Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697-4540, USA.
Am J Pathol. 2013 May;182(5):1740-9. doi: 10.1016/j.ajpath.2013.01.021. Epub 2013 Mar 5.
The deposition of amyloid-β peptides (Aβ) in the cerebral vasculature, a condition known as cerebral amyloid angiopathy, is increasingly recognized as an important component leading to intracerebral hemorrhage, neuroinflammation, and cognitive impairment in Alzheimer disease (AD) and related disorders. Recent studies demonstrated a role for the bradykinin B1 receptor (B1R) in cognitive deficits induced by Aβ in mice; however, its involvement in AD and cerebral amyloid angiopathy is poorly understood. Herein, we investigated the effect of B1R inhibition on AD-like neuroinflammation and amyloidosis using the transgenic mouse model (Tg-SwDI). B1R expression was found to be up-regulated in brains of Tg-SwDI mice, specifically in the vasculature, neurons, and astrocytes. Notably, administration of the B1R antagonist, R715, to 8-month-old Tg-SwDI mice for 8 weeks resulted in higher Aβ40 levels and increased thioflavin S-positive fibrillar Aβ deposition. Moreover, blockage of B1R inhibited neuroinflammation, as evidenced by the decreased accumulation of activated microglia and reactive astrocytes, diminished NF-κB activation, and reduced cytokine and chemokine levels. Together, our results indicate that B1R activation plays an important role in limiting the accumulation of Aβ in AD-like brain, likely through the regulation of activated glial cell accumulation and release of pro-inflammatory mediators. Therefore, the modulation of the receptor may represent a novel therapeutic approach for AD.
淀粉样蛋白-β肽（Aβ）在脑血管中的沉积，即众所周知的脑淀粉样血管病，被认为是导致阿尔茨海默病（AD）及相关疾病中脑出血、神经炎症和认知障碍的重要因素。最近的研究表明，缓激肽 B1 受体（B1R）在 Aβ诱导的小鼠认知缺陷中发挥作用；然而，其在 AD 和脑淀粉样血管病中的作用仍知之甚少。在此，我们使用转 AD 模型（Tg-SwDI）研究了 B1R 抑制对 AD 样神经炎症和淀粉样变性的影响。结果发现，Tg-SwDI 小鼠大脑中 B1R 表达上调，特别是在血管、神经元和星形胶质细胞中。值得注意的是，在 8 月龄 Tg-SwDI 小鼠中给予 B1R 拮抗剂 R715 治疗 8 周，导致 Aβ40 水平升高，并增加硫黄素 S 阳性纤维状 Aβ沉积。此外，B1R 阻断抑制神经炎症，表现为活化小胶质细胞和反应性星形胶质细胞的积累减少，NF-κB 激活减少，细胞因子和趋化因子水平降低。总之，我们的结果表明，B1R 激活在限制 AD 样脑内 Aβ积累中发挥重要作用，可能通过调节活化的小胶质细胞积累和释放促炎介质。因此，受体的调节可能代表 AD 的一种新的治疗方法。
