INVESTIGATION OF THE RELATIONSHIP BETWEEN NAV1.1 SODIUM CHANNELS AND METABOLIC PATHWAYS IN ALZHEIMER’S DISEASE

Abstract

Voltage-gated sodium channel Nav1.1 (SCN1A) is a critical regulator of neuronal excitability and network stability. While excitability remodeling contributes to Alzheimer’s disease (AD) pathophysiology, the systemic metabolic mechanisms underlying Nav1.1 dysregulation remain poorly understood. This study aims to investigate Nav1.1 alterations in a 5xFAD mouse model and their associations with multi-tissue metabolic shifts via the liver-brain axis. Materials and Ten-month-old 5xFAD mice (n=6) and controls (n=8) were evaluated using Morris water maze, open field, and elevated plus maze. Nav1.1 protein levels were quantified in total brain and liver tissues by ELISA. Untargeted LC-HRMS metabolomic profiling was conducted in serum, brain, and liver to characterize metabolic alterations and tissue-specific metaboliteNav1.1 interactions. Behavioral analysis revealed severe motor and exploratory deficits in AD mice, with total distance and velocity significantly dropping (p=0.0006) and center entries drastically reduced (p=0.0009). While spatial memory tests were performed, the profound motor collapse emerged as the dominant phenotype. Hepatic Nav1.1 levels were significantly reduced in AD mice (p<0.001). LC-HRMS revealed a significant downregulation of 3-phosphoglyceric acid in the liver (p<0.05). In the brain, a massive spike in glycerophosphorylcholine (GPC) was observed (FDR=0.037). Correlation analyses showed that hepatic Nav1.1 was positively associated with GPC (r=0.77), whereas total brain Nav1.1 showed strong negative correlations with both L-DOPA and GPC (r=-0.60). AD is characterized by hepatic Nav1.1 reduction and multi-tissue metabolic dysregulation. The contrasting correlation of GPC suggests a broken metabolic dialogue across the liver-brain axis, supporting the idea that systemic failure contributes to sodium channel remodeling.