Neural stem/progenitor cell (NSPC) based therapy represents an attractive treatment for Alzheimer's disease (AD), the most common neurodegenerative disorder with no effective treatment to date. This can be achieved by stimulating endogenous NSPCs and/or administrating exogenously produced NSPCs. Successful repair requires the migration of NSPCs to the loci where neuronal loss occurs, differentiation and integration into neural networks. However, the progressive loss of neurons in the brain of AD patients suggests that the repair by endogenous NSPCs in the setting of AD may be defective. The production and deposition of amyloid-β_1-42 (Aβ_1-42) peptides is thought to be a central event in the pathogenesis of AD. Here we report that Aβ_1-42 peptides inhibit the migration of in vitro cultured NSPCs by disturbing the ERK-MAPK signal pathway. We found that the migratory capacity of NSPCs was compromised upon treatment with oligomeric Aβ_1-42; the inhibitory effect occurred in a dose-dependent manner. Our previous studies have shown that Aβ_1-42 triggers the expression of GRK2 by unknown mechanism. Herein we found that the Aβ_1-42 evoked upregulation of GRK2 expression was attenuated upon treatment with the ERK inhibitor SCH772984 at 2.5 μM, but not with inhibitors for p38 or JNK. We detected a dose-dependent increase in levels of phosphorylated ERK1/2 after incubation of cells with oligomeric Aβ_1-42 peptides for 3 days. We observed that an increase in the phosphorylation of p38 and JNK coincided with reduced phosphorylation of ERK1/2 upon treatment with Aβ_1-42 for 6 and/or 9 days. We hypothesize that the divergence of the activation of the MAPK family of pathways may contribute to the inhibition of NSPCs migration after the long-term incubation with Aβ_1-42. Pretreatment with 1 μM MEK inhibitor U0126 reversed the effects of Aβ_1-42 on GRK2 expression of and NSPC migration. Together, our results suggest that Aβ_1-42 oligomers compromise the migratory capacity of NSPCs through the MEK-ERK pathway.

基于神经干/祖细胞（NSPC）的疗法代表了对阿尔茨海默氏病（AD）的一种有吸引力的治疗方法，这是迄今为止最常见的神经退行性疾病，目前尚无有效的治疗方法。这可以通过刺激内源性NSPC和/或施用外源性NSPC来实现。成功的修复需要将NSPC迁移到发生神经元丢失，分化并整合到神经网络中的基因座。然而，AD患者大脑中神经元的逐渐丧失表明内源性NSPCs在AD环境中的修复可能是有缺陷的。淀粉样_β1-42（_Aβ1-42）肽的产生和沉积被认为是AD发病机理中的重要事件。在这里我们报告说_Aβ1-42肽通过干扰ERK-MAPK信号通路来抑制体外培养的NSPC的迁移。我们发现NSPCs的迁移能力在寡聚_Aβ1-42处理后受到损害; 抑制作用以剂量依赖性方式发生。我们以前的研究表明，_Aβ1-42通过未知的机制触发GRK2的表达。在本文中，我们发现在用2.5μM的ERK抑制剂SCH772984而不是p38或JNK抑制剂处理后，_Aβ1-42引起的GRK2表达上调被减弱。与寡聚_Aβ1-42孵育细胞后，我们检测到磷酸化ERK1 / 2的水平呈剂量依赖性增加肽治疗3天。我们观察到，用_Aβ1-42处理6天和/或9天后，p38和JNK磷酸化的增加与ERK1 / 2磷酸化的降低同时发生。我们假设，与_Aβ1-42长期孵育后，MAPK家族通路的激活差异可能有助于抑制NSPCs迁移。用1μMMEK抑制剂U0126预处理可逆转_Aβ1-42对GRK2表达和NSPC迁移的影响。总之，我们的结果表明，_Aβ1-42寡聚体通过MEK-ERK途径损害了NSPC的迁移能力。