Kehoe Patrick Gavin, Wong Steffenny, Al Mulhim Noura, Palmer Laura Elyse, Miners J Scott
Dementia Research Group, University of Bristol, Level 1, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK.
Alzheimers Res Ther. 2016 Nov 25;8(1):50. doi: 10.1186/s13195-016-0217-7.
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.
肾素 - 血管紧张素系统（RAS）经典轴的活性亢进，由血管紧张素II（Ang II）激活血管紧张素II 1型受体（AT1R）介导，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）），并对RAS经典轴起反向调节作用。我们研究了死后人类脑组织中ACE - 2的表达和分布与AD病理及RAS经典轴活性的关系。
我们通过荧光肽底物测定法测量了一组AD患者（n = 90）和年龄匹配的非痴呆对照者（n = 59）额中回皮质（布罗德曼9区）的ACE - 2活性，我们之前已有这些患者的ACE - 1活性、淀粉样β蛋白（Aβ）水平、tau病理数据，以及已知的ACE1（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。
与年龄匹配的对照组相比，AD患者的ACE - 2活性显著降低（P < 0.0001），且与Aβ水平呈负相关（r = -0.267，P < 0.001），与磷酸化tau（p - tau）病理呈负相关（r = -0.327，P < 0.01）。携带APOE ε4等位基因的个体ACE - 2活性降低（P < 0.05），且与ACE1插入/缺失多态性有关（P < 0.05），ACE1插入型AD风险等位基因纯合个体的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），AD患者中ACE - 1与ACE - 2的比值显著升高（P < 0.0001）。最后，我们发现AD患者中Ang II与Ang（1 - 7）的比值（ACE - 2活性的替代指标，表明Ang II向Ang（1 - 7）的转化）降低。
总之，我们的研究结果表明，AD患者的ACE - 2活性降低，它是RAS中枢经典ACE - 1/Ang II/AT轴的重要调节因子，并且该途径的失调可能在AD的发病机制中起重要作用。
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