Development of methods to inhibit apoptosis induced by intracellular amyloid β-protein in Alzheimer's disease

开发抑制阿尔茨海默病细胞内β淀粉样蛋白诱导的细胞凋亡的方法

• 批准号: 18590948
• 负责人: OHYAGI Yasumasa
• 金额: $ 2.49万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590948/
• 关键词: Alzheimer's disease; amyloid β-protein; apoptosis; apomorphine sulfate; 3x transgenic mouse; cognitive function; neurofibrillary tangle; oxidative stress; p53; プロテアソーム; 神経保護

It is known as "amyloid hypothesis" that extracellular amyloid β-protein (Aβ) is neurotoxic in Alzheimer's disease (AD). While, intraneuronal Aβ accumulation is recently suggested to be neurotoxic. We have found apomorphine sulf ate (APO) to enhance intracellular Aβ degradation. Also, we found that APO protected neurons markedly from oxida tive stress induced by hydrogen peroxide. Furthermore, protective effects of APO were remarkable against oxidative stress and these effects were mediated by elevation of glutathione peroxidase (GPx) activity.We further investigated therapeutic efficacy of APO on an AD mouse model. 3XTg mice, which had two familial AD-related mutant genes (APP-KM670/671NL and PS1-M146V) and a mutation of Tau P301L, demonstrated intrane uronal Aβ accumulation, hyperphosphorylated tau accumulation and memory disturbance at the age of 4 months. Af ter subcutaneous injection of APO at 5 mg/kg once a week until 4 weeks, short-term memory evaluated by Morris water maze test was significantly improved. In pathological study, intraneuronal accumulation of Aβ and hyperphosp horylated tau was very mild in APO-injected mice brain. Accordingly, APO was not only cell protective against oxid ative damage-induced apoptosis but also effective on cognitive dysfunction and pathological change in AD mouse mo del, and proved to be a powerful candidate drug for AD patients.

阿尔茨海默病（Alzheimer's disease，AD）中细胞外淀粉样β蛋白（amyloid β-protein，Aβ）具有神经毒性，被称为“淀粉样假说”。然而，最近认为神经元内Aβ蓄积具有神经毒性。我们发现硫酸阿扑吗啡（APO）可促进细胞内Aβ降解。此外，我们还发现APO对过氧化氢诱导的神经元氧化应激有明显的保护作用。此外，APO对氧化应激的保护作用是显着的，这些作用是通过升高谷胱甘肽过氧化物酶（GPx）的活性介导的。3XTg小鼠具有两个家族性AD相关突变基因（APP-KM 670/671 NL和PS1-M146 V）和Tau P301 L突变，在4月龄时表现出神经元内Aβ蓄积、过度磷酸化tau蓄积和记忆障碍。每周1次皮下注射APO 5 mg/kg，连续4周后，Morris水迷宫实验评价的短时记忆能力明显改善。在病理学研究中，Aβ和高磷酸化tau蛋白在注射APO的小鼠脑中的神经元内积聚非常轻微。因此，APO不仅对氧化损伤诱导的细胞凋亡具有保护作用，而且对AD小鼠模型的认知功能障碍和病理改变也有明显的改善作用，是治疗AD的有效候选药物。

项目成果

Intracellular amyloid β-protein and its associated molecules in the pathogenesis of Alzheimer's disease

细胞内β淀粉样蛋白及其相关分子在阿尔茨海默病发病机制中的作用

• 发表时间: 2006
• 期刊: Mini-Reviews in Medicinal Chemistry 6
• 作者: Ohvagi;Y;Tabira;T
• 通讯作者: T

アルツハイマー病の分子病態と治療-特にアミロイドβ蛋白を標的として-

阿尔茨海默氏病的分子病理学和治疗 - 特别是针对淀粉样β蛋白 -

• 发表时间: 2006
• 期刊: 福岡医学雑誌 97・9
• 作者: Ohyagi Y;Tabira T;大八木保政;大八木保政
• 通讯作者: 大八木保政

Intraneuronal amyloid β42 enhanced by heating but counteracted by formic acid

• DOI: 10.1016/j.jneumeth.2006.06.010
• 发表时间: 2007-01
• 期刊: Journal of Neuroscience Methods
• 影响因子: 3
• 作者: Y. Ohyagi;Y. Tsuruta;K. Motomura;Katsue Miyoshi;H. Kikuchi;T. Iwaki;T. Taniwaki;J. Kira

アルツハイマー病の予防・治療剤

阿尔茨海默病的预防和治疗

• 发表时间: 2007

アルツハイマー病の新しい治療法の開発新規医薬品Aβ分解促進薬塩酸アポモルフィン

开发阿尔茨海默病新疗法 新药盐酸阿扑吗啡，Aβ降解促进剂

• 发表时间: 2008
• 期刊: 日本臨床増刊号 66
• 作者: 大八木 保政;ら
• 通讯作者: ら