ABSTRACT Gut microbiota disruption has been implicated in Alzheimer's disease (AD) pathogenesis. Although Astragalus polysaccharides (APS) exert neuroprotective effects and modulate gut microbial composition, the precise mechanisms underlying these actions remain unknown. This research sought to clarify how APS modulates the gut microbiota during AD progression. Triple‐transgenic (3xTg) AD mice received daily oral APS for 4 weeks. Cognitive performance was evaluated with the Morris water maze (MWM). Immunofluorescence (IF), immunohistochemistry (IHC), and western blotting measured β‐amyloid (Aβ) deposition and microglial and astrocyte markers. IHC also evaluated intestinal tight‐junction proteins (zonula occludens‐1 and occludin). Inflammatory markers in the brain, blood, and intestine were quantified using enzyme‐linked immunosorbent assay (ELISA). Gut microbiota was analyzed through 16S rRNA sequencing. Treatment with APS significantly improved learning and memory performance in 3xTg mice. APS administration reduced cerebral Aβ deposition, decreased phosphorylated tau, presenilin‐1, and β‐secretase 1 levels, and elevated ADAM10 expression. APS significantly altered gut microbiota, notably increasing Akkermansia and decreasing Alistipes . At the intestinal level, APS enhanced expression of tight‐junction proteins ZO‐1 and occludin and reversed AD‐associated structural alterations in the intestinal lining. Furthermore, APS reduced inflammatory cytokine levels in intestinal tissue, peripheral blood, and brain tissue, as reflected by modulated IL‐4, IL‐10, TGF‐β, TNF‐α, IL‐1β, and IL‐6 expressions. The attenuation of neuroinflammation may be attributed to the inhibitory effect of APS on microglial and astrocyte activation. APS reduces neuroinflammation in AD by modulating gut microbiota, contributing to cognitive and pathological improvements, thus indicating its therapeutic potential for AD.
Wang et al. (2026) studied this question.