Synapse-centered novel omics targets in Alzheimer’s disease - miRNA

Synapse dysfunction is an early event of Alzheimer’s disease (AD). It is caused by multiple cellular and pathological factors such as Amyloid beta, p-tau, inflammation, and aging. However, the exact molecular mechanism of synapse dysfunction in AD is largely unknown. Therefore, to understand the molecular basis of synapse dysfunction in AD, we conducted a high throughput multi-omics analysis of the synaptosome fraction in postmortem brain samples from AD patients and cognitively normal individuals. First, microRNA and mRNA HiSeq analysis were performed on the synaptosomes extracted from the postmortem brains of unaffected control (UC) individuals and AD patients. Next, we conducted the mass spectrometry analysis of synaptosomal proteins in the same sample group of HC and AD. The transcriptomic and proteomic profiling of synaptosome showed the significant deregulation of miRNA, mRNA and protein signatures in AD vs HC. Further, we used an integrated transcriptomic and proteomic approach to understand the molecular interactions of deregulated synapse miRNAs, mRNAs, and proteins in the same samples of AD and HC. Multi-omics integration analysis of synapse miRNAs-mRNAs-proteins revealed the involvement of omics targets in several biological processes and molecular functions such as signal transduction, protein binding, GABAergic synapse, and synaptic vesicle cycle, etc. Our study unveiled synapse-centered novel omics candidates that could be potential therapeutic targets to restore synapse dysfunction in AD. We used postmortem brains from AD (n=42) and controls (n=14). Synaptosomes were isolated from AD and control brains. Further, total RNA were isolated from the synaptosome and subjected to miRNA and mRNA HiSeq analysis.

突触功能障碍是阿尔茨海默病（Alzheimer’s disease, AD）的早期事件，其发生与多种细胞及病理因素相关，包括β淀粉样蛋白（Amyloid beta）、磷酸化tau蛋白（p-tau）、炎症反应与衰老过程。然而，阿尔茨海默病中突触功能障碍的确切分子机制仍未完全阐明。为揭示阿尔茨海默病突触功能障碍的分子基础，本研究对阿尔茨海默病患者与认知正常个体的死后脑组织突触体组分（synaptosome fraction）开展了高通量多组学分析（high throughput multi-omics analysis）。首先，我们对未受影响对照（unaffected control, UC）个体及阿尔茨海默病患者死后脑组织中提取的突触体，开展了微小RNA（microRNA）与信使RNA（messenger RNA, mRNA）HiSeq测序分析；随后，针对同一健康对照（healthy control, HC）与阿尔茨海默病样本组的突触体蛋白质，进行了质谱分析（mass spectrometry analysis）。突触体的转录组与蛋白质组谱分析显示，相较于健康对照，阿尔茨海默病样本中的miRNA、mRNA及蛋白质特征存在显著失调。进一步地，我们采用整合转录组与蛋白质组学方法（integrated transcriptomic and proteomic approach），解析了阿尔茨海默病与健康对照样本中失调的突触相关miRNA、mRNA及蛋白质的分子互作关系。对突触体miRNA-mRNA-蛋白质的多组学整合分析揭示，这些组学靶点参与了多种生物学过程与分子功能，如信号转导、蛋白质结合、γ-氨基丁酸能突触（GABAergic synapse）及突触囊泡循环（synaptic vesicle cycle）等。本研究揭示了以突触为核心的全新组学候选靶点，这些靶点或可作为恢复阿尔茨海默病突触功能障碍的潜在治疗靶点。本研究使用的样本包括阿尔茨海默病患者死后脑组织（n=42）与对照样本（n=14）：我们从阿尔茨海默病患者与对照脑组织中分离得到突触体，随后从突触体中提取总RNA（total RNA），并进行miRNA与mRNA HiSeq测序分析。