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当代阿耳茨海默病研究

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Review Article

针对阿尔茨海默病中淀粉样β蛋白的治疗策略

卷 16, 期 5, 2019

页: [418 - 452] 页: 35

弟呕挨: 10.2174/1567205016666190321163438

价格: $65

摘要

阿尔茨海默病(AD)是一种与蛋白质错误折叠和聚集相关的神经退行性疾病。 AD的病理特征在于由细胞外淀粉样蛋白-β(Aβ)肽和由过度磷酸化的tau蛋白形成的细胞内神经原纤维缠结(NFT)形成的老年斑。 广泛的突触丧失和神经元变性是AD典型的记忆障碍,认知衰退和行为功能障碍的原因。淀粉样变性与乙酰胆碱合成和释放的抑制, N-甲基-D-天冬氨酸(NMDA)受体的过度活化和导致兴奋毒性神经元变性的细胞内钙水平升高有关。目前用于AD治疗的药物是胆碱酯酶抑制剂或NMDA受体拮抗剂;然而,它们仅提供症状缓解并且不改变疾病的进展。Aβ是β-淀粉酶和γ-分泌酶连续切割后淀粉样蛋白前体蛋白(APP)加工的产物,而α-分泌酶的APP蛋白水解产生非淀粉样蛋白产物。根据淀粉样蛋白级联假说,Aβ阻滞抑制导致Aβ积聚和聚集成可溶性低聚物和不溶性原纤维。前者是突触毒性的并且可以诱导tau过度磷酸化,而后者沉积在老年斑中并引发促炎反应,导致氧化应激,神经元变性和神经炎症。因此,Aβ-蛋白质靶向治疗策略是用于治疗和预防AD的有希望的疾病修饰方法。本综述总结了Aβ-蛋白靶向AD药物的最新发现,包括β-分泌酶抑制剂,γ-分泌酶抑制剂和调节剂,α-分泌酶激活剂,Aβ聚集的直接抑制剂和靶向Aβ的免疫疗法,主要集中在目前正在临床试验中的那些。

关键词: 阿尔茨海默病,淀粉样蛋白β,蛋白质聚集,疾病改善疗法,聚集抑制剂,免疫疗法。

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