Lingguizhugan decoction improves cognitive impairment in APP/PS1 mice by promoting meningeal lymphatic drainage based on fatty acid degradation pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Lingguizhugan Decoction (LGZG), a classic traditional Chinese medicine formula, has been demonstrated in numerous studies to possess therapeutic potential for Alzheimer's disease (AD). However, it remains unclear whether its mechanism of action involves the meningeal lymphatic system. AIM OF THE STUDY: Investigate if LGZG improves cognition in APP/PS1 mice by restoring meningeal lymphatic vessels (mLVs) drainage. MATERIALS AND METHODS: Assessed cognitive behavior and pathology in LGZG-treated APP/PS1 mice. Used tracers and immunofluorescence (LYVE-1/TR-d3) to evaluate mLVs drainage and markers. Conducted untargeted brain metabolomics and dura mater micro-proteomics. Performed molecular docking and functional analysis focusing on fatty acid pathways. RESULTS: LGZG ameliorated cognitive impairment and Aβ deposition in mice. Improved Aβ clearance correlated with enhanced mLVs function (confirmed by tracing). Metabolomics and micro-proteomics identified impaired fatty acid degradation as a key pathological factor. LGZG, at clinically relevant doses, restored mLVs drainage and rescued cognition by activating the fatty acid degradation pathway. CONCLUSION: Lingguizhugan Decoction ameliorates AD-like pathologies and cognitive deficits in APP/PS1 mice by enhancing Aβ clearance via regulating the "fatty acid degradation-meningeal lymphatic axis." This finding reveals a novel multi-target mechanism of LGZG and offers a fresh perspective on metabolic intervention for AD treatment.