ABSTRACT

Alzheimer’s disease (AD) has devastating consequences for patients during its slow, progressive course. It is important to understand the pathology of AD onset. Recently, circular RNAs (circRNAs) have been found to participate in many human diseases including cancers and neurodegenerative conditions. In this study, we mined the published dataset on the AMP-AD Knowledge Portal from the Mount Sinai Brain Bank (MSBB) to describe the circRNA profiles at different AD stages in brain samples from four brain regions: anterior prefrontal cortex, superior temporal lobe, parahippocampal gyrus and inferior frontal gyrus. In total, we found 147 circRNAs to be differentially expressed (DE) for different AD severity levels in the four regions. We also characterized the mRNA-circRNA co-expression network and annotated the potential function of circRNAs based on the co-expressed modules. Based on our results, we found that the most circRNA-regulated region in AD patients with severe symptoms was the parahippocampal gyrus. The strongest negatively AD severity-correlated module in the parahippocampal gyrus was enriched in cognitive disability and pathological-associated pathways such as synapse organization and regulation of membrane potential. Finally, a regression model based on the expression pattern of DE circRNAs in the module could help to distinguish the disease severity of patients, further supporting a role for circRNAs in AD pathology. In conclusion, our findings indicate that circRNAs in parahippocampal gyrus are possible biomarkers and regulators of AD as well as potential therapeutic targets.

摘要

阿尔茨海默氏病 (AD) 在缓慢、进展的过程中会给患者带来毁灭性的后果。了解 AD 发病的病理学非常重要。最近，人们发现环状RNA（circRNA）参与许多人类疾病，包括癌症和神经退行性疾病。在这项研究中，我们挖掘了西奈山脑库 (MSBB) AMP-AD 知识门户上已发布的数据集，以描述来自四个大脑区域的大脑样本中 AD 不同阶段的 circRNA 图谱：前额叶皮层、上颞叶、海马旁回和额下回。总的来说，我们发现 147 个 circRNA 在四个区域的不同 AD 严重程度下存在差异表达（DE）。我们还表征了 mRNA-circRNA 共表达网络，并根据共表达模块注释了 circRNA 的潜在功能。根据我们的研究结果，我们发现症状严重的 AD 患者中 circRNA 调控最多的区域是海马旁回。海马旁回中最强的 AD 严重程度负相关模块富含认知障碍和病理相关通路，例如突触组织和膜电位调节。最后，基于模块中 DE circRNA 表达模式的回归模型可以帮助区分患者的疾病严重程度，进一步支持 circRNA 在 AD 病理学中的作用。总之，我们的研究结果表明，海马旁回中的 circRNA 可能是 AD 的生物标志物和调节因子，也是潜在的治疗靶点。