ABSