Table7_Single-cell transcriptome profiling highlights the role of APP in blood vessels in assessing the risk of patients with proliferative diabetic retinopathy developing Alzheimer’s disease.xls

Introduction: The incidence of diabetic retinopathy (DR) has been found to be associated with the risk of developing Alzheimer‘s disease (AD). In addition to the common properties of neurodegeneration, their progressions are involved with abnormal vascular functions. However, the interactions between them have not been fully understood. This study aimed to investigate the key factor for the underlying interactions and shared signaling pathways in the vasculature of DR and AD.
Methods: We retrieved single-cell RNA sequencing (scRNA-seq) data regarding human fibrovascular membrane (FVM) of proliferative diabetic retinopathy (PDR) and human hippocampus vessels of AD from the NCBI-GEO database. GSEA analysis was performed to analyze AD-related genes in endothelial cells and pericytes of PDR. CellChat was used for predicting cell-cell communication and the signaling pathway.
Results: The data suggested that amyloid-beta precursor protein (APP) signaling was found crucial in the vasculature of PDR and AD. Endothelial cells and pericytes could pose influences on other cells mainly via APP signaling in PDR. The endothelial cells were mainly coordinated with macrophages in the hippocampus vasculature of AD via APP signaling. The bulk RNA-seq in mice with PDR validated that the expression of APP gene had a significant correlation with that of the AD genome-wide association studies (GWAS) gene.
Discussion: Our study demonstrates that the vasculopathy of PDR and AD is likely to share a common signaling pathway, of which the APP-related pathway is a potential target.

引言：已有研究表明，糖尿病视网膜病变（diabetic retinopathy, DR）的发病率与阿尔茨海默病（Alzheimer's disease, AD）的发病风险存在关联。除神经退行性疾病共有的特征外，二者的进展均与血管功能异常相关。然而，二者之间的相互作用尚未被完全阐明。本研究旨在探究糖尿病视网膜病变与阿尔茨海默病血管系统中潜在相互作用的关键因素及共同信号通路。
方法：我们从NCBI-GEO数据库中获取了增殖性糖尿病视网膜病变（proliferative diabetic retinopathy, PDR）患者的人纤维血管膜（fibrovascular membrane, FVM）以及阿尔茨海默病患者海马血管的单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）数据。采用基因集富集分析（Gene Set Enrichment Analysis, GSEA）对增殖性糖尿病视网膜病变患者内皮细胞与周细胞中的阿尔茨海默病相关基因进行分析。使用CellChat工具预测细胞间通信及信号通路。
结果：研究数据显示，淀粉样前体蛋白（amyloid-beta precursor protein, APP）信号通路在糖尿病视网膜病变与阿尔茨海默病的血管系统中至关重要。在增殖性糖尿病视网膜病变中，内皮细胞与周细胞主要通过淀粉样前体蛋白信号通路对其他细胞产生调控作用。在阿尔茨海默病的海马血管系统中，内皮细胞主要通过淀粉样前体蛋白信号通路与巨噬细胞发生协同作用。对增殖性糖尿病视网膜病变模型小鼠的批量RNA测序数据验证显示，APP基因的表达水平与阿尔茨海默病全基因组关联研究（Genome-Wide Association Studies, GWAS）相关基因的表达水平存在显著相关性。
讨论：本研究表明，增殖性糖尿病视网膜病变与阿尔茨海默病的血管病变可能共享一条共同的信号通路，其中淀粉样前体蛋白相关通路是潜在的干预靶点。