Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan.
J Neurosci Res. 2011 Jun;89(6):815-21. doi: 10.1002/jnr.22615. Epub 2011 Mar 10.
Monoclonal 2C3 specific to β-amyloid (Aβ) oligomers (AβOs) enabled us to test our hypothesis that the alteration of lipoprotein-Aβ interaction in the central nervous system (CNS) initiates and/or accelerates the cascade favoring Aβ assembly. Immunoprecipitation of frontal cortex employing 2C3 unequivocally detected soluble 4-, 8-, and 12-mers in Alzheimer's disease (AD) brains. Immunoblot analysis of the entorhinal cortex employing 2C3 revealed that the accumulation of soluble 12-mers precedes the appearance of neuronal loss or cognitive impairment and is enhanced as the Braak neurofibrially tangle (NFT) stages progress. The dissociation of soluble Aβ from lipoprotein particles occurs in cerebrospinal fluid (CSF), and the presence of lipoprotein-free oligomeric 2C3 conformers (4- to 35-mers) was evident, which mimic CNS environments. Such CNS environments may strongly affect conformation of soluble Aβ peptides, resulting in the conversion of soluble Aβ(42) monomers into soluble Aβ(42) assembly. The findings suggest that functionally declined lipoproteins may accelerate the generation of metabolic conditions leading to higher levels of soluble Aβ(42) assembly in the CNS.
针对β-淀粉样蛋白（Aβ）寡聚物（AβOs）的单克隆 2C3 使我们能够验证我们的假设，即中枢神经系统（CNS）中脂蛋白-Aβ相互作用的改变引发和/或加速了有利于 Aβ组装的级联反应。使用 2C3 对额叶皮质进行免疫沉淀，明确检测到阿尔茨海默病（AD）大脑中的可溶性 4-、8-和 12-三聚体。使用 2C3 对内侧颞叶皮质进行免疫印迹分析显示，可溶性 12-三聚体的积累先于神经元丢失或认知障碍的出现，并随着 Braak 神经原纤维缠结（NFT）阶段的进展而增强。脂蛋白结合的可溶性 Aβ在脑脊液（CSF）中解离，并且存在脂蛋白游离寡聚 2C3 构象异构体（4-至 35-三聚体），这模拟了 CNS 环境。这种 CNS 环境可能会强烈影响可溶性 Aβ肽的构象，导致可溶性 Aβ（42）单体转化为可溶性 Aβ（42）组装。这些发现表明，功能下降的脂蛋白可能会加速产生代谢条件，导致 CNS 中可溶性 Aβ（42）组装水平升高。
