Center for Cognitive Neurology, Department of Neurology, New York University School of Medicine, New York, USA.
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, Korea.
Sci Rep. 2017 Aug 14;7(1):8009. doi: 10.1038/s41598-017-08604-8.
Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late onset Alzheimer's disease (AD). Studies have shown that apoE, apoE4 in particular, binds to amyloid-β (Aβ) peptides at residues 12-28 of Aβ and this binding modulates Aβ accumulation and disease progression. We have previously shown in several AD transgenic mice lines that blocking the apoE/Aβ interaction with Aβ12-28 P reduced Aβ and tau-related pathology, leading to cognitive improvements in treated AD mice. Recently, we have designed a small peptoid library derived from the Aβ12-28 P sequence to screen for new apoE/Aβ binding inhibitors with higher efficacy and safety. Peptoids are better drug candidates than peptides due to their inherently more favorable pharmacokinetic properties. One of the lead peptoid compounds, CPO_Aβ17-21 P, diminished the apoE/Aβ interaction and attenuated the apoE4 pro-fibrillogenic effects on Aβ aggregation in vitro as well as apoE4 potentiation of Aβ cytotoxicity. CPO_Aβ17-21 P reduced Aβ-related pathology coupled with cognitive improvements in an AD APP/PS1 transgenic mouse model. Our study suggests the non-toxic, non-fibrillogenic peptoid CPO_Aβ17-21 P has significant promise as a new AD therapeutic agent which targets the Aβ related apoE pathway, with improved efficacy and pharmacokinetic properties.
载脂蛋白 E4 (apoE4) 基因型的遗传已被确定为晚期发病阿尔茨海默病 (AD) 的主要遗传风险因素。研究表明，载脂蛋白 E，尤其是 apoE4，与 Aβ 肽的残基 12-28 结合，这种结合调节 Aβ 的积累和疾病进展。我们之前在几种 AD 转基因小鼠系中表明，用 Aβ12-28 P 阻断 apoE/Aβ 相互作用可减少 Aβ 和 tau 相关病理，从而改善治疗的 AD 小鼠的认知能力。最近，我们设计了一个源自 Aβ12-28 P 序列的小肽类似物文库，以筛选具有更高疗效和安全性的新型 apoE/Aβ 结合抑制剂。肽类似物比肽类更适合作为药物候选物，因为它们具有内在更有利的药代动力学特性。一种先导肽类似物化合物 CPO_Aβ17-21 P，可减弱 apoE/Aβ 相互作用，并减弱 apoE4 对 Aβ 聚集的原纤维形成效应以及 apoE4 对 Aβ 细胞毒性的增强作用。CPO_Aβ17-21 P 减少了 Aβ 相关病理，同时改善了 AD APP/PS1 转基因小鼠模型的认知能力。我们的研究表明，非毒性、非纤维形成肽类似物 CPO_Aβ17-21 P 具有很大的潜力成为一种新型 AD 治疗剂，其针对的是与 Aβ 相关的 apoE 途径，具有改善的疗效和药代动力学特性。
