Vaccination with soluble Aβ oligomers generates toxicity-neutralizing antibodies
Vaccination with soluble Aβ oligomers generates toxicity-neutralizing antibodies
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DOI：
10.1046/j.1471-4159.2001.00592.x
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发表时间：
2001-11-01
影响因子：
4.7
通讯作者：
Klein, WL
中科院分区：
文献类型：
--
作者：
Lambert, MP;Viola, KL;Klein, WL
在最近对阿尔茨海默病（AD）转基因模型的研究中，有报道称，老化β -淀粉样肽1-42 （A β(1-42)）溶液（A β单体、低聚物和淀粉样原纤维的混合物）的抗体可显著减少淀粉样斑块和改善神经系统。然而，在某些情况下，神经系统的改善与明显的斑块减少无关，有人认为免疫可能中和可溶性的非纤维形式的A β。现在已知A β毒性不仅存在于原纤维中，也存在于可溶性原纤维和低聚物中。目前的研究调查了低剂量A β(1-42)寡聚物的免疫反应及其诱导的抗体的特征。兔注射了只含有单体和低聚物的A β(1-42)溶液，产生抗体，在免疫印迹和生理溶液中优先结合A β的组装形式。这些抗体已被证明可用于检测低聚物形成抑制剂的检测，用于细胞附着的低聚物与受体样点的免疫荧光定位，以及用于显示阿尔茨海默氏症脑组织中小岛屿稳定低聚物存在的免疫印迹。此外，在细胞培养中发现抗体可以中和可溶性低聚物的毒性。结果支持了转基因小鼠的免疫接种从可溶性A β衍生毒素的免疫中和中获得治疗益处的假设。人类低聚物的类似免疫中和可能是AD疫苗的关键。
In recent studies of transgenic models of Alzheimers disease (AD), it has been reported that antibodies to aged beta amyloid peptide 1-42 (A beta (1-42)) solutions (mixtures of A beta monomers, oligomers and amyloid fibrils) cause conspicuous reduction of amyloid plaques and neurological improvement. In some cases, however, neurological improvement has been independent of obvious plaque reduction, and it has been suggested that immunization might neutralize soluble, nonfibrillar forms of A beta. It is now known that A beta toxicity resides not only in fibrils, but also in soluble protofibrils and oligomers. The current study has investigated the immune response to low doses of A beta (1-42) oligomers and the characteristics of the antibodies they induce. Rabbits that were injected with A beta (1-42) solutions containing only monomers and oligomers produced antibodies that preferentially bound to assembled forms of A beta in immunoblots and in physiological solutions. The antibodies have proven useful for assays that can detect inhibitors of oligomer formation, for immunofluorescence localization of cell-attached oligomers to receptor-like puncta, and for immunoblots that show the presence of SIDS-stable oligomers in Alzheimers brain tissue. The antibodies, moreover, were found to neutralize the toxicity of soluble oligomers in cell culture. Results support the hypothesis that immunizations of transgenic mice derive therapeutic benefit from the immunoneutralization of soluble A beta -derived toxins. Analogous immuno-neutralization of oligomers in humans may be a key in AD vaccines.