LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide
LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide
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DOI：
10.1093/brain/awh531
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发表时间：
2005-08-01
期刊：
影响因子：
14.5
通讯作者：
Fassbender, K
中科院分区：
文献类型：
--
作者：
Liu, Y;Walter, S;Fassbender, K
淀粉样蛋白 β 肽 42 (A beta(42)) 在阿尔茨海默病的神经毒性中发挥着关键作用。单核吞噬细胞，即小胶质细胞，具有通过吞噬作用清除 Aβ 的潜力。最近，脂多糖 (LPS) 受体 CD14 被证明可以介导细菌成分的吞噬作用，此外还有助于阿尔茨海默氏病的神经炎症。在这里，我们研究了这种关键的先天免疫受体是否可以与 A beta(42) 相互作用并介导该肽的吞噬作用。使用流式细胞术、共聚焦显微镜和双光子荧光寿命成像（FLIM）结合荧光共振能量转移（FRET），我们证明了在人CD14转染的中国仓鼠卵巢细胞中Aβ（42）和CD14之间在几纳米范围内的直接分子相互作用。使用遗传缺陷该受体的细胞进行的研究表明，添加到培养的原代小胶质细胞中的外源 A beta(42) 在不到 30 分钟内以 CD14 依赖性方式被吞噬到细胞质区室中。这种吞噬作用发生在 A beta(42) 浓度范围内，该浓度范围远低于激活细胞炎症反应的阈值。相反，CD14 与微珠的小胶质细胞内化没有关联。在补充临床实验中，我们在阿尔茨海默病患者的脑切片中检测到与特征性阿尔茨海默病病变部位空间相关的实质小胶质细胞上明显的 CD14 免疫反应性，但在对照受试者的脑切片中则没有。通过显示 CD14 和 A beta(42) 之间的密切相互作用、证明 CD14 在 A beta(42) 吞噬作用中的直接作用以及检测阿尔茨海默病患者大脑中的 CD14 特异性染色，我们的结果表明 LPS 受体在阿尔茨海默病的病理生理学中的作用，这可能具有治疗相关性。
The amyloid beta peptide 42 (A beta(42)) plays a key role in neurotoxicity in Alzheimer's disease. Mononuclear phagocytes, i.e. microglia, have the potential to clear A beta by phagocytosis. Recently, the lipopolysaccharide (LPS) receptor CD14 was shown to mediate phagocytosis of bacterial components and furthermore to contribute to neuroinflammation in Alzheimer's disease. Here, we investigated whether this key innate immunity receptor can interact with A beta(42) and mediate phagocytosis of this peptide. Using flow cytometry, confocal microscopy and two-photon fluorescence lifetime imaging (FLIM) combined with fluorescence resonance energy transfer (FRET), we demonstrated a direct molecular interaction in the range of a few nanometers between A beta(42) and CD14 in human CD14-transfected Chinese hamster ovary cells. Investigations using cells that were genetically deficient for this receptor showed that in < 30 minutes exogenous A beta(42) added to cultured primary microglial cells was phagocytosed into the cytoplasmic compartment in a CD14-dependent manner. This phagocytosis occurred at A beta(42) concentration ranges that were considerably lower than the threshold to activate a cellular inflammatory reaction. In contrast, there was no association of CD14 to microglial internalization of microbeads. In complementary clinical experiments, we detected a pronounced CD14 immunoreactivity on parenchymal microglia spatially correlated to characteristic Alzheimer's disease lesion sites in brain sections of Alzheimer's disease patients but not in brain sections of control subjects. By showing a close interaction between CD14 and A beta(42), demonstrating a direct role of CD14 in A beta(42) phagocytosis, and detecting CD14-specific staining in brains of Alzheimer's disease patients, our results indicate a role of the LPS receptor in the pathophysiology of Alzheimer's disease, which could be of therapeutic relevance.