Exploring the involvement of Na pump inhibitor marinobufagenin in the interactions between age-associated vascular and neurodegenerative processes in cognitive impairment and Alzheimer's disease

Dahl-S大鼠模型表现出过早的中枢和脑血管重构，并与过早的认知能力下降有关。在这个模型中，以脉搏波速度(PWV)为指标的CAS增加是由动脉壁促纤维化途径的激活所介导的，这些途径与在人类衰老中观察到的相似，并导致MBG水平增加(Fedorova等人)。2000年和2002年发行量；Fedorova等人。高血压2001)和动脉壁胶原沉积增加。采用回交方法，选择血压盐敏感的Dahl-S大鼠。我们的初步数据表明，低盐饮食的Dahl-S大鼠的中位寿命为12个月，而野生型SD(S-D)大鼠的中位寿命为24个月。 Dahl-S大鼠的一个主要异常是即使在低盐饮食下也会出现肾脏和心血管组织纤维化。血管紧张素II(AngII)信号参与了MBG的产生，在Dahl-S大鼠中，MBG随增龄而增加。AngII和MBG均与促纤维化信号转导和CAS增加有关。正因为如此，Dahl-S是研究动脉纤维化导致的CAS增加和微血管疾病的优秀模型。MBG在血浆、尿液、脑脊液、肾上腺皮质和脑组织中检测到。随着年龄的增长，低盐饮食的Dahl-S大鼠(12月龄)与青年(3月龄)Dahl-S大鼠相比，外周血糖值和CAS显著增加2倍，表现为脉搏血容量增加和主动脉、冠状动脉和周围动脉胶原丰度增加。此外，与AD有关的基因在老年Dahl-S大鼠的海马区过度表达。本实验室已研制出抗MBG的3E9单抗(Fedorova等)。J Hyperten 2008)，它可以成功地中和慢性肾功能衰竭动物模型中增加的促纤维化和促高血压的MBG(Haller等人。该药能降低老年Dahl-S大鼠的动脉和肾间质纤维化，改善肾功能损害，降低血压和脉搏血流量。因此，抗MBG单抗诱导的中枢和脑血管血管纤维化的减少可能改善血管认知障碍。 Dahl-S大鼠在年轻时表现出认知功能障碍，即使在低盐摄入量下也是如此(Ruiz-Opazo等人。高血压，2004年；Pelisch等人。Am J Hyperten 2011)。我们对年轻的Dahl-S大鼠进行的初步研究显示，与年龄匹配的野生型S-D大鼠相比，关键转移试验(水迷宫试验)中目标位置的海马区依赖空间记忆显著受损，核磁共振显示脑组织结构发生变化，脑小动脉胶原沉积增加(6.01+/0.63vs.3.58+/0.62；p=0.015)，主动脉僵硬(2.90+/-0.1vs.2.3+/-0.2；p=0.06)。 Dahl-S和S-D大鼠脑磁共振参数的数据解释 平均扩散系数可以解释为组织完整性的度量，或组织水平移运动的度量；扩散系数越低，意味着更致密，更少的水化，更多的大分子含量限制了水分子的平移运动。在病理学上，扩散率上升。Dahl-S组较S-D组升高(1.17±0.11vs.0.82+/-0.32，x~(-3)mm~2/S；p&lt；0.05)，可能提示脑水肿，神经元含量减少，支持组织丧失。 R2是由于组织界面(第一近似值)引起的松弛速率，可以指示组织微结构和亚细胞边界的变化。这一参数在Dahl-S组高于S-D组(6.36+/-2.49vs.1.34+/-2.40，S-1；p&lt；0.01)。 与S-D大鼠相比，Dahl-S大鼠的脑体积(1531±/-67vs.1772+/-77，mm~3；p&lt；0.01)和海马区体积(79.9±/-3.9vs.95.1+/-6.8，mm~3；p&lt；0.01)较小。大脑皮质厚度呈下降趋势(7.08±0.19vs.7.27±0.21)，脑室相对增大(脑室体积/脑体积：0.015±/-0.0029 vs.0.008+/-0.0028；p&lt0.01)。 结论： Dahl-S大鼠由于脑微血管和中央动脉壁的改变而导致的致炎和促纤维化因子状态的改变，是研究认知功能障碍和痴呆发生发展的合适模型。 我们预计，在Dahl-S大鼠中，与年龄相关的组织肾素-血管紧张素系统激活、外周血糖值增加和中央动脉僵硬将与脑微血管疾病、小脑血管密度、脑血流减少和认知障碍平行，这是对人类研究的总结。此外，我们预计外周血糖值和其他动脉壁促纤维化标志物的纵向变化将把动脉纤维化的变化与老年Dahl-S大鼠加速的记忆障碍联系起来。

The Dahl-S rat animal model exhibits premature central and cerebral vascular remodeling, associated with premature cognitive decline. Increased CAS in this model, indexed as pulse wave velocity (PWV), is mediated by activation of arterial wall pro-fibrotic pathways that are similar to those observed in human aging, and result in increased MBG levels (Fedorova et al. Circulation 2000 and 2002; Fedorova et al. Hypertension 2001) and increased arterial wall col-lagen deposition. Dahl-S rats were selected, by backcrossing, for the trait of salt-sensitivity of blood pressure. Our preliminary data demonstrated that the median life span in Dahl-S rats on a low salt diet is 12 month vs. 24 months in wild type Sprague-Dawley (S-D) rats. A major abnormality in Dahl-S rats is the development of renal and cardiovascular tissue fibrosis even on a low salt diet. Angiotensin II (ANGII) signaling participates in production of MBG which becomes increased in Dahl-S rats with advancing age. Both ANGII and MBG are implicated in pro-fibrotic signaling and CAS increase. Because of that Dahl-S is an excellent model to study arterial fibrosis resulting in increased CAS and microvascular disease. MBG is detected in plasma, urine, CSF and adrenocortical and brain tissues. With advancing age, Dahl-S rats (12 months old) on a low salt diet exhibit a marked 2-fold increase in peripheral MBG and increase in CAS, evaluated as an increased PWV and an increase in