Ergothioneine-rich water extracts of Hericium erinaceus HE-17 alleviate Alzheimer’s disease in mice by regulating oxidative stress, inflammation, and the gut microenvironment

Alzheimer’s disease (AD) imposes a significant global disease burden, necessitating simple dietary interventions to prevent or delay disease progression. However, the neuroprotective effects of ergothioneine (EGT)-rich natural extracts as dietary supplements remain largely unexplored. This study aimed to screen a high EGT-producing Hericium erinaceus strain (HE-17) from 29 isolates, optimize its culture conditions and amino acid supplementation using single-factor and orthogonal experiments, and evaluate the neuroprotective effects of its extract in an APP/PS1 transgenic mouse model. Cognitive function, neuronal damage, inflammation, oxidative stress, and gut microbiota composition were assessed using the Morris Water Maze test, histopathology, immunofluorescence, biochemical assays, enzyme-linked immunosorbent assay (ELISA), and 16S rRNA gene sequencing. The results showed that the water extract of H. erinaceus HE-17 (WEH) contained 2.57 ± 0.14 mg/g EGT and exhibited no acute toxicity in mice. High-dose WEH (2 g/kg BW/d, containing 5.76 mg/kg EGT), low-dose WEH (0.50 g/kg BW/d, containing 1.44 mg/kg EGT), and pure EGT (1.44 mg/kg), administered for 90 days, were found to improve cognitive function and enhance spatial learning and memory, while reducing Aβ aggregation and tau phosphorylation. Meanwhile, WEH supplementation was associated with decreased pro-inflammatory cytokine levels (IL-1β, IL-6, and TNF- α ) in both the brain and serum. It also reduced oxidative stress markers while increasing antioxidant indicators in brain tissue, with the high-dose group showing the most pronounced effects in APP/PS1 mice. Gut microbiota analysis revealed that low-dose WEH was associated with a reduced abundance of Fusobacteriota and Proteobacteria and an increased abundance of Lactobacillus . These findings suggest that WEH may help mitigate AD-related pathological changes in APP/PS1 mice.