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

细胞外淀粉样蛋白β蛋白(Aβ)在阿尔茨海默病(AD)中具有神经毒性作用，被称为淀粉样蛋白假说。而神经细胞内Aβ蓄积最近被认为是神经毒性的。我们发现阿朴吗啡能促进细胞内Aβ的降解。此外，我们还发现APO对过氧化氢诱导的氧化应激有明显的保护作用。此外，APO对氧化应激具有明显的保护作用，这种保护作用是通过提高谷胱甘肽过氧化物酶(GPX)活性来实现的。携带两个家族性AD相关突变基因(APP-KM670/671NL和PS1-M146V)和Tau P301L突变的3xTg小鼠在4个月龄时出现尿酸Aβ蓄积、过度磷酸化tau蓄积和记忆障碍。皮下注射APO 5 mg/kg，每周1次，直至4周，Morris水迷宫测试的短时记忆明显改善。在病理学研究中，Aβ和过度磷酸化tau在注射APO的小鼠脑内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模型小鼠的认知功能障碍和病理改变也有较好的治疗作用，是治疗AD患者的有效候选药物。

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.