation, thioflavin T-labeling, and circular dichroism spectroscopy revealed that both LBOS-Sia and pLBOS-Sia can inhibit Aβ42 aggregation. MTT assay showed that LBOS-Sia and pLBOS-Sia had no cytotoxicity to BV-2 cells, and could substantially reduce the release of pro-inflammatory factor TNF-α induced by Aβ42 in BV-2 cells, and inhibit the occurrence of neuroinflammation. In future, this novel structure of mannan oligosaccharide-sialic acid conjugate can be potentially used to for the development of glycoconjugates against AD targeting Aβ.
Surface chirality plays an important role in determining the biological effect, but the molecular nature beyond stereoselectivity is still unknown. Herein, through surface-enhanced infrared absorption spectroscopy, electrochemistry, and theoretical simulations, we found diasteromeric monolayers induced by assembled density on chiral gold nanofilm and identified the positive contribution of water dipole potential at chiral interface and their different interfacial interactions, which result in a difference both in the positive dipoles of interfacial water compensating the negative surface potential of the SAM and in the hindrance effect of interface dehydration, thereby regulating the interaction between amyloid-β peptide (Aβ) and N -isobutyryl-cysteine (NIBC). Water on L-NIBC interface which shows stronger positive dipole potential weakens the negative surface potential, but its local weak binding to the isopropyl group facilitates hydrophobic interaction between Aβ42 and L-NIBC and resulted fiber aggregate. Conversely, electrostatic interaction between Aβ42 and D-NIBC induces spherical oligomer. These findings provide new insight into molecular nature of chirality-regulated biological effect.
He Li,Changxin Zheng,Yanru Zheng,Kai Wen,Yingjiu Zhang
Aggregation and deposition of amyloid beta-protein 1–42 (Aβ42) in the brain, primarily owing to hydrophobic interactions between Aβ42 chains, is a common pathology in all forms of Alzheimer's disease (AD). Hydrophilic oligosaccharides are widely present in the extracellular matrix and on the cytoplasmic membrane. To determine if oligosaccharides bind to Aβ42 or its aggregates and consequently affect their aggregation and cellular function, this study examined the interaction of typical functional oligosaccharides with Aβ42 or its aggregates. Isomaltooligosaccharides (IMOs), particularly isomaltotriose, panose, and isomaltotetraose, functioned as molecular chaperones for Aβ42 by binding directly to Aβ42, preserving Aβ42’s active conformation and cytotrophic activity. Oral IMOs reduced total plasma Aβ level and indirectly caused a slight reduction in the load of Aβ42 spots/plaques in the brain of AD model mice (male). Another branched oligosaccharide, bianntennary core pentasaccharide (BCP), had a relatively high binding specificity for Aβ42 oligomers (Aβ42O) and acted as an antagonistic binding partner for Aβ42O. Free BCP effectively blocked/prevented further assembly of Aβ42O and their toxicity to neural and vascular endothelial cell lines. Since BCP is also a signaling component of membrane targets (glycolipids, glycoproteins or receptors), it seemed that BCP had two opposing effects on the binding of Aβ42O to target cells. This study’s findings suggest that these branched oligosaccharides may be potential candidates for blocking or preventing Aβ42 aggregation and Aβ42O cytotoxicity/neurotoxicity, respectively, and that IMO-like or free BCP-like oligosaccharide deficiencies in the brain may be one of the underlying mechanisms for Aβ42 aggregation and Aβ42O cytotoxicity.
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