Cross‐Organ Multi‐Omics Profiling of Systemic Alterations in 5xFAD Mice and Changes Associated with Huanglian Jiedu Decoction Treatment

Alzheimer's disease (AD) is increasingly recognized as a systemic disorder involving metabolic abnormalities beyond the brain, but links between hepatic alterations and neuroinflammation remain unclear. We integrated behavioral, histopathological, transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses in male mice assigned to WT (n = 15), AD (n = 16), high-dose HLJDD (n = 16), low-dose HLJDD (n = 11), and donepezil (n = 10) groups and treated for 10 weeks. Longitudinal behavioral data were analyzed using repeated-measures models, and omics p-values were adjusted using the Benjamini-Hochberg FDR procedure. Cognitive impairment, glial activation, and neuroinflammation were accompanied by hepatic metabolic disturbances and alterations in insulin signaling and energy metabolism, implicating PPAR and PI3K/Akt-related processes. HLJDD, particularly at the high dose, improved behavioral and neuropathological outcomes and shifted abnormalities in TCA-cycle metabolites, amino acid neurotransmitters, and oxidative balance toward WT levels. To assess hepatocyte contributions to microglial inflammation, we established an AML12-BV2 conditioned-medium model with hepatocyte PPAR-γ knockdown. Conditioned medium from LPS/HLJDD-cotreated AML12 cells elicited lower inflammatory responses in BV2 cells than medium from LPS-treated hepatocytes. PPAR-γ knockdown attenuated this effect, supporting a hepatocyte PPAR-γ-dependent contribution to microglial regulation and further investigation of hepatic involvement in HLJDD-associated neuroprotection.