Investigation of the mechanism of Buyang Huanwu decoction in improving learning and memory impairment in Alzheimer's disease mice based on lipidomics

In this study, a lipid disorder Alzheimer's disease (AD) model was developed with high-fat diet and d-galactose injected intraperitoneally (HFD & d-gal) to evaluate the activities of Buyang Huanwu Decoction (BYHWD) compared with donepezil hydrochloride. The learning and memory abilities of BYHWD were evaluated by Morris water maze test (MWM). The lipid levels in serum, histopathology, and immunohistochemistry of hyperphosphorylated tau protein in hippocampal neurons were conducted to prove the therapy effects of BYHWD. After the identification of constituents absorbed into the brain using LC-MS, UPLC-TQ-MS was employed to analyze endogenous lipid metabolites in the hippocampi of mice. Based on the validated differential markers identified through lipidomics analysis, we further substantiated potential therapeutic pathway of BYHWD through the application of molecular docking technology. The mechanism underlying BYHWD was subsequently confirmed by palmitic acid-injured HT22 cells. The results showed that BYHWD significantly improved the cognitive deficits and regulated the lipid levels of HFD & D-gal mice. BYHWD also protected the neuronal cell condition of hippocampal neurons, increased the density of dendritic spines, and reduced the expression of P-tau. Lipidomics revealed that 41 differential lipid metabolites were retuned after BYHWD administration, and this change may be related to the PPAR gamma pathway. Calycosin-7-glucoside showed good interaction with PPAR gamma in vivo composition analysis. Calycosin-7-glucoside increased the mRNA expression levels of lipid metabolism-related enzymes and PPAR gamma, as well as the expression of PPAR gamma protein in vitro study. BYHWD activated the PPAR gamma pathway to induce peroxisome proliferation and regulated lipid metabolism disorders in the AD mice brain.