Design and Development of a Novel LXRβ/PPARδ Dual Agonist for Memory Impairment and Pathology in 3xTg-AD Animal Model of Alzheimer’s Disease

The rising prevalence of Alzheimer’s disease (AD) underscores an urgent need for neuroprotective strategies that modulate cholesterol metabolism, neuroinflammation, improve pathology, and cognitive function. While Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are validated targets for enhancing amyloid-β and tau clearance, clinical translation of first-generation LXR agonists has been hindered by LXRα-mediated hepatic steatosis and hypertriglyceridemia. Here, we report the structure-based design of AU403, a potent, isoform-selective LXRβ/PPARδ dual agonist designed to bypass LXRα-driven hepatotoxicity. Molecular modeling indicates that AU403 achieves LXRβ selectivity by engaging residues Phe329 and Leu330 while avoiding the corresponding LXRα residues Arg305 and Leu316. This structural precision translates to robust functional activity, with luciferase assays confirming potent activation of LXRβ (EC 50 ≈ 45 nM) and PPARδ (EC 50 ≈ 40 nM). Notably, AU403 exhibits a superior safety profile, circumventing hepatotoxicity, neutropenia, and hERG inhibition that have limited the clinical development of prior agonists. Furthermore, chronic administration of AU403 in 3xTg-AD mice significantly improved cognitive functions and reduced amyloid-β plaque burden, establishing AU403 as a promising dual-acting agonist for the treatment of Alzheimer’s Disease.