Fiala M, Zhang L, Gan X, Sherry B, Taub D, Graves M C, Hama S, Way D, Weinand M, Witte M, Lorton D, Kuo Y M, Roher A E
Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA.
Mol Med. 1998 Jul;4(7):480-9.
Aside from numerous parenchymal and vascular deposits of amyloid beta (A beta) peptide, neurofibrillary tangles, and neuronal and synaptic loss, the neuropathology of Alzheimer's disease is accompanied by a subtle and chronic inflammatory reaction that manifests itself as microglial activation. However, in Alzheimer's disease, alterations in the permeability of the blood-brain barrier and chemotaxis, in part mediated by chemokines and cytokines, may permit the recruitment and transendothelial passage of peripheral cells into the brain parenchyma.
Human monocytes from different donors were tested for their capacity to differentiate into macrophages and their ability to secrete cytokines and chemokines in the presence of A beta 1-42. A paradigm of the blood-brain barrier was constructed utilizing human brain endothelial and astroglial cells with the anatomical and physiological characteristics observed in vivo. This model was used to test the ability of monocytes/macrophages to transmigrate when challenged by A beta 1-42 on the brain side of the blood-brain barrier model.
In cultures of peripheral monocytes, A beta 1-42 induced the secretion of proinflammatory cytokines TNF-alpha, IL-6, IL-1 beta, and IL-12, as well as CC chemokines MCP-1, MIP-1 alpha, and MIP-1 beta, and CXC chemokine IL-8 in a dose-related fashion. In the blood-brain barrier model, A beta 1-42 and monocytes on the brain side potentiated monocyte transmigration from the blood side to the brain side. A beta 1-42 stimulated differentiation of monocytes into adherent macrophages in a dose-related fashion. The magnitude of these proinflammatory effects of A beta 1-42 varied dramatically with monocytes from different donors.
In some individuals, circulating monocytes/macrophages, when recruited by chemokines produced by activated microglia and macrophages, could add to the inflammatory destruction of the brain in Alzheimer's disease.
除了淀粉样β（Aβ）肽的大量实质和血管沉积物、神经原纤维缠结以及神经元和突触丧失外，阿尔茨海默病的神经病理学还伴有一种微妙的慢性炎症反应，表现为小胶质细胞激活。然而，在阿尔茨海默病中，血脑屏障通透性和趋化性的改变，部分由趋化因子和细胞因子介导，可能允许外周细胞募集并经内皮进入脑实质。
检测来自不同供体的人单核细胞在Aβ1-42存在下分化为巨噬细胞的能力以及分泌细胞因子和趋化因子的能力。利用具有体内观察到的解剖和生理特征的人脑内皮细胞和星形胶质细胞构建血脑屏障模型。该模型用于测试单核细胞/巨噬细胞在血脑屏障模型脑侧受到Aβ1-42刺激时的迁移能力。
在外周单核细胞培养中，Aβ1-·42以剂量相关方式诱导促炎细胞因子肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和白细胞介素-12（IL-12）以及CC趋化因子单核细胞趋化蛋白-1（MCP-1）、巨噬细胞炎性蛋白-1α（MIP-1α）和巨噬细胞炎性蛋白-1β（MIP-1β）以及CXC趋化因子白细胞介素-8（IL-8）的分泌。在血脑屏障模型中，脑侧的Aβ1-42和单核细胞增强了单核细胞从血侧到脑侧的迁移。Aβ1-42以剂量相关方式刺激单核细胞分化为贴壁巨噬细胞。Aβ1-42的这些促炎作用的程度因不同供体的单核细胞而有很大差异。
在一些个体中，循环单核细胞/巨噬细胞在被活化的小胶质细胞和巨噬细胞产生的趋化因子募集时，可能会加剧阿尔茨海默病中脑的炎症性破坏。
