Suppression of Alzheimer's disease by Agaricus sinodeliciosus var. Chaidam exopolysaccharide with amyloid-β clearance activity via gut microbiota-metabolite regulation.

Amyloid-β (Aβ) aggregation is a hallmark of Alzheimer's disease (AD), characterized by cognitive impairment, and there remains a lack of effective functional compound with Aβ clearance activity. To elucidate the effect of exopolysaccharide (EPS) extracted from Agaricus sinodeliciosus var. Chaidam on Aβ1-42- induced AD rat and uncover the underlying mechanism, the neuroprotective activity of EPS was evaluated using immunofluorescence, immunohistochemistry, western blot, RT-qPCR, microbiomics and metabolomics. The results demonstrated that EPS exhibited significant anti-AD efficacy, as evidenced by improved cognitive function and spatial memory, balanced brain redox status, suppressed neuroinflammatory responses. EPS substantially reduced Aβ1-42 accumulation in the hippocampus by activating Aβ-phagocytic microglia through the mTOR-HIF-1α pathway. Importantly, EPS reconstructed gut microbiota composition by increasing the relative abundance of Ruminococcaceae and reduced Erysipelotrichaceae. The reshaped gut microbiome and the formation of the metabolite serotonin were associated with behavioral alterations, neuroinflammation, and brain oxidative status. Thus, EPS significantly alleviated cognitive deficit and neuroinflammation in Aβ1-42-induced AD rats, potentially by enhancing microglial phagocytosis of Aβ1-42 and modulating the gut microbiome and serotonin production. Collectively, EPS from A. sinodeliciosus var. Chaidam polysaccharide may serve as a novel Aβ1-42-targeted approach for anti-AD therapy.