collagen abundance in the aorta, coronary and peripheral arteries vs. young (3 months old) Dahl-S rats. In addition, genes implicated in AD, are overexpressed in the hippocampus in aged Dahl-S rats. Our laboratory has developed a monoclonal 3E9 anti-MBG antibody (mAb) (Fedorova et al. J Hypertens 2008), which can successfully immunoneutralize increased pro-fibrotic and pro-hypertensive MBG in animal models of chronic renal failure (Haller et al. Am J Hypertens 2012) and hypertension, and reduce arterial and interstitial fibrosis, improve renal impairment, decrease BP and PWV in aged Dahl-S rats. Thus, an anti-MBG mAb-induced reduction of vascular fibrosis in central and cerebral vasculature may ameliorate vascular cognitive impairment. Dahl-S rats exhibit cognitive dysfunction at a young age even on a low salt intake (Ruiz-Opazo et al. Hypertension 2004; Pelisch et al. Am J Hypertens 2011). Our pilot study of young Dahl-S rats showed significant impairment of hippocampal-dependent spatial memory for a goal location on a critical transfer test (water maze test), and alteration in brain structures, as detected by MRI (see below), elevated collagen deposition in small cerebral arteries (6.01 +/ 0.63 vs. 3.58 +/0 0.62; p=0.015), and increased aortic stiffness (2.9 +/- 0.1 vs. 2.3 +/- 0.2; p=0.06) vs. age-matched wild type S-D rats. Data interpretation of brain parameters assessed by MRI in Dahl-S and S-D rats: The mean diffusivity can be interpreted as a measure of tissue integrity, or a measure of the translational motion of tissue water; lower diffusivity means more dense, less hydration, more macromolecular content restricting water molecule translational motion. In pathology, diffusivity goes up. It increases in Dahl-S vs. S-D rats (1.17 +/- 0.11 vs. 0.82 +/- 0.32, x10-3 mm2/s; p<0.05 by t-test) which may indicate edema, decreased neuronal content, loss of supportive tissue. R2 is the relaxation rate due to tissue interfaces (to a first approximation) and may indicate changes in tissue microstructure and subcellular boundaries. This parameter is higher in Dahl-S than in S-D rats (6.36 +/- 2.49 vs. 1.34 +/- 2.40, s-1; p<0.01) Dahl-S rats have smaller brain (1531 +/- 67 vs.1772 +/- 77, mm3; p<0.01) and hippocampus volumes (79.9 +/- 3.9 vs. 95.1 +/- 6.8, mm3; p<0.01) compared to S-D rats. Cortical thickness is showing a trend to decrease (7.08 +/- 0.19 vs. 7.27 +/- 0.21), and the ventricles are relatively enlarged (ventricle volume/brain volume: 0.015 +/- 0.0029 vs. 0.008 +/- 0.0028; p<0.01) in Dahl-S vs. S-D rats. Conclusion: Dahl-S rats represent a suitable model to study the development of cognitive impairment and dementia due to the changes in cerebral microvasculature and central arterial wall, which underlie by changes in the status of pro-inflammatory and pro-fibrotic factors. We expect that in Dahl-S rats, the age-associated tissue renin-angiotensin system activation, increase in peripheral MBG and central arterial stiffness will be paralleled by cerebral microvascular disease, small cerebral blood vessel density, reduction in cerebral blood flow and cognitive impairment, recapitulating the study in humans. Further, we expect that longitudinal changes in peripheral MBG and other arterial wall pro-fibrotic markers will link the changes in arterial fibrosis to the accelerated memory impairment in old Dahl-S rats.