Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease.
Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease.
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DOI：
10.4049/jimmunol.0901005
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发表时间：
2009-07-15
期刊：
影响因子：
--
通讯作者：
Tenner AJ
中科院分区：
文献类型：
--
作者：
Fonseca MI;Ager RR;Chu SH;Yazan O;Sanderson SD;LaFerla FM;Taylor SM;Woodruff TM;Tenner AJ
阿尔茨海默病（Alzheimer's disease，AD）是一种与年龄相关的痴呆，以脑内淀粉样斑块、神经元缠结、神经炎症和神经元缺失为特征。已知产生局部炎症反应的补体系统的组分与AD脑中的斑块和缠结相关，因此已经提出补体介导的炎症在疾病加速或进展中的作用。已知补体激活产物C5 a通过激活G蛋白偶联的细胞表面C5 aR在体外募集和激活小胶质细胞和星形胶质细胞。在此，口服递送环状六肽C5 a受体拮抗剂（PMX 205）2-3个月导致两种AD小鼠模型中病理标志物如纤维状淀粉样蛋白沉积物（49 - 62%）和活化的神经胶质（42- 68%）的显著减少。病理学的减少与Tg 2576小鼠被动回避行为任务的改善相关。在3xTg小鼠中，PMX 205还显著减少了过度磷酸化的tau（69%）。这些数据提供了第一个证据，表明抑制促炎受体介导的补体级联功能（即，C5 aR）可以干扰AD啮齿动物模型中的神经炎症和神经变性，这表明了用于减少人类AD患者的病理和改善认知功能的新的治疗靶标。
Alzheimer’s disease (AD) is an age-related dementia, characterized by amyloid plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss in the brain. Components of the complement system, known to produce a local inflammatory reaction, are associated with the plaques and tangles in AD brain, and thus a role for complement-mediated inflammation in the acceleration or progression of disease has been proposed. A complement activation product, C5a, is known to recruit and activate microglia and astrocytes in vitro by activation of a G protein-coupled cell-surface C5aR. Here, oral delivery of a cyclic hexapeptide C5a receptor antagonist (PMX205) for 2–3 mo resulted in substantial reduction of pathological markers such as fibrillar amyloid deposits (49 – 62%) and activated glia (42– 68%) in two mouse models of AD. The reduction in pathology was correlated with improvements in a passive avoidance behavioral task in Tg2576 mice. In 3xTg mice, PMX205 also significantly reduced hyperphosphorylated tau (69%). These data provide the first evidence that inhibition of a proinflammatory receptor-mediated function of the complement cascade (i.e., C5aR) can interfere with neuroinflammation and neurodegeneration in AD rodent models, suggesting a novel therapeutic target for reducing pathology and improving cognitive function in human AD patients.
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