Luo Dan, Liu Haotian, Liu Hanyou, Wu Wei, Zhu Hanyang, Ge Wei, Ma Chao
1Institute of Basic Medical Sciences, Department of Human Anatomy, Histology and Embryology, Neuroscience Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
2National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
Aging Dis. 2023 Feb 1;14(1):229-244. doi: 10.14336/AD.2022.0607.
Alzheimer's disease (AD) is the most common neurodegenerative disorder. Extracellular vesicles (EVs), carriers of nucleic acids, lipids, and proteins, are known to play significant roles in neurodegenerative pathogenesis. Studies have shown that EVs from AD human brain tissue contain toxic proteins that may lead to neuron cell damage and loss. However, the potential contribution of EV long RNAs (exLR) to AD pathobiology is less well known, and their biochemical functions and molecular properties remain obscure. Here, EVs were isolated from the frontal cortex of normal control (NC; N = 10) and AD (N = 8) brain tissue donors. We performed exLR profiling on the isolated EVs followed by pathway analysis and weighted gene co-expression network analysis (WGCNA). A total of 1012 mRNAs, 320 long non-coding RNAs (lncRNAs), and 119 circular RNAs (circRNAs) were found to be differentially expressed (DE) in AD-EVs compared with NC-EVs. Functional analysis of the DEmRNAs revealed that metal ion transport, calcium signaling, and various neuronal processes were enriched. To investigate the possible functions of the identified DElncRNAs and DEcircRNAs, competing endogenous RNA (ceRNA) networks were constructed and subjected to WGCNA, in which two gene modules were identified to be significantly correlated with AD. Moreover, we discovered that NC-EVs were more effective than AD-EVs in promoting cytokine expression, phagocytosis, and induction of calcium signaling in microglia. Our study provides an in-depth characterization of brain tissue exLR and identifies several RNAs that correlate with the pathogenesis of AD.
阿尔茨海默病（AD）是最常见的神经退行性疾病。细胞外囊泡（EVs）作为核酸、脂质和蛋白质的载体，在神经退行性疾病的发病机制中发挥着重要作用。研究表明，来自AD患者脑组织的EVs含有可能导致神经元细胞损伤和丢失的毒性蛋白。然而，EV长链RNA（exLR）对AD病理生物学的潜在贡献鲜为人知，其生化功能和分子特性仍不清楚。在这里，我们从正常对照（NC；n = 10）和AD（n = 8）脑组织供体的额叶皮质中分离出EVs。我们对分离出的EVs进行了exLR分析，随后进行了通路分析和加权基因共表达网络分析（WGCNA）。与NC-EVs相比，共发现1012个mRNA、320个长链非编码RNA（lncRNAs）和119个环状RNA（circRNAs）在AD-EVs中差异表达（DE）。对DEmRNAs的功能分析表明，金属离子转运、钙信号传导和各种神经元过程得到了富集。为了研究已鉴定的DElncRNAs和DEcircRNAs的可能功能，构建了竞争性内源RNA（ceRNA）网络并进行WGCNA，其中鉴定出两个基因模块与AD显著相关。此外，我们发现NC-EVs在促进小胶质细胞中细胞因子表达、吞噬作用和钙信号诱导方面比AD-EVs更有效。我们的研究提供了脑组织exLR的深入特征，并鉴定了几种与AD发病机制相关的RNA。
