Clarification of the molecular mechanism underlying the neuronal death induced by ACE inhibition in APP transgenic mouse

淀粉样蛋白1-42(Aβ-Protein 1-42，Aβ42)以及Aβ42与Aβ40较短主型的比值升高，在阿尔茨海默病的发病机制中被认为是重要的早期事件。我们已报道Aβ40对金属诱导的氧化损伤和Aβ42诱导的神经元死亡具有神经保护作用。然后我们鉴定血管紧张素转换酶是一种Aβ42-to-Aβ40-转换酶，发现血管紧张素转换酶抑制Aβ42沉积。ACE是老年高血压人群中最常被抑制剂靶向的酶之一。为了研究ACE抑制是否会导致阿尔茨海默病小鼠模型脑神经退行性变，我们对Tg2576小鼠进行了高剂量或低剂量ACE抑制剂的长期治疗。与对照组和低剂量组相比，大剂量ACE抑制剂治疗可显著降低血压，降低小鼠存活率。除Aβ42沉积增加外，大剂量血管紧张素转换酶抑制剂治疗组大鼠脑内还出现其他类似阿尔茨海默病的病理改变，如大脑皮层变薄、侧脑室扩大和tau蛋白磷酸化增强。这些结果表明，对ACE的有效抑制可能是阿尔茨海默病发展的一个危险因素。

Amyloidβ-protein 1-42(Aβ42), as well as the elevation of the ratio of Aβ42 to the shorter major form of Aβ40, has been identified as important in early events in the pathogenesis of Alzheimer's disease. We have reported that Aβ40 has neuroprotective effects against metal-induced oxidative damage and Aβ42-induced neuronal death. We then identified angiotensin-converting enzyme(ACE) as an Aβ42-to-Aβ40-converting enzyme and found that ACE inhibition enhances Aβ42 deposition. ACE is one of the most commonly targeted enzymes by inhibitors in elderly hypertensive populations. To investigate whether ACE inhibition leads to neurodegeneration in the brain of Alzheimer's disease mouse model, we performed a long-term treatment of Tg2576 mice with a high or a low dose of ACE inhibitor. The treatment with high dose ACE inhibitor significantly reduced blood pressure and resulted in a lower survival rate of mice compared with the control and the low-dose treatment. In addition to the increase of Aβ42 deposition, other Alzheimer-like pathologies were also found in the brain of the high-dose ACE inhibitor treatment group, such as a thinner cerebral cortex, an enlarged lateral ventricle and enhanced tau phosphorylation. These results suggest that potent inhibition of ACE may be a risk factor for the development of Alzheimer's disease.