The neurotoxicity of amyloid β-protein oligomers is reversible in a primary neuron model.
The neurotoxicity of amyloid β-protein oligomers is reversible in a primary neuron model.
复制标题
淀粉样β-蛋白质低聚物的神经毒性在原发性神经元模型中是可逆的。
DOI：
10.1186/s13041-016-0284-5
复制
发表时间：
2017-01-31
期刊：
影响因子：
3.6
通讯作者：
Araki W
中科院分区：
文献类型：
--
作者：
Tanokashira D;Mamada N;Yamamoto F;Taniguchi K;Tamaoka A;Lakshmana MK;Araki W
阿尔茨海默病（AD）的特征是细胞外淀粉样蛋白β (Aβ)和细胞内过度磷酸化的tau蛋白的积累。最近的证据表明，可溶性Aβ低聚物可引起神经毒性和突触毒性，包括tau异常，并在AD病理发展中起初始作用。在这项研究中，我们关注的是a β低聚物的神经毒性是否是一个可逆过程这一尚未澄清的问题。使用原代神经元培养模型，我们检测了a β42低聚物（a β- o）治疗2天所引起的神经毒性效应在随后的2天停药期间是否可逆。a - β- o处理导致caspase-3和eIF2α的激活，在a - β- o去除后，这种作用显著减弱。免疫细胞化学分析显示，Aβ-O诱导了tau蛋白的异常磷酸化和caspase介导的裂解，这两种情况都可以通过Aβ-O的去除而逆转。此外，a β- o引起神经元内β-连环蛋白的错位和其水平的降低，这些改变在a β- o退出后部分逆转。β-连环蛋白的错位似乎反映了突触的紊乱。这些发现表明，在我们的神经元模型中，去除细胞外Aβ-O可以完全或部分逆转Aβ-O诱导的神经毒性改变。因此，我们提出a β低聚物诱导神经毒性是一个可逆的过程，这对阿尔茨海默病治疗的发展具有重要意义。本文的在线版本（doi:10.1186/s13041-016-0284-5）包含补充材料，可供授权用户使用。
Alzheimer’s disease (AD) is characterized by the accumulation of extracellular amyloid β-protein (Aβ) and intracellular hyperphosphorylated tau proteins. Recent evidence suggests that soluble Aβ oligomers elicit neurotoxicity and synaptotoxicity, including tau abnormalities, and play an initiating role in the development of AD pathology. In this study, we focused on the unclarified issue of whether the neurotoxicity of Aβ oligomers is a reversible process. Using a primary neuron culture model, we examined whether the neurotoxic effects induced by 2-day treatment with Aβ42 oligomers (Aβ-O) are reversible during a subsequent 2-day withdrawal period. Aβ-O treatment resulted in activation of caspase-3 and eIF2α, effects that were considerably attenuated following Aβ-O removal. Immunocytochemical analyses revealed that Aβ-O induced aberrant phosphorylation and caspase-mediated cleavage of tau, both of which were mostly reversed by Aβ-O removal. Furthermore, Aβ-O caused intraneuronal dislocation of β-catenin protein and a reduction in its levels, and these alterations were partially reversed upon Aβ-O withdrawal. The dislocation of β-catenin appeared to reflect synaptic disorganization. These findings indicate that removal of extracellular Aβ-O can fully or partially reverse Aβ-O-induced neurotoxic alterations in our neuron model. Accordingly, we propose that the induction of neurotoxicity by Aβ oligomers is a reversible process, which has important implications for the development of AD therapies. The online version of this article (doi:10.1186/s13041-016-0284-5) contains supplementary material, which is available to authorized users.