Total salvianolic acids protect APP/PS1 mice from Alzheimer's disease by attenuating neuroinflammation through hippocampal lipid regulation

Background Total salvianolic acids (TSA) have been shown to exert neuroprotective effects in cognition-associated behavioral tests in APP/PS1 mice in our previous research; however, research on TSA-mediated modulation of hippocampal lipid metabolism remains limited. Objective This study elucidated the therapeutic mechanisms underlying prophylactic TSA administration by integrating lipidomic profiling and demonstrating TSA-induced neuroprotection through suppression of hippocampal neuroinflammation in APP/PS1 mice. Methods Ten 3.5-month-old APP/PS1 mice and ten age-matched wild-type mice received intraperitoneal saline injections as the disease model and healthy control groups. Another twenty APP/PS1 mice were allocated to two TSA treatment groups (30 mg/kg/day and 60 mg/kg/day). After fifteen weeks of intervention, memory performance was assessed using the Y-maze test. Hippocampal Aβ, IBA1, and GFAP protein expression levels were quantified by western blotting. Targeted UHPLC-MS/MS was used for quantitative detection of hippocampal lipid biomarkers. Results The 60 mg/kg TSA group exhibited improved memory in Y-maze tests, with elevated spontaneous alternation rate ( p < 0.05) and arm entries ( p < 0.01). The latency to enter the novel arm was significantly reduced at both doses of TSA ( p < 0.01). TSA at 60 mg/kg reduced hippocampal inflammation markers IBA1 ( p < 0.05), GFAP ( p < 0.05), and Aβ ( p < 0.01) in APP/PS1 mice. Lipids revealed significant changes in 41 lipid species after TSA treatment. TSA suppressed the levels of glycerides, sterol lipids, and free fatty acids while increasing glycolipids including monogalactosyldiacylglycerols. TSA also regulated sphingomyelins by reducing acyl chain–modified PCs and increasing phosphatidylserines. Conclusions This study reveals TSA's preventive potential against Alzheimer's disease by modulating inflammation-associated lipid metabolism in APP/PS1 mice.