Pharmaceutical Sciences Division and Wisconsin Center for NanoBioSystems, University of Wisconsin, Madison, Wisconsin 53705, United States.
ACS Chem Neurosci. 2021 Jan 6;12(1):99-108. doi: 10.1021/acschemneuro.0c00606. Epub 2020 Dec 17.
Amyloid-β (Aβ) aggregated forms are highly associated with the onset of Alzheimer's disease (AD). Aβ abnormally accumulates in the brain and induces neuronal damages and symptoms of AD such as cognitive impairment and memory loss. Since an antibody drug, aducanumab, reduces Aβ aggregates and delays clinical decline, clearance of accumulated Aβ in the brain is accounted as a therapeutic approach to treat AD. In this study, we synthesized 17 benzofuran derivatives that may disaggregate Aβ oligomers and plaques into inert monomers. By a series of Aβ aggregation inhibition and aggregates' disaggregation assays utilizing thioflavin T assays and gel electrophoresis, , 2-((5-methoxy-3-(4-methoxyphenyl)benzofuran-6-yl)oxy)acetic acid, was selected as the final Aβ-disaggregator candidate. When it was orally administered to the 8-month-old male transgenic mouse model with five familial AD mutations (5XFAD) via drinking water daily for two months, Aβ oligomers and plaques in hippocampus were reduced. Consequently, decreased astrogliosis and rescued synaptic dysfunction were observed in the hippocampus of -treated 5XFAD mice compared with the untreated transgenic control group.
淀粉样蛋白-β（Aβ）聚集形式与阿尔茨海默病（AD）的发病高度相关。Aβ在大脑中异常积聚，并诱导神经元损伤和 AD 的症状，如认知障碍和记忆力减退。由于抗体药物 aducanumab 可减少 Aβ 聚集并延缓临床衰退，因此清除大脑中积累的 Aβ被认为是治疗 AD 的一种方法。在这项研究中，我们合成了 17 种苯并呋喃衍生物，这些化合物可能将 Aβ 低聚物和斑块解聚为无活性的单体。通过一系列利用硫代黄素 T 测定法和凝胶电泳的 Aβ 聚集抑制和聚集物解聚测定，选择 2-((5-甲氧基-3-(4-甲氧基苯基)苯并呋喃-6-基)氧基)乙酸作为最终的 Aβ 解聚剂候选物。当通过饮用水每天向 8 个月大的携带有五个家族性 AD 突变（5XFAD）的雄性转基因小鼠模型口服给药两个月时，海马体中的 Aβ 低聚物和斑块减少。因此，与未经处理的转基因对照组相比，-处理的 5XFAD 小鼠的海马体中的星形胶质细胞增生减少和突触功能障碍得到挽救。
