Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology.
Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology.
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DOI：
10.1186/s13195-016-0217-7
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发表时间：
2016-11-25
期刊：
影响因子：
--
通讯作者：
Miners JS
中科院分区：
文献类型：
--
作者：
Kehoe PG;Wong S;Al Mulhim N;Palmer LE;Miners JS
由血管紧张素 II (Ang II) 激活血管紧张素 II 1 型受体 (AT1R) 介导的肾素-血管紧张素系统 (RAS) 经典轴的过度活跃，与阿尔茨海默病 (AD) 的发病机制有关。血管紧张素转换酶 2 (ACE-2) 将 Ang II 降解为血管紧张素 1-7 (Ang (1-7)) 并反向调节 RAS 的经典轴。我们研究了死后人类脑组织中 ACE-2 的表达和分布与 AD 病理学和经典 RAS 轴活动的关系。我们通过荧光肽底物测定法测量了一组 AD (n = 90) 和年龄匹配的非痴呆对照 (n = 59) 中额叶皮质（布罗德曼 9 区）的 ACE-2 活性，我们之前有关于 ACE-1 活性、β 淀粉样蛋白 (Aβ) 水平和 tau 病理学以及已知 ACE1 的数据。 (rs1799752) 插入缺失 多态性、载脂蛋白 E (APOE) 基因型和脑淀粉样血管病严重程度评分。与年龄匹配的对照相比，AD 中的 ACE-2 活性显着降低 (P < 0.0001)，并且与 Aβ 水平 (r = −0.267，P < 0.001) 和磷酸化 tau (p-tau) 病理学 (r = −0.327， P < 0.01）。 ACE-2 在具有 APOE ε4 等位基因的个体中减少 (P<0.05)，并且与 ACE1 插入缺失多态性相关 (P<0.05)，在 ACE1 插入 AD 风险等位基因纯合子个体中 ACE-2 活性较低。 ACE-2活性与ACE-1活性呈负相关（r = −0.453，P < 0.0001），并且AD中ACE-1与ACE-2的比率显着升高（P < 0.0001）。最后，我们发现 AD 中 Ang II 与 Ang (1-7) 的比率（ACE-2 活性的替代指标，表明 Ang II 转化为 Ang (1-7)）降低。总之，我们的研究结果表明，AD 中 ACE-2 活性降低，并且是 RAS 中央经典 ACE-1/Ang II/AT1R 轴的重要调节因子，并且该通路的失调可能在 AD 的发病机制中发挥重要作用。本文的在线版本 (doi:10.1186/s13195-016-0217-7) 包含补充材料，可供授权用户使用。
Hyperactivity of the classical axis of the renin-angiotensin system (RAS), mediated by angiotensin II (Ang II) activation of the angiotensin II type 1 receptor (AT1R), is implicated in the pathogenesis of Alzheimer’s disease (AD). Angiotensin-converting enzyme-2 (ACE-2) degrades Ang II to angiotensin 1–7 (Ang (1-7)) and counter-regulates the classical axis of RAS. We have investigated the expression and distribution of ACE-2 in post-mortem human brain tissue in relation to AD pathology and classical RAS axis activity. We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores. ACE-2 activity was significantly reduced in AD compared with age-matched controls (P < 0.0001) and correlated inversely with levels of Aβ (r = −0.267, P < 0.001) and phosphorylated tau (p-tau) pathology (r = −0.327, P < 0.01). ACE-2 was reduced in individuals possessing an APOE ε4 allele (P < 0.05) and was associated with ACE1 indel polymorphism (P < 0.05), with lower ACE-2 activity in individuals homozygous for the ACE1 insertion AD risk allele. ACE-2 activity correlated inversely with ACE-1 activity (r = −0.453, P < 0.0001), and the ratio of ACE-1 to ACE-2 was significantly elevated in AD (P < 0.0001). Finally, we show that the ratio of Ang II to Ang (1–7) (a proxy measure of ACE-2 activity indicating conversion of Ang II to Ang (1–7)) is reduced in AD. Together, our findings indicate that ACE-2 activity is reduced in AD and is an important regulator of the central classical ACE-1/Ang II/AT1R axis of RAS, and also that dysregulation of this pathway likely plays a significant role in the pathogenesis of AD. The online version of this article (doi:10.1186/s13195-016-0217-7) contains supplementary material, which is available to authorized users.
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作者：
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