Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, 3801 University Street, Montréal, QC H3A 2B4, Canada.
J Neuroinflammation. 2013 May 4;10:57. doi: 10.1186/1742-2094-10-57.
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).
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.
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.
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.
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。本研究旨在鉴定阿尔茨海默病（AD）小鼠模型中 B1R 在认知和脑血管功能中的细胞分布和潜在的有害作用。
过表达人淀粉样前体蛋白突变形式（APPSwe，Ind，line J20）的转基因小鼠用选择性和穿透血脑屏障的 B1R 拮抗剂（SSR240612，10mg/kg/天，5 或 10 周）或载体处理。B1R 阻断的影响通过 i）在 Morris 水迷宫中的空间学习和记忆表现，ii）使用激光多普勒流量测量法测量感觉刺激引起的脑血流（CBF）反应，以及 iii）使用在线视频显微镜测量分离的脑动脉的反应性来测量。通过 ELISA 和免疫染色定量 Aβ 负荷，同时通过 Western blot 和免疫组织化学测量其他 AD 标志物。
APP 小鼠海马体中的 B1R 蛋白水平升高，尤其是在围绕 Aβ 斑块的反应性星形胶质细胞中升高。在 APP 小鼠中，SSR240612 对 B1R 的拮抗作用改善了空间学习、记忆，并使海马齿状回中的记忆相关早期基因 Egr-1 的蛋白水平正常化。B1R 拮抗作用恢复了感觉诱发的 CBF 反应、内皮依赖性扩张，并使内皮型一氧化氮合酶和 B2R 的脑血管蛋白水平正常化。此外，SSR240612 降低了（约 50%）小胶质细胞但不星形胶质细胞的激活、脑可溶性 Aβ1-42、弥散和致密核心 Aβ 斑块的水平，并增加了脑微血管中 Aβ 脑外排转运蛋白脂蛋白受体相关蛋白-1 的蛋白水平。
这些发现表明，APP 小鼠脑中星形胶质细胞 B1R 选择性上调，B1R 拮抗剂能够消除淀粉样变性、脑血管和记忆缺陷。总之，这些发现为 B1R 在 AD 发病机制中的作用提供了令人信服的证据。
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