Investigation of Kai-Xin-San in alleviating cognitive impairment in aβ transgenic Caenorhabditis elegans through mitochondrial function regulation.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, mitochondrial dysfunction, and amyloid β-protein (Aβ) accumulation, with limited safe and effective treatments available. Kai-Xin-San (KXS), a traditional Chinese medicine formula (Panax ginseng, Poria cocos, Polygala tenuifolia, Acorus calamus), has shown potential in alleviating AD symptoms, but its mechanisms, especially mitochondrial regulation-related ones, remain unclear. Using Aβ-overexpressing Caenorhabditis elegans (Aβ-C. elegans) as an AD model, this study evaluated KXS's pharmacodynamic effects via serotonin sensitivity and chemotaxis assays, identified its absorbed components via UPLC-Q/TOF-MS, predicted anti-AD mechanisms via bioinformatics (GO/KEGG) and metabolomics, and assessed mitochondrial function via ROS, ATP, SOD, MDA, JC-1 assays, as well as RT-qPCR/Western blotting of mitochondrial pathways. Results showed that 10 mg/mL KXS significantly reduced Aβ-C. elegans paralysis by 27.1 % (P < 0.01) and improved associative learning (P < 0.01); 20 KXS components were characterized in vivo, and KXS reduced ROS/MDA, elevated ATP/SOD (P < 0.01), restored mitochondrial membrane potential, regulated mitochondrial biogenesis/autophagy (hmg-5, bec-1, lgg-1) and fission genes (drp-1, fis-1), and activated the AMPK/SIRT1 pathway (aak-1, sir-2.1, SIRT1/p-AMPK), thereby improving cognitive impairment in Aβ-C. elegans. This finding clarifies its neuroprotective mechanism and provides evidence for its potential as a therapeutic candidate for AD.