Sciadonic acid ameliorates cognitive impairment in APP/PS1 mice with concomitant modulation of gut microbiota and brain metabolism.

Sciadonic acid (SCA) is a fatty acid derived from Torreya grandis oil with known anti-inflammatory and antioxidant properties; however, its role in Alzheimer's disease (AD) remains undefined. In this study, oral SCA administration to APP/PS1 transgenic mice significantly improved spatial learning and memory, as assessed by Morris water maze and Y-maze tests. Histological examination revealed reduced neuronal loss, preserved neuropil architecture, and diminished Aβ plaque burden in the hippocampus and cerebral cortex. SCA treatment enhanced antioxidant capacity, as indicated by elevated superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, alongside decreased malondialdehyde (MDA) and nitric oxide (NO) levels. Furthermore, SCA restored colonic mucosal integrity and suppressed pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Gut microbiota analysis revealed reversal of dysbiosis, with an increased Bacillota/Bacteroidetes ratio, enrichment of beneficial taxa such as Lactobacillus, and elevated short-chain fatty acid (SCFA) levels. Non-targeted hippocampal metabolomics identified modulation of 16 metabolites, predominantly in taurine and hypotaurine, and pyrimidine pathways. Collectively, SCA administration was associated with cognitive and neuropathological improvements alongside alterations in gut microbiota and hippocampal metabolism.