Shozawa Hidenobu, Oguchi Tatsunori, Tsuji Mayumi, Yano Satoshi, Kiuchi Yuji, Ono Kenjiro
Department of Internal Medicine, Division of Neurology, Showa University School of Medicine, Tokyo, Japan.
Department of Pharmacology, Showa University School of Medicine, Tokyo, Japan.
Neurosci Lett. 2018 Jun 11;677:19-25. doi: 10.1016/j.neulet.2018.04.032. Epub 2018 Apr 21.
Alzheimer disease (AD) is the most common type of dementia, and is currently incurable. The efficacy of existing treatments for AD such as acetylcholinesterase inhibitors is limited to symptom improvement. Research on disease-modifying therapies (DMTs) has conventionally focused on amelioration of CNS pathogenesis. Two neuropathological changes correlate strongly with AD, the appearance of neurofibrillary tangles containing the microtubule-associated protein tau and extracellular amyloid deposits containing amyloid β-protein (Aβ). The aggregation of Aβ is believed to be the key pathogenic event in AD, with oligomeric assemblies thought to be the most neurotoxic form. Inhibitors of oligomer formation, therefore, could be valuable therapeutics for AD patients. The clinical phosphodiesterase type-3 inhibitor cilostazol (CSZ) was recently found to suppress the progression of cognitive decline in patients with stable AD receiving acetylcholinesterase inhibitors. Here we examined the effects of CSZ on in vitro aggregations of Aβ and Aβ including oligomerization, using the thioflavin T assay, photo-induced cross-linking of unmodified proteins, and electron microscopy. CSZ (25-100 μM) inhibited Aβ aggregation, especially oligomer formation. Considering that CSZ might be a key molecule for DMTs of AD, it cannot be ruled out that the low concentration of CSZ achievable in patient dosing may display some ant-oligomeric activity in synergy with its known therapeutic effects.
阿尔茨海默病（AD）是最常见的痴呆类型，目前无法治愈。现有AD治疗方法如乙酰胆碱酯酶抑制剂的疗效仅限于症状改善。疾病修饰疗法（DMTs）的研究传统上集中于改善中枢神经系统发病机制。两种神经病理学变化与AD密切相关，即含有微管相关蛋白tau的神经原纤维缠结的出现以及含有淀粉样β蛋白（Aβ）的细胞外淀粉样沉积物的出现。Aβ的聚集被认为是AD中的关键致病事件，寡聚体组装被认为是最具神经毒性的形式。因此，寡聚体形成抑制剂可能是AD患者的有价值的治疗方法。临床磷酸二酯酶3型抑制剂西洛他唑（CSZ）最近被发现可抑制接受乙酰胆碱酯酶抑制剂治疗的稳定AD患者认知衰退的进展。在这里，我们使用硫黄素T测定法、未修饰蛋白质的光诱导交联和电子显微镜检查了CSZ对Aβ体外聚集包括寡聚化的影响。CSZ（25 - 100μM）抑制Aβ聚集，尤其是寡聚体形成。考虑到CSZ可能是AD的DMTs的关键分子，不能排除患者给药时可达到的低浓度CSZ可能与其已知治疗效果协同发挥一些抗寡聚活性。
