Ni Ruiqing, Kindler Diana Rita, Waag Rebecca, Rouault Marie, Ravikumar Priyanka, Nitsch Roger, Rudin Markus, Camici Giovanni G, Liberale Luca, Kulic Luka, Klohs Jan
Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Zürich, Switzerland.
Zurich Neuroscience Center, Zürich, Switzerland.
Front Aging Neurosci. 2019 Feb 15;11:27. doi: 10.3389/fnagi.2019.00027. eCollection 2019.
Functional magnetic resonance imaging (fMRI) techniques can be used to assess cerebrovascular dysfunction in Alzheimer's disease, an important and early contributor to pathology. We hypothesized that bradykinin receptor inhibition alleviates the vascular dysfunction in a transgenic arcAβ mouse model of cerebral amyloidosis and that fMRI techniques can be used to monitor the treatment response. Transgenic arcAβ mice, and non-transgenic littermates of 14 months-of-age were either treated with the bradykinin receptors 1 and 2 blocker noscapine or received normal drinking water as control over 3 months ( = 8-11/group) and all mice were assessed using fMRI at the end of the treatment period. Perfusion MRI using an arterial spin labeling technique showed regional hypoperfusion in arcAβ compared to non-transgenic controls, which was alleviated by noscapine treatment. Similarly, measuring cerebral blood volume changes upon pharmacological stimulation using vessel dilator acetazolamide revealed recovery of regional impairment of cerebral vascular reactivity in arcAβ mice upon noscapine treatment. In addition, we assessed with immunohistochemistry beta-amyloid (Aβ) and inflammation levels in brain sections. Immunohistological stainings for Aβ deposition (6E10) and related microgliosis (Iba1) in the cortex and hippocampus were found comparable between noscapine-treated and untreated arcAβ mice. In addition, levels of soluble and insoluble Aβ, Aβ, Aβ were found to be similar in brain tissue homogenates of noscapine-treated and untreated arcAβ mice using electro-chemiluminescent based immunoassay. In summary, bradykinin receptors blockade recovered cerebral vascular dysfunction in a mouse model of cerebral amyloidosis. fMRI methods revealed the functional deficit in disease condition and were useful tools to monitor the treatment response.
功能磁共振成像（fMRI）技术可用于评估阿尔茨海默病中的脑血管功能障碍，这是该疾病病理过程中一个重要的早期因素。我们假设缓激肽受体抑制可减轻脑淀粉样变性转基因arcAβ小鼠模型中的血管功能障碍，并且fMRI技术可用于监测治疗反应。14月龄的转基因arcAβ小鼠及其非转基因同窝小鼠，在3个月内分别用缓激肽受体1和2阻滞剂那可丁治疗，或饮用正常饮用水作为对照（每组n = 8 - 11），在治疗期结束时对所有小鼠进行fMRI评估。使用动脉自旋标记技术的灌注MRI显示，与非转基因对照相比，arcAβ小鼠存在局部灌注不足，而那可丁治疗可缓解这种情况。同样，使用血管扩张剂乙酰唑胺进行药理刺激时测量脑血容量变化，结果显示那可丁治疗后arcAβ小鼠局部脑血管反应性损伤得到恢复。此外，我们通过免疫组织化学评估了脑切片中的β淀粉样蛋白（Aβ）和炎症水平。发现那可丁治疗组和未治疗组的arcAβ小鼠在皮质和海马中Aβ沉积（6E10）和相关小胶质细胞增生（Iba1）的免疫组织化学染色相当。此外，使用基于电化学发光的免疫测定法发现，那可丁治疗组和未治疗组的arcAβ小鼠脑组织匀浆中可溶性和不可溶性Aβ、Aβ、Aβ的水平相似。总之，缓激肽受体阻断可恢复脑淀粉样变性小鼠模型中的脑血管功能障碍。fMRI方法揭示了疾病状态下的功能缺陷，是监测治疗反应的有用工具。
