Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
J Neurosci Res. 2013 Oct;91(10):1371-81. doi: 10.1002/jnr.23256. Epub 2013 Aug 1.
The aggregation of β-amyloid protein (Aβ) and α-synuclein (αS) are hypothesized to be the key pathogenic event in Alzheimer's disease (AD) and Lewy body diseases (LBD), with oligomeric assemblies thought to be the most neurotoxic. Inhibitors of oligomer formation, therefore, could be valuable therapeutics for patients with AD and LBD. Here, we examined the effects of antiparkinsonian agents (dopamine, levodopa, trihexyphenidyl, selegiline, zonisamide, bromocriptine, peroxide, ropinirole, pramipexole, and entacapone) on the in vitro oligomer formation of Aβ40, Aβ42, and αS using a method of photo-induced cross-linking of unmodified proteins (PICUP), electron microscopy, and atomic force microscopy. The antiparkinsonian agents except for trihexyphenidyl inhibited both Aβ and αS oligomer formations, and, among them, dopamine, levodopa, pramipexole, and entacapone had the stronger in vitro activity. Circular dichroism and thioflavin T(S) assays showed that secondary structures of Aβ and αS assemblies inhibited by antiparkinsonian agents were statistical coil state and that their seeding activities had disappeared. The antiparkinsonian agents could be potential therapeutic agents to prevent or delay AD and LBD progression.
β-淀粉样蛋白（Aβ）和α-突触核蛋白（αS）的聚集被认为是阿尔茨海默病（AD）和路易体病（LBD）的关键致病事件，寡聚体被认为是最具神经毒性的。因此，寡聚体形成抑制剂可能是 AD 和 LBD 患者有价值的治疗药物。在这里，我们使用未经修饰的蛋白质光交联（PICUP）方法、电子显微镜和原子力显微镜检查了抗帕金森病药物（多巴胺、左旋多巴、三己芬迪、司来吉兰、佐尼沙米、溴隐亭、过氧化物、罗匹尼罗、普拉克索和恩他卡朋）对 Aβ40、Aβ42 和 αS 体外寡聚形成的影响。除了三己芬迪，抗帕金森病药物都抑制了 Aβ和αS 寡聚体的形成，其中多巴胺、左旋多巴、普拉克索和恩他卡朋具有更强的体外活性。圆二色性和硫黄素 T（S）试验表明，抗帕金森病药物抑制的 Aβ和αS 组装的二级结构是统计线圈状态，并且它们的接种活性已经消失。抗帕金森病药物可能是预防或延缓 AD 和 LBD 进展的潜在治疗药物。
