Polysaccharides extracted from common buckwheat (Fagopyrum esculentum) attenuate cognitive impairment via suppressing RAGE/p38/NF-κB signaling and dysbiosis in AlCl-treated rats.

Patients may find it challenging to accept several FDA-approved drugs for Alzheimer's disease (AD) treatment due to their unaffordable prices and side effects. Despite the known antioxidant, anti-inflammatory, and microbiota-regulating effects of common buckwheat (Fagopyrum esculentum) polysaccharides (FEP), their specific role in preventing AD has not been determined. Here, this study investigated the preventive effects of FEP on AD development in AlCl-treated rats. The physical properties of FEP were evaluated using X-ray diffraction, FTIR, TGA, DSC, monosaccharide composition, molecular weight, and scanning electron microscopy. The results demonstrated that FEP administration improved memory and learning ability in AlCl-treated rats. Additionally, AD pathological biomarkers (APP, BACE1, Aβ, and p-Tau), inflammatory-associated proteins (IL-1β, IL-6, TNF-α, and Iba1), and MDA and the RAGE/p38/NF-κB pathway were elevated in AlCl-treated rats. Moreover, these effects were reversed by the upregulation of LRP1, anti-inflammatory cytokines (IL-4 and IL-10), antioxidant enzymes (SOD and catalase), and autophagy proteins (Atg5, Beclin-1, and LC3B). Furthermore, FEP treatment increased the levels of short-chain fatty acids (SCFAs) and the abundance of SCFAs-producing microbes ([Eubacterium]_xylanophilum_group, Lachnospiraceae_NK4A136_group, Lactobacillus). Overall, FEP mitigated oxidative stress, RAGE/p38/NF-κB-mediated neuroinflammation, and AD-associated proteins by upregulating autophagy and SCFA levels, which led to the amelioration of cognitive impairment through microbiota-gut-brain communication in AlCl-treated rats.