LXRβ-Selective Agonism to Simultaneously Enhance APOE Lipidation and Reduce Mic…

LXRβ-selective agonism represents a targeted strategy to simultaneously enhance APOE lipidation and reduce microglial cholesterol accumulation, addressing two interrelated pathogenic mechanisms in APOE4-associated neurodegeneration. The approach exploits the predominant CNS expression of LXRβ (NR1H2) to achieve therapeutic effects while potentially avoiding the hepatic lipogenic effects mediated by LXRα. Supporting this rationale, LXRβ-deficient mice develop age-dependent neurodegeneration with cholesterol accumulation, and APOE4 carriers demonstrate impaired LXR-driven ABCA1 transcription compared to APOE3, suggesting that enhanced LXRβ signaling could restore APOE lipidation in this vulnerable population. However, significant challenges temper this hypothesis: global LXR agonists have failed in clinical trials due to hepatomegaly and hypertriglyceridemia, LXRβ expression in liver contributes to lipogenesis with deletion causing hepatic triglyceride accumulation in aging, and activation-induced APOE expression in microglia could paradoxically increase APOE4 quantity and worsen pathological seeding. The selective agonism strategy aims to maintain therapeutic benefit while mitigating these adverse effects through tissue-specific targeting.