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首页> 外文期刊>Journal of neuroinflammation >Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer’s disease mice
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Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer’s disease mice

机译：激肽B 1 受体阻滞对阿尔茨海默病小鼠的认知和脑血管功能的改善

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Background Recent evidence suggests that the inducible kinin B1 receptor (B1R) contributes to pathogenic neuroinflammation induced by amyloid-beta (Aβ) peptide. The present study aims at identifying the cellular distribution and potentially detrimental role of B1R on cognitive and cerebrovascular functions in a mouse model of Alzheimer’s disease (AD). Methods Transgenic mice overexpressing a mutated form of the human amyloid precursor protein (APPSwe,Ind, line J20) were treated with a selective and brain penetrant B1R antagonist (SSR240612, 10 mg/kg/day for 5 or 10 weeks) or vehicle. The impact of B1R blockade was measured on i) spatial learning and memory performance in the Morris water maze, ii) cerebral blood flow (CBF) responses to sensory stimulation using laser Doppler flowmetry, and iii) reactivity of isolated cerebral arteries using online videomicroscopy. Aβ burden was quantified by ELISA and immunostaining, while other AD landmarks were measured by western blot and immunohistochemistry. Results B1R protein levels were increased in APP mouse hippocampus and, prominently, in reactive astrocytes surrounding Aβ plaques. In APP mice, B1R antagonism with SSR240612 improved spatial learning, memory and normalized protein levels of the memory-related early gene Egr-1 in the dentate gyrus of the hippocampus. B1R antagonism restored sensory-evoked CBF responses, endothelium-dependent dilations, and normalized cerebrovascular protein levels of endothelial nitric oxide synthase and B2R. In addition, SSR240612 reduced (approximately 50%) microglial, but not astroglial, activation, brain levels of soluble Aβ1-42, diffuse and dense-core Aβ plaques, and it increased protein levels of the Aβ brain efflux transporter lipoprotein receptor-related protein-1 in cerebral microvessels. Conclusion These findings show a selective upregulation of astroglial B1R in the APP mouse brain, and the capacity of the B1R antagonist to abrogate amyloidosis, cerebrovascular and memory deficits. Collectively, these findings provide convincing evidence for a role of B1R in AD pathogenesis.
机译：背景技术最近的证据表明，诱导型激肽B1受体（B1R）有助于淀粉样β（Aβ）肽诱导的致病性神经炎症。本研究旨在确定Alzheimer病（AD）小鼠模型中B1R对认知和脑血管功能的细胞分布和潜在的有害作用。方法用选择性和脑渗透剂B1R拮抗剂（SSR240612，10 mg / kg /天，持续5或10周）或溶媒处理过表达人类淀粉样蛋白前体蛋白（APPSwe，Ind，品系J20）突变形式的转基因小鼠。在i）莫里斯水迷宫中的空间学习和记忆性能，ii）使用激光多普勒血流仪对感觉刺激产生的脑血流量（CBF）响应和iii）使用在线视频显微镜对孤立的脑动脉的反应性中，测量了B1R阻滞的影响。通过ELISA和免疫染色定量Aβ负担，而通过蛋白质印迹和免疫组织化学测量其他AD标志物。结果APP小鼠海马中B1R蛋白水平升高，并且Aβ斑块周围的反应性星形胶质细胞中B1R蛋白水平显着升高。在APP小鼠中，与SSR240612的B1R拮抗作用改善了海马齿状回中与记忆有关的早期基因Egr-1的空间学习，记忆和标准化蛋白质水平。 B1R拮抗作用可恢复感觉诱发的CBF反应，内皮依赖性舒张反应以及内皮型一氧化氮合酶和B2R的正常脑血管蛋白水平。此外，SSR240612减少（约50％）小胶质细胞活化，但不减少星形胶质细胞活化，降低可溶性Aβ1-42的脑水平，弥散性和致密性Aβ斑块，并增加Aβ脑外排转运蛋白脂蛋白受体相关蛋白的蛋白水平。 -1在脑微血管中。结论这些发现表明APP小鼠大脑中星形胶质B1R的选择性上调，以及B1R拮抗剂消除淀粉样变性，脑血管和记忆缺陷的能力。总的来说，这些发现为B1R在AD发病机理中的作用提供了令人信服的证据。

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