BACKGROUND Roles for extracellular vesicles (EVs) enriched with micro-RNAs (miRNAs) have been proposed in Alzheimer’s disease (AD) pathogenesis, leading to the discovery of blood miRNAs as AD biomarkers. However, the diagnostic utility of specific miRNAs is not consistent. This study aimed to discover blood miRNAs that are differentially expressed in Korean AD patients, evaluate their clinical performance, and investigate their role in amyloidogenesis. METHODS We discovered miRNAs differentially expressed in AD (N=8) from cognitively normal subjects (CN, N=7) or Parkinson’s disease (PD) patients (N=8). We evaluated clinical performance of these miRNAs in plasma of subgroup (N=99) and in plasma EVs isolated from the total cohort (N=251). The effects of miRNAs on amyloidogenesis and on the regulation of their target genes were investigated in vitro. RESULTS Among 17 upregulated and one downregulated miRNAs in AD (>2-fold), miR-122-5p, miR-210-3p, and miR-590-5p were differentially expressed compared with CN or PD. However, the diagnostic performance of the selected plasma or EV miRNAs in total subjects was limited (AUC<0.8). Nevertheless, levels of three miRNAs in plasma or plasma EVs of subjects who were Aβ-PET positive were significantly higher than those from the Aβ-PET negative subjects (P<0.05). The selected miRNAs induced Aβproduction (P<0.05) through activation of β-cleavage of amyloid precursor protein (CTF-β; P<0.01), and downregulated their target genes (ADAM10, BDNF and JAG1; P<0.05), which was further supported by pathway enrichment analysis of target genes of the miRNAs. CONCLUSION In conclusion, despite of the limited diagnostic utility of selected miRNAs as plasma or plasma EV biomarkers, the discovered miRNAs may play a role in amyloidogenesis during AD onset and progression.

中文翻译：

---

韩国阿尔茨海默病患者脑 A 积聚中差异表达的循环微 RNA 激活淀粉样变

背景 已经提出富含微 RNA (miRNA) 的细胞外囊泡 (EV) 在阿尔茨海默病 (AD) 发病机制中的作用，导致发现血液 miRNA 作为 AD 生物标志物。然而，特定 miRNA 的诊断效用并不一致。本研究旨在发现在韩国 AD 患者中差异表达的血液 miRNA，评估它们的临床表现，并研究它们在淀粉样变性中的作用。方法 我们发现 miRNA 在 AD (N=8) 中与认知正常受试者 (CN, N=7) 或帕金森病 (PD) 患者 (N=8) 差异表达。我们评估了这些 miRNA 在亚组 (N=99) 血浆和从总队列 (N=251) 分离的血浆 EV 中的临床表现。在体外研究了 miRNA 对淀粉样变及其靶基因调控的影响。结果 在 AD 中的 17 种上调和 1 种下调 miRNA（> 2 倍）中，与 CN 或 PD 相比，miR-122-5p、miR-210-3p 和 miR-590-5p 表达差异。然而，所选血浆或 EV miRNA 在总受试者中的诊断性能有限 (AUC < 0.8)。尽管如此，Aβ-PET 阳性受试者的血浆或血浆 EV 中三种 miRNA 的水平显着高于 Aβ-PET 阴性受试者（P <0.05）。所选择的 miRNAs 通过激活淀粉样蛋白前体蛋白 (CTF-β) 的 β-裂解 (CTF-β; P<0.01) 诱导 Aβ 的产生 (P<0.05)，并下调其靶基因 (ADAM10、BDNF 和 JAG1; P<0.05)，这进一步由 miRNA 靶基因的通路富集分析支持。结论 总之，