Amyloid β-protein oligomers upregulate the β-secretase, BACE1, through a post-translational mechanism involving its altered subcellular distribution in neurons.
Amyloid β-protein oligomers upregulate the β-secretase, BACE1, through a post-translational mechanism involving its altered subcellular distribution in neurons.
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DOI：
10.1186/s13041-015-0163-5
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发表时间：
2015-11-09
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：
Mamada N;Tanokashira D;Hosaka A;Kametani F;Tamaoka A;Araki W
β位点淀粉样前体蛋白裂解酶1（BACE 1）是一种膜结合的β-淀粉样蛋白酰蛋白酶，可启动淀粉样β蛋白（Aβ）的生成。阿尔茨海默病（AD）患者脑内BACE 1水平异常升高可能与Aβ有关。本研究采用神经元培养模型系统，探讨Aβ对BACE 1表达的影响及其机制。用相对低浓度（2.5 μM）的Aβ42寡聚体（Aβ-O）或原纤维（Aβ-F）处理大鼠原代皮层神经元2-3天。Aβ-O诱导BACE 1蛋白水平显著增加，而Aβ-F仅具有边际效应。淀粉样前体蛋白（APP）和主要α-分泌酶ADAM 10的水平在两种类型Aβ治疗后保持不变。Aβ-O处理导致eIF 2 α和caspase 3以时间依赖性方式活化，而内质网（ER）应激标志物GRP 78无变化，表明在我们的实验条件下未诱导典型的ER应激反应。此外，Aβ-O不影响BACE 1 mRNA的表达，但增加了重组腺病毒表达的外源性BACE 1的水平，表明BACE 1蛋白表达的调节不是在转录或翻译水平，而是在翻译后水平。免疫细胞化学分析显示，Aβ-O导致神经突（轴突和树突）中BACE 1免疫反应性显著增加，但不导致神经元索马中BACE 1免疫反应性显著增加;这种变化似乎与Aβ-O诱导的BACE 1升高机制有关，可能涉及BACE 1运输和降解受损。相反，Aβ-O对APP免疫反应性无影响。我们的研究结果共同表明，Aβ寡聚体通过翻译后机制诱导BACE 1升高，涉及其在神经元中的亚细胞分布的改变，这可能触发Aβ生成的恶性循环，从而有助于AD的发病机制。本文的在线版本（doi：10.1186/s13041-015-0163-5）包含补充材料，可供授权用户使用。
β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is a membrane-bound aspartyl protease that initiates amyloid β-protein (Aβ) generation. Aberrant elevation of BACE1 levels in brains of Alzheimer’s disease (AD) patients may involve Aβ. In the present study, we used a neuron culture model system to investigate the effects of Aβ on BACE1 expression as well as the underlying mechanisms. Rat primary cortical neurons were treated with relatively low concentrations (2.5 μM) of Aβ42 oligomers (Aβ-O) or fibrils (Aβ-F) for 2–3 days. Aβ-O induced a significant increase in protein levels of BACE1, while Aβ-F only had a marginal effect. Levels of amyloid precursor protein (APP) and the major α-secretase, ADAM10, remained unaltered upon treatment with both types of Aβ. Aβ-O treatment resulted in activation of eIF2α and caspase 3 in a time-dependent manner, with no changes in the endoplasmic reticulum (ER) stress marker, GRP78, indicating that a typical ER stress response is not induced under our experimental conditions. Furthermore, Aβ-O did not affect BACE1 mRNA expression but augmented the levels of exogenous BACE1 expressed via recombinant adenoviruses, indicating regulation of BACE1 protein expression, not at the transcriptional or translational but the post-translational level. Immunocytochemical analysis revealed that Aβ-O causes a significant increase in BACE1 immunoreactivity in neurites (both axons and dendrites), but not soma of neurons; this change appears relevant to the mechanism of Aβ-O-induced BACE1 elevation, which may involve impairment of BACE1 trafficking and degradation. In contrast, Aβ-O had no effect on APP immunoreactivity. Our results collectively suggest that Aβ oligomers induce BACE1 elevation via a post-translational mechanism involving its altered subcellular distribution in neurons, which possibly triggers a vicious cycle of Aβ generation, thus contributing to the pathogenetic mechanism of AD. The online version of this article (doi:10.1186/s13041-015-0163-5) contains supplementary material, which is available to authorized users.