Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer’s Disease Validated in a Mouse Model Expressing Human APOE3/APOE4,Journal of Medicinal Chemistry

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Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer’s Disease Validated in a Mouse Model Expressing Human APOE3/APOE4
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-27 , DOI: 10.1021/acs.jmedchem.4c00733
Ganga Reddy Velma ₁ , Megan S Laham ₂ , Cutler Lewandowski ₃ , Ana C Valencia-Olvera ₄ , Deebika Balu ₄ , Annabelle Moore ₄ , Martha Ackerman-Berrier ₁ , Pavel Rychetsky ₁ , Christopher Penton ₁ , Soumya Reddy Musku ₁ , Anandhan Annadurai ₁ , Maha Ibrahim Sulaiman ₁ , Nina Ma ₁ , Gregory R J Thatcher _{1,

2}

Affiliation

Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer’s disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark amyloid-β pathology.

中文翻译：

用于治疗阿尔茨海默病的非脂肪生成 ABCA1 诱导剂 (NLAI) 在表达人 APOE3/APOE4 的小鼠模型中得到验证

增强载脂蛋白 (APOE) 阳性功能的治疗是当务之急，因为APOE4是阿尔茨海默病 (AD) 的主要遗传风险因素。 APOE 是在大脑中转运胆固醇和脂质的脂蛋白颗粒的关键成分，其功能依赖于细胞膜胆固醇转运蛋白 ABCA1 的脂质化。 ABCA1 转录受肝脏 X 受体 (LXR) 调节：激动剂已被证明可以增加 ABCA1，通常伴随着不需要的脂肪生成和甘油三酯 (TG) 升高。因此，需要非脂肪生成 ABCA1 诱导剂 (NLAI)。对源自表型筛选的 HTS 命中进行两轮优化，得到先导化合物39，该化合物在表达人 APOE3/4 和五种突变 APP 和 PSEN1 人转基因的 E3/4FAD 小鼠中进行了验证和测试。 39治疗增加了 ABCA1 表达，增强了 APOE 脂化，并逆转了多种 AD 表型，而没有增加 TG。这项 NLAI/LXR 激动剂研究是第一个针对具有标志性淀粉样蛋白-β 病理学的人类APOE表达模型的研究。

更新日期：2024-08-27

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