Structure-activity relationship of uronic acid oligosaccharides as potential anti-Alzheimer's disease agents.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the primary cause of dementia. Although natural polysaccharides exhibit significant therapeutic potential against AD due to their multi-target activities, the structure-activity relationship (SAR) of uronic acid oligosaccharides-particularly the influence of specific glycosidic linkages and monosaccharide compositions-remains insufficiently characterized. To address this, we utilized a highly selective TEMPO oxidation system to prepare four structurally distinct uronic acid oligosaccharides (α1,4-G, β1,4-G, β1,3-G, and β1,4-M/G) from diverse natural polysaccharides. NMR spectroscopy showed that the resulting oligosaccharides retained the major glycosidic linkage characteristics of their parent polysaccharides, while oxidation and depolymerization also occurred during the reaction. Comprehensive in vitro and in vivo evaluations demonstrated that the β-1,4-glycosidic linkage is a critical structural determinant for neuroprotective activity against Aβ-induced neuronal damage and cognitive impairment, while β1,4-M/G and β1,4-G showed different effects under the present experimental conditions. Mechanistic studies revealed that both β1,4-G and β1,4-M/G ameliorated Aβ-induced cognitive impairment and were associated with alterations in the gut microbiota and related metabolites. Importantly, fermentation products generated from these oligosaccharides by the AD microbiota were associated with enhanced Treg differentiation, which may potentially contribute to the observed neuroprotective effects. These findings provide systematic insights into the SAR of uronic acid oligosaccharides and support the further investigation of β-1,4-linked uronic acid oligosaccharides as potential neuroprotective candidates.