A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice
A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice
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DOI：
10.1074/jbc.ra118.006420
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发表时间：
2019-06-21
影响因子：
4.8
通讯作者：
Zou, Kun
中科院分区：
文献类型：
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作者：
Liu, Shuyu;Ando, Fujiko;Zou, Kun
抑制血管紧张素转换酶（ACE）是全世界用于治疗高血压的策略。除了将血管紧张素 I 转化为血管紧张素 II 之外，ACE 还将神经毒性淀粉样蛋白 42 (A42) 转化为 A40。由于其神经毒性，A42 被认为在阿尔茨海默病 (AD) 的发展中发挥着致病作用，而 A40 对 A42 聚集以及金属诱导的氧化损伤具有神经保护作用。 ACE 抑制是否会增强 A42 聚集或损害人类认知能力对于预防 AD 发病和最佳高血压管理非常重要。在一项为期 8 年的纵向研究中，我们发现服用 ACE 抑制剂的男性高血压患者（而非女性）的平均智商下降速度比未服用 ACE 抑制剂的其他患者更快。此外，与年龄匹配的健康个体的血清相比，所有 AD 患者的血清均表现出 A42 至 A40 转化活性的降低。使用人类淀粉样蛋白前体蛋白转基因小鼠，我们发现临床剂量的 ACE 抑制剂足以增加大脑淀粉样蛋白沉积。我们还培育了人类淀粉样前体蛋白/ACE(+/-)小鼠，发现ACE水平的降低促进了A42沉积并增加了凋亡神经元的数量。这些结果表明，ACE 活性的抑制是人类认知受损和引发 AD 发作的危险因素。
Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic -amyloid protein 42 (A42) to A40. Because of its neurotoxicity, A42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas A40 has neuroprotective effects against A42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances A42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in A42-to-A40-converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE(+/-) mice and found that a decrease in ACE levels promoted A42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.