Mironenko Iaroslav V, Kryukova Olga V, Buianova Anastasiia A, Churov Alexey V, Arbatsky Mikhail S, Kubrikova Alyona A, Petrusenko Yunna S, Repinskaia Zhanna A, Shmitko Anna O, Ilyina Galit A, Kost Olga A, Dudek Steven M, Strazhesko Irina D, Isaev Ruslan I, Mkhitaryan Elen A, Tkacheva Olga N, Rebrikov Denis V, Danilov Sergei M
Institute on Aging Research, Russian Clinical Research Center of Gerontology, Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, 129226 Moscow, Russia.
Chemistry Faculty, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia.
Int J Mol Sci. 2025 Sep 18;26(18):9099. doi: 10.3390/ijms26189099.
Damaging mutations of the Angiotensin I-converting enzyme (ACE) that result in low ACE levels may increase the risk of developing late-onset Alzheimer's disease (AD) We quantified blood ACE levels in EDTA-plasma from 147 subjects with 23 different heterozygous mutations (and 70 controls) and estimated the effect of these mutations on ACE phenotype, using a set of monoclonal antibodies (mAbs) to ACE and two ACE substrates. We identified several mutations in both ACE domains (including the most frequent mutation, Y215C), which led to decreased ACE levels in the blood, and thus could be considered as putative risk factors for late-onset AD. The precipitation of several ACE mutants (Q259R, A725P, C734Y) by specific mAbs changed significantly, and therefore, these mAbs could be markers of these mutations. Analysis of 50 of the most frequent mutations demonstrates that more than 1.5% of the adult population may have mutations which lead to decreased ACE levels, and thus, the role of low ACE levels in the development of AD may be underappreciated. Intriguingly, statistical and cluster analyses of longevity patients revealed trends towards higher frequency of cognitive impairment among affected individuals with damaging mutations. Systematic analysis of blood ACE levels in patients with various mutations identifies individuals with low blood ACE levels who may be at increased risk for late-onset AD. Patients with transport-deficient mutations theoretically could benefit from therapeutic treatment with a combination of chemical and pharmacological chaperones and proteasome inhibitors, as was demonstrated previously on a cell model of the transport-deficient mutation Q1069R. Moreover, clinical association analysis suggests a trend linking damaging mutations with increased risk of cognitive impairment.
血管紧张素I转换酶（ACE）的有害突变会导致ACE水平降低，这可能会增加患迟发性阿尔茨海默病（AD）的风险。我们对147名携带23种不同杂合突变的受试者（以及70名对照）的乙二胺四乙酸血浆中的血液ACE水平进行了量化，并使用一组针对ACE的单克隆抗体（mAb）和两种ACE底物来估计这些突变对ACE表型的影响。我们在ACE的两个结构域中都发现了几个突变（包括最常见的突变Y215C），这些突变导致血液中ACE水平降低，因此可被视为迟发性AD的潜在危险因素。几种ACE突变体（Q259R、A725P、C734Y）被特异性mAb沉淀的情况发生了显著变化，因此，这些mAb可作为这些突变的标志物。对50种最常见突变的分析表明，超过1.5%的成年人口可能携带导致ACE水平降低的突变，因此，低ACE水平在AD发病中的作用可能未得到充分认识。有趣的是，对长寿患者的统计和聚类分析显示，携带有害突变的受影响个体中认知障碍的频率有升高趋势。对各种突变患者的血液ACE水平进行系统分析，可识别出血液ACE水平低且可能患迟发性AD风险增加的个体。理论上，携带转运缺陷突变的患者可能受益于化学伴侣、药理伴侣和蛋白酶体抑制剂联合治疗，正如之前在转运缺陷突变Q1069R的细胞模型上所证明的那样。此外，临床关联分析表明，有害突变与认知障碍风险增加之间存在关联趋势。
