Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide.
Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide.
复制标题
阿尔茨海默氏病β-肽的补体依赖性促炎特性。
DOI：
10.1084/jem.188.3.431
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发表时间：
1998-08-03
影响因子：
15.3
通讯作者：
Cooper, N R
中科院分区：
文献类型：
--
作者：
Bradt, B M;Kolb, W P;Cooper, N R
在阿尔茨海默病(AD)患者的海马区和大脑皮层中发现了大量的神经性斑块，主要由纤维状的β-淀粉样多肽(A-β)组成，与神经元突起受损、激活的星形胶质细胞和小胶质细胞数量增加以及包括促炎补体系统成分在内的几种蛋白质有关。这些研究提出了一种假设，即激活的补体系统介导了NP中纤维状Aβ沉积周围的细胞变化。我们报道，Aβ多肽直接和独立地激活替代补体途径和经典补体途径，触发Aβ与第三补体成分(C3)的活化产物形成共价的酯连接的复合体，产生细胞因子样的C5a补体激活片段，以及介导致炎的C5b-9膜攻击复合体的形成，其功能活性形式能够插入神经前体细胞膜并使其通透性。这些发现提供了基于炎症的机制，解释了NP中补体成分的存在与神经元受损和激活的神经胶质细胞数量增加有关，这些发现对AD的治疗具有潜在的意义。
Large numbers of neuritic plaques (NP), largely composed of a fibrillar insoluble form of the β-amyloid peptide (Aβ), are found in the hippocampus and neocortex of Alzheimer's disease (AD) patients in association with damaged neuronal processes, increased numbers of activated astrocytes and microglia, and several proteins including the components of the proinflammatory complement system. These studies address the hypothesis that the activated complement system mediates the cellular changes that surround fibrillar Aβ deposits in NP. We report that Aβ peptides directly and independently activate the alternative complement pathway as well as the classical complement pathway; trigger the formation of covalent, ester-linked complexes of Aβ with activation products of the third complement component (C3); generate the cytokine-like C5a complement-activation fragment; and mediate formation of the proinflammatory C5b-9 membrane attack complex, in functionally active form able to insert into and permeabilize the membrane of neuronal precursor cells. These findings provide inflammation-based mechanisms to account for the presence of complement components in NP in association with damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.