Ribeiro Victor Teatini, Cordeiro Thiago Macedo E, Filha Roberta da Silva, Perez Lucas Giandoni, Caramelli Paulo, Teixeira Antônio Lúcio, de Souza Leonardo Cruz, Simões E Silva Ana Cristina
Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Front Neurosci. 2021 Apr 6;15:636754. doi: 10.3389/fnins.2021.636754. eCollection 2021.
Alzheimer's disease (AD) is the leading cause of dementia worldwide. Despite the extensive research, its pathophysiology remains largely unelucidated. Currently, more attention is being given to the disease's vascular and inflammatory aspects. In this context, the renin-angiotensin system (RAS) emerges as a credible player in AD pathogenesis. The RAS has multiple physiological functions, conducted by its two opposing axes: the classical, led by Angiotensin II (Ang II), and the alternative, driven by Angiotensin-(1-7) [Ang-(1-7)]. These peptides were shown to interact with AD pathology in animal studies, but evidence from humans is scarce. Only 20 studies dosed RAS molecules in AD patients' bloodstream, none of which assessed both axes simultaneously. Therefore, we conducted a cross-sectional, case-control exploratory study to compare plasma levels of Ang II and Ang-(1-7) in AD patients vs. age-matched controls. Within each group, we searched for correlations between RAS biomarkers and measures from magnetic resonance imaging (MRI).
We evaluated patients with AD (n = 14) and aged-matched controls (n = 14). Plasma Ang II and Ang-(1-7) were dosed using ELISA. Brain MRI was performed in a 3 Tesla scan, and a three-dimensional T1-weighted volumetric sequence was obtained. Images were then processed by FreeSurfer to calculate: (1) white matter hypointensities (WMH) volume; (2) volumes of hippocampus, medial temporal cortex, and precuneus. Statistical analyses used non-parametrical tests (Mann-Whitney and Spearman).
Ang-(1-7) levels in plasma were significantly lower in the AD patients than in controls [median (25th-75th percentiles)]: AD [101.5 (62.43-126.4)] vs. controls [209.3 (72-419.1)], = 0.014. There was no significant difference in circulating Ang II. In the AD patients, but not in controls, there was a positive and significant correlation between Ang-(1-7) values and WMH volumes (Spearman's rho = 0.56, = 0.038). Ang-(1-7) did not correlate with cortical volumes in AD or in controls. Ang II did not correlate with any MRI variable in none of the groups.
If confirmed, our results strengthen the hypothesis that RAS alternative axis is downregulated in AD, and points to a possible interaction between Ang-(1-7) and cerebrovascular lesions in AD.
阿尔茨海默病（AD）是全球痴呆症的主要病因。尽管进行了广泛研究，但其病理生理学在很大程度上仍未阐明。目前，人们对该疾病的血管和炎症方面给予了更多关注。在这种背景下，肾素 - 血管紧张素系统（RAS）在AD发病机制中成为一个可信的参与者。RAS具有多种生理功能，由其两个相反的轴介导：经典轴，由血管紧张素II（Ang II）主导；替代轴，由血管紧张素 -（1 - 7）[Ang -（1 - 7）]驱动。在动物研究中，这些肽已被证明与AD病理相互作用，但来自人类的证据很少。仅有20项研究检测了AD患者血液中RAS分子的剂量，其中没有一项同时评估两个轴。因此，我们进行了一项横断面病例对照探索性研究，以比较AD患者与年龄匹配对照组中Ang II和Ang -（1 - 7）的血浆水平。在每组中，我们寻找RAS生物标志物与磁共振成像（MRI）测量值之间的相关性。
我们评估了AD患者（n = 14）和年龄匹配的对照组（n = 14）。使用酶联免疫吸附测定（ELISA）检测血浆Ang II和Ang -（1 - 7）。在3特斯拉扫描仪上进行脑部MRI检查，并获得三维T1加权容积序列。然后使用FreeSurfer软件处理图像以计算：（1）白质低信号（WMH）体积；（2）海马体、内侧颞叶皮质和楔前叶的体积。统计分析采用非参数检验（曼 -惠特尼检验和斯皮尔曼检验）。
AD患者血浆中Ang -（1 - 7）水平显著低于对照组[中位数（第25 - 75百分位数）]：AD组[101.5（62.43 - 126.4）] vs.对照组[209.3（72 - 419.1）]，P = 0.014。循环Ang II无显著差异。在AD患者中，而非对照组中，Ang -（1 - 7）值与WMH体积之间存在正相关且具有统计学意义（斯皮尔曼相关系数rho = 0.56，P = 0.038）。在AD患者或对照组中，Ang -（1 - 7）与皮质体积均无相关性。在任何一组中，Ang II与任何MRI变量均无相关性。
如果得到证实，我们的结果强化了RAS替代轴在AD中下调的假说，并指出了Ang -（1 - 7）与AD中脑血管病变之间可能存在的相互作用。
