Interleukin-1 mediates Alzheimer and Lewy body pathologies
Interleukin-1 mediates Alzheimer and Lewy body pathologies
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DOI：
10.1186/1742-2094-3-5
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发表时间：
2006-03-16
影响因子：
9.3
通讯作者：
Barger, Steven W.
中科院分区：
文献类型：
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作者：
Griffin, W. Sue T.;Liu, Ling;Barger, Steven W.
背景：阿尔茨海默病 (AD) 和帕金森病 (PD) 之间的临床和神经病理学重叠现已得到广泛认可。此类并发 AD 和路易体病 (AD/LBD) 的病例显示出神经病理学变化，包括路易体（α-突触核蛋白聚集体）、神经炎淀粉样斑块和神经原纤维缠结（过度磷酸化 tau 聚集体）。这些临床和神经病理学变化的同时发生表明这些疾病具有共同的致病机制，而以前被认为是不同的。神经胶质细胞的激活，以及白细胞介素-1 (IL-1) 和其他促炎细胞因子的过度表达，越来越多地与 AD 和 PD 的发病机制有关。方法：大鼠小胶质细胞和皮质神经元的原代培养物单独培养或混合培养。用 β-淀粉样前体蛋白 (β APP) 的分泌片段 (sAPP α) 处理小胶质细胞或共培养物。用 IL-1 β 或来自 sAPP α 激活的小胶质细胞的条件培养基（含或不含 IL-1 受体拮抗剂）处理神经元。将含有 IL-1β 或牛血清白蛋白（对照）的缓释颗粒植入大鼠皮层，并通过 RT-PCR 分析各种神经病理标志物的 mRNA。在人类 AD/LBD 病例的组织切片中评估了许多相同的标记物。结果：用 sAPP α 激活小胶质细胞导致分泌的 IL-1 β 呈剂量依赖性增加。用 IL-1 β 处理的皮层神经元显示 sAPP α 释放呈剂量依赖性增加，这种效应在小胶质细胞存在时增强。 IL-1 beta 还会升高 α-突触核蛋白、活化的 MAPK-p38 和磷酸化 tau 蛋白的水平；突触素水平随之下降。与对照相比，通过缓释颗粒递送 IL-1 β 可以提高编码 α-突触核蛋白、β APP、tau 和 MAPK-p38 的 mRNA。最后，人类 AD/LBD 病例显示表达 IL-1 的小胶质细胞与同时过表达 β APP 并含有路易体和神经原纤维缠结的神经元共定位。 结论：我们的研究结果表明，IL-1 驱动形成 AD/LBD 的主要神经病理变化特征所需的底物的产生。
Background: Clinical and neuropathological overlap between Alzheimer's (AD) and Parkinson's disease (PD) is now well recognized. Such cases of concurrent AD and Lewy body disease (AD/LBD) show neuropathological changes that include Lewy bodies (alpha-synuclein aggregates), neuritic amyloid plaques, and neurofibrillary tangles (hyperphosphorylated tau aggregates). The co-occurrence of these clinical and neuropathological changes suggests shared pathogenic mechanisms in these diseases, previously assumed to be distinct. Glial activation, with overexpression of interleukin-1 (IL-1) and other proinflammatory cytokines, has been increasingly implicated in the pathogenesis of both AD and PD.Methods: Rat primary cultures of microglia and cortical neurons were cultured either separately or as mixed cultures. Microglia or cocultures were treated with a secreted fragment (sAPP alpha) of the beta-amyloid precursor protein (beta APP). Neurons were treated with IL-1 beta or conditioned medium from sAPP alpha-activated microglia, with or without IL-1 receptor antagonist. Slow-release pellets containing either IL-1 beta or bovine serum albumin (control) were implanted in cortex of rats, and mRNA for various neuropathological markers was analyzed by RT-PCR. Many of the same markers were assessed in tissue sections from human cases of AD/LBD.Results: Activation of microglia with sAPP alpha resulted in a dose-dependent increase in secreted IL-1 beta. Cortical neurons treated with IL-1 beta showed a dose-dependent increase in sAPP alpha release, an effect that was enhanced in the presence of microglia. IL-1 beta also elevated the levels of alpha-synuclein, activated MAPK-p38, and phosphorylated tau; a concomitant decrease in levels of synaptophysin occurred. Delivery of IL-1 beta by slow-release pellets elevated mRNAs encoding alpha-synuclein, beta APP, tau, and MAPK-p38 compared to controls. Finally, human cases of AD/LBD showed colocalization of IL-1-expressing microglia with neurons that simultaneously overexpressed beta APP and contained both Lewy bodies and neurofibrillary tangles.Conclusion: Our findings suggest that IL-1 drives production of substrates necessary for formation of the major neuropathological changes characteristic of AD/LBD.