Microglial C5aR (CD88) expression correlates with amyloid-beta deposition in murine models of Alzheimer's disease.
Microglial C5aR (CD88) expression correlates with amyloid-beta deposition in murine models of Alzheimer's disease.
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DOI：
10.1111/j.1471-4159.2010.06595.x
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发表时间：
2010-04
影响因子：
4.7
通讯作者：
Tenner AJ
中科院分区：
文献类型：
--
作者：
Ager RR;Fonseca MI;Chu SH;Sanderson SD;Taylor SM;Woodruff TM;Tenner AJ
阿尔茨海默病(AD)是一种以淀粉样蛋白β积聚和神经元丢失为特征的进行性神经退行性疾病，是当今世界老年性痴呆的主要原因。这种疾病还与神经炎症、星形胶质细胞和小胶质细胞的强烈激活以及补体系统激活的证据有关，这些证据都定位于纤维淀粉样蛋白(Fifiillar Amyloid-β，FAβ)斑块和缠结。这些观察结果与AD进展的补体依赖成分是一致的。我们以前已经证明，用C5a受体拮抗剂(PMX205)抑制C5a的主要补体受体(CD88)导致两种AD小鼠模型的病理学显著减轻。为了进一步研究补体在AD相关神经炎症中的作用，我们用流式细胞术、免疫印迹和免疫组织化学方法检测了CD88在AD转基因小鼠脑内的表达，以及PMX205对多种补体激活产物的影响。CD88在淀粉样斑块附近的小胶质细胞中表达上调。尽管PMX205治疗后硫代黄素斑块负荷和胶质细胞募集显著减少，但C1q仍与FAβ斑块共定位，C3仍由募集的星形胶质细胞表达。因此，在PMX205中，这些早期补体成分的潜在有益活性可能保持不变，而C5a-CD88相互作用产生的有害活性被抑制。这进一步支持有针对性地抑制特定补体介导的活动作为AD治疗的一种方法。
Alzheimer Disease (AD), a progressive neurodegenerative disease characterized by the accumulation of amyloid-β protein and neuronal loss, is the leading cause of age-related dementia in the world today. The disease is also associated with neuroinflammation, robust activation of astrocytes and microglia and evidence of activation of the complement system, localized with both fibrillar amyloid-β (fAβ) plaques and tangles. The observations are consistent with a complement dependent component of AD progression. We have previously shown that inhibition of the major complement receptor for C5a (CD88) with the C5a receptor antagonist (PMX205) results in a significant reduction in pathology in two mouse models of AD. To further characterize the role of complement in AD related neuroinflammation, we examined the age and disease associated expression of CD88 in brain of transgenic mouse models of AD and the influence of PMX205 on the presence of various complement activation products using flow cytometry, western blot and immunohistochemistry. CD88 was found to be upregulated in microglia, in the immediate vicinity of amyloid plaques. While thioflavine plaque load and glial recruitment is significantly reduced after treatment with PMX205, C1q remains co-localized with fAβ plaques and C3 is still expressed by the recruited astrocytes. Thus, with PMX205, potentially beneficial activities of these early complement components may remain intact, while detrimental activities resulting from C5a-CD88 interaction are inhibited. This further supports the targeted inhibition of specific complement mediated activities as an approach for AD therapy.
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影响因子：
5.5
作者：
Farkas, I;Baranyi, L;Okada, H
通讯作者：
Okada, H
影响因子：
5.3
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Afagh, A;Cummings, BJ;Tenner, AJ
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通讯作者：
Gordon, MN
阿尔茨海默氏病β-肽的补体依赖性促炎特性。
影响因子：
15.3
作者：
Bradt, B M;Kolb, W P;Cooper, N R
通讯作者：
Cooper, N R