Liver-X receptor β-selective agonist CE9A215 regulates Alzheimer's disease-associated pathology in a 3xTg-AD mouse model

Abstract

In Alzheimer's disease (AD), tau pathology is closely associated with disease progression. Therefore, therapeutics that alleviate tau pathology are essential. Liver-X receptor (LXR) has garnered interest as a potential target for the treatment of AD. We previously investigated the potent anti-allergic and anti-inflammatory effects of inotodiol, hereafter referred to as CE9A215, in various disease models. In this study, we explored the potential of CE9A215 as a treatment for AD. CE9A215 preferentially activated LXRβ (EC₅₀ <10 nM), with no significant activation observed for LXRα at concentrations up to 1000 nM. Pharmacokinetic analysis confirmed that CE9A215 crosses the blood-brain barrier and accumulates in the brain. Moreover, CE9A215 modulated the expression of ABCA1, APOE, SREBP-1c and AQP4 in the brains of wild-type and LXR α/β knockout mice in LXRβ-dependent manner. The efficacy of CE9A215 on AD-related pathologies was evaluated using 3xTg-AD mice. CE9A215 exerted both prophylactic and therapeutic effects on AD-associated behaviors and pathologies, including reductions in amyloid-β, phosphorylated tau, and neuroinflammation in the hippocampus. Transcriptomic analysis revealed that CE9A215 induced significant changes in genes associated with tau pathology, particularly in pathways related to protein phosphorylation and PI3K/AKT signaling. Our findings suggest that CE9A215 could be a promising therapeutic candidate for AD, particularly in mitigating tau hyperphosphorylation and related AD pathologies.

Keywords: 3xTg mouse; Alzheimer’s disease; inotodiol; liver X receptor; tau.