Linking the association between circRNAs and Alzheimer’s disease progression by multi-tissue circular RNA characterization

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.

阿尔茨海默病（Alzheimer’s disease, AD）病程缓慢且呈进行性发展，会为患者带来毁灭性的不良影响。阐明阿尔茨海默病的发病病理机制具有重要意义。近年来，环状RNA（circular RNAs, circRNAs）已被发现参与包括恶性肿瘤、神经退行性疾病在内的多种人类疾病的发生发展。本研究从西奈山脑库（Mount Sinai Brain Bank, MSBB）的AMP-AD知识门户（AMP-AD Knowledge Portal）中调取已公开数据集，对四个脑区——前额前皮层、颞上叶、海马旁回及额下回——的脑样本中不同阿尔茨海默病病程阶段的环状RNA表达谱进行分析。本研究共在上述四个脑区中鉴定出147个随阿尔茨海默病严重程度呈差异表达（differentially expressed, DE）的环状RNA。此外，本研究构建了mRNA-环状RNA共表达网络，并基于共表达模块对环状RNA的潜在功能进行了注释。研究结果显示，在出现严重症状的阿尔茨海默病患者中，受环状RNA调控最为显著的脑区为海马旁回；该脑区内与阿尔茨海默病严重程度呈最强负相关的共表达模块，富集于认知功能障碍、突触组织及膜电位调控等与疾病病理相关的通路中。基于该模块内差异表达环状RNA的表达模式构建的回归模型，可有效区分患者的疾病严重程度，进一步佐证了环状RNA在阿尔茨海默病病理过程中的作用。综上，本研究结果表明，海马旁回中的环状RNA有望成为阿尔茨海默病的生物标志物、调控因子及潜在治疗靶点。