Comparative Hippocampal and Serum Metabolomics Reveals Dose-related Metabolic Alterations Consistent with TDMQ20...

Copper (Cu) dyshomeostasis and metabolic dysfunction have been implicated as key drivers of Alzheimer's disease (AD). Tetradentate monoquinoline 20 (TDMQ20), a Cu chelator, reportedly improves behavioral deficits in AD model mice, but its underlying metabolic mechanism is unclear. Here, we addressed this via untargeted ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) metabolomics in the hippocampus and serum of AD model mice induced by intrahippocampal injection of Cu amyloid-β₄₂ (Cu-Aβ₄₂) and then treated with TDMQ20 at low (LT, 5 mg/kg) and high (HT, 10 mg/kg) doses. Results showed that AD was associated with tissue-specific metabolic perturbations: hippocampal disorders were enriched in linoleic acid and glycerophospholipid metabolism, while serum perturbations centered on tryptophan, sphingolipid, and purine metabolism, with organic acids, lipids, and benzenoids as core differential metabolite classes. TDMQ20 reversed these abnormalities in a dose-associated manner: LT regulated tryptophan/linoleic acid metabolism in the hippocampus and purine/arachidonic acid metabolism in serum, while HT shifted the hippocampal metabolic profile substantially toward that of the control group. Cross-matrix analysis identified PS (15:0/22:0) and LPC (18:2/0:0) as key lipid metabolites with opposite expression patterns between hippocampus and serum, and four serum endogenous metabolites (pipecolic acid, PGG2, N-sulfo-D-glucosamine, and hex-2-ulose) as exploratory candidate metabolites. TDMQ20 was associated with metabolomic changes in both hippocampus and serum consistent with attenuated oxidative stress, neuroinflammation, and membrane lipid remodeling, suggesting preferential central metabolic modulation and dose-associated action. This study provides metabolomic evidence consistent with TDMQ20's potential tissue-resolved regulatory properties and identifies exploratory candidate metabolites for monitoring therapeutic efficacy in AD.