PDF(Pubmed)
Abstract：
At the time of diagnosis, Alzheimer\'s disease (AD) patients already suffer from significant neuronal loss. The identification of proteins that influence disease progression before the onset of symptoms is thus an essential part of the development of new effective drugs and biomarkers. Here, we used an unbiased 18O labelling proteomics approach to identify proteins showing altered levels in the AD brain. We studied the relationship between the protein with the highest increase in hippocampus, DEAD box Helicase 24 (DDX24), and AD pathology. We visualised DDX24 in the human brain and in a mouse model for Aβ42-induced AD pathology-AppNL-F-and studied the interaction between Aβ and DDX24 in primary neurons. Immunohistochemistry in the AD brain confirmed the increased levels and indicated an altered subcellular distribution of DDX24. Immunohistochemical studies in AppNL-F mice showed that the increase of DDX24 starts before amyloid pathology or memory impairment is observed. Immunocytochemistry in AppNL-F primary hippocampal neurons showed increased DDX24 intensity in the soma, nucleus and nucleolus. Furthermore, siRNA targeting of DDX24 in neurons decreased APP and Aβ42 levels, and the addition of Aβ42 to the medium reduced DDX24. In conclusion, we have identified DDX24 as a protein with a potential role in Aβ-induced AD pathology.
摘要：
在诊断的时候,阿尔茨海默病(AD)患者已经患有显著的神经元损失。因此，在症状发作之前识别影响疾病进展的蛋白质是开发新的有效药物和生物标志物的重要组成部分。这里,我们使用无偏见的18O标记蛋白质组学方法来鉴定AD脑中显示水平改变的蛋白质。我们研究了海马中增加最多的蛋白质之间的关系，死亡盒螺旋酶24(DDX24)，和AD病理学。我们在人脑和Aβ42诱导的AD病理-AppNL-F的小鼠模型中可视化了DDX24，并研究了Aβ和DDX24在原代神经元中的相互作用。AD脑中的免疫组织化学证实了增加的水平，并表明DDX24的亚细胞分布改变。在AppNL-F小鼠中的免疫组织化学研究显示DDX24的增加在观察到淀粉样蛋白病理学或记忆障碍之前开始。AppNL-F原代海马神经元的免疫细胞化学显示体细胞中DDX24强度增加，细胞核和核仁.此外，siRNA靶向DDX24在神经元中降低APP和Aβ42水平，并且向培养基中添加Aβ42减少了DDX24。总之,我们已经确定DDX24是一种在Aβ诱导的AD病理中具有潜在作用的蛋白质。
