Atractylenolide I mitigates Alzheimer’s disease pathology in ApoE‑/‑mice via ARG1/nNOS axis and lipid homeostasis regulationOA

Apolipoprotein E(ApoE)serves as a critical molecular nexus between Alzheimer’s disease(AD)and atherosclerosis,two age‑associated inflammatory disorders that share vascular pathology,amyloid‑beta(Aβ)deposition,and lipid dysregulation.Atractylenolide I(AI),a promising therapeutic candidate derived from Atractylodes macrocephala Koidz.,exhibits multimodal bioactivities with demonstrated anti‑inflammatory and neuroprotective properties.To explore its therapeutic potential against AD pathology,we use high‑fat diet(HFD)‑fed ApoE knockout(ApoE‑/‑)mice treated with or without AI for 12 weeks.Integrated bioinformatics analyses and experimental validation reveal that AI treatment markedly attenuates systemic lipid dyshomeostasis,particularly cerebral lipid deposition,suppresses neuroinflammation via downregulation of M1 macrophage polarization markers,and restores cognitive function through neuronal preservation in hippocampal regions.Mechanistically,AI orchestrates cholesterol efflux by up‑regulating ATP‑binding cassette transporter A1(ABCA1)and liver X receptor(LXR)expression,while concurrently modulating the abundance of arginine biosynthesis metabolites(urea,malic acid,and creatinine)to rebalance neurovascular homeostasis.Notably,western blot and RT‑qPCR analyses reveal that AI differentially regulates key enzymes including arginase 1(ARG1)and simultaneously upregulates the expression of neuronal nitric oxide synthase(nNOS).Further molecular docking and surface plasmon resonance(SPR)analyses confirm the direct binding of AI to ARG1,indicating a novel neuroprotective mechanism involving the modulation of arginine metabolism.These findings delineate the pleiotropic effects of AI against AD pathology and establish a preclinical foundation for the development of AI‑based therapeutics targeting neurodegenerative‑cardiovascular comorbidities.