Dept of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA.
J Neuroinflammation. 2013 Feb 8;10:25. doi: 10.1186/1742-2094-10-25.
Alzheimer's disease (AD) is a neurodegenerative dementia characterized by the decline of cognition and the presence of neuropathological changes including neuronal loss, neurofibrillary pathology and extracellular senile plaques. A neuroinflammatory process is also triggered and complement activation has been hypothesized to have a relevant role in this local inflammatory response. C5a, a proinflammatory anaphylatoxin generated after complement activation, exerts its chemotactic and inflammatory functions through the CD88 receptor while the more recently discovered C5L2 receptor has been postulated to have an anti-inflammatory role. Previously, we reported that a CD88 specific antagonist (PMX205) decreased the pathology and improved cognition in transgenic models of AD suggesting that C5a/C5aR interaction has an important role in the progression of the disease.
The present study characterizes the expression of the two receptors for C5a in human brain with confirmed post mortem diagnosis of vascular dementia (VD) or AD as well as age matched controls by immunohistochemistry and Western blot analysis using several antibodies against different epitopes of the human receptors.
The CD88 and C5L2 antibodies revealed increased expression of both receptors in AD samples as compared to age-matched controls or VD brain tissue by Western blot and immunohistochemistry, using multiple antibodies and distinct cohorts of brain tissue. Immunostaining showed that both the C5L2 and CD88 antibodies similarly labeled abundant neurofibrillary tangles, neuropil threads and dystrophic neurites associated with plaques in the hippocampus and frontal cortex of AD cases. In contrast, little or no neuronal staining, tangles or dystrophic neurites associated with plaques were observed in control or VD brains. CD88 and C5L2 receptors are associated with both early (AT8) and mature (PHF1) neurofibrillary tangles and can be found either independently or colocalized with each other.
The observed association of CD88 and C5L2 with neurofibrillary pathology suggests a common altered pathway of degradation.
阿尔茨海默病（AD）是一种神经退行性痴呆，其特征是认知能力下降，存在神经病理学变化，包括神经元丧失、神经纤维病理学和细胞外老年斑。也会引发神经炎症过程，并且补体激活被假设在这种局部炎症反应中具有相关作用。C5a，一种补体激活后产生的促炎过敏毒素，通过 CD88 受体发挥其趋化和炎症作用，而最近发现的 C5L2 受体被推测具有抗炎作用。此前，我们报道 CD88 特异性拮抗剂（PMX205）可减少 AD 转基因模型的病理学并改善认知，表明 C5a/C5aR 相互作用在疾病进展中具有重要作用。
本研究通过免疫组织化学和 Western blot 分析，使用针对人受体不同表位的几种抗体，对经证实有血管性痴呆（VD）或 AD 死后诊断的人脑中两种 C5a 受体的表达进行了特征描述。
与年龄匹配的对照组或 VD 脑组织相比，AD 样本中的 CD88 和 C5L2 抗体通过 Western blot 和免疫组织化学分析显示两种受体的表达均增加，使用了多种抗体和不同批次的脑组织。免疫染色显示，C5L2 和 CD88 抗体均相似地标记了丰富的神经原纤维缠结、神经丝缠结和与 AD 病例海马和额叶皮质中斑块相关的退行性神经突。相比之下，在对照组或 VD 脑中观察到很少或没有神经元染色、缠结或与斑块相关的退行性神经突。CD88 和 C5L2 受体与早期（AT8）和成熟（PHF1）神经原纤维缠结相关，并且可以独立存在或彼此共定位。
观察到 CD88 和 C5L2 与神经原纤维病理学的关联表明存在共同的改变的降解途径。
