Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.
Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel.
Mol Neurobiol. 2020 Oct;57(10):4156-4169. doi: 10.1007/s12035-020-02013-1. Epub 2020 Jul 17.
Alzheimer's disease (AD) is a progressive neurodegenerative brain pathology and the most common form of dementia. Evidence suggests that extracellular vesicles (EVs) containing cytokines and microRNA are involved in inflammation regulation. The current study aimed to explore a potential impact of AD patients' EVs on disease progression. Blood samples were collected after obtaining signed informed consent (No. 0462-14-RMB) from 42 AD patients at three stages of disease severity and from 19 healthy controls (HC). EV size and concentration were studied by nanotracking analysis. EV membrane antigens were defined by flow cytometry and Western blot; EV protein contents were screened by protein array; the miRNA content was screened by nanostring technology and validated by RT-PCR. HC and AD patients' EVs consisted of a mixture of small (< 100 nm) and larger vesicles. The myelin oligodendrocyte glycoprotein (MOG) expression on EVs correlated with disease severity. EVs of patients with moderate and severe AD had significantly higher levels of MOG, compared with mild AD patients. Levels of EVs expressing the axonal glycoprotein CD171 were significantly higher in severe AD patients than in HC. Increase in endothelial EVs was observed in AD patients. An above twofold increase was found in the content of inflammatory cytokines and > 50% decrease in growth factors in AD patients' EVs compared with HC-EVs. Levels of let-7g-5p, miR126-3p, miR142-3p, miR-146a-5p, and mir223-3p correlated with disease severity. Neural damage, specific miRNA downregulation, and inflammatory cytokine upregulation, found in patients' EVs, might be used as a biomarker reflecting AD severity.
阿尔茨海默病（AD）是一种进行性神经退行性脑病理学，是最常见的痴呆症形式。有证据表明，含有细胞因子和 microRNA 的细胞外囊泡（EVs）参与炎症调节。本研究旨在探讨 AD 患者 EVs 对疾病进展的潜在影响。在获得 42 名 AD 患者（疾病严重程度 3 期）和 19 名健康对照者（HC）的书面知情同意书（No. 0462-14-RMB）后采集血液样本。通过纳米跟踪分析研究 EV 的大小和浓度；通过流式细胞术和 Western blot 定义 EV 膜抗原；通过蛋白质芯片筛选 EV 蛋白含量；通过 nanostring 技术筛选 miRNA 含量，并通过 RT-PCR 进行验证。HC 和 AD 患者的 EV 由小（<100nm）和较大囊泡的混合物组成。EV 上的少突胶质细胞髓鞘糖蛋白（MOG）表达与疾病严重程度相关。与轻度 AD 患者相比，中重度 AD 患者的 EVs 中 MOG 水平明显更高。与 HC 相比，严重 AD 患者的 EV 表达轴突糖蛋白 CD171 的水平明显更高。AD 患者中观察到内皮 EV 增加。与 HC-EVs 相比，AD 患者的 EV 中炎症细胞因子的含量增加了两倍以上，生长因子的含量下降了>50%。let-7g-5p、miR126-3p、miR142-3p、miR-146a-5p 和 mir223-3p 的水平与疾病严重程度相关。在患者 EVs 中发现的神经损伤、特定 miRNA 下调和炎症细胞因子上调，可能作为反映 AD 严重程度的生物标志物。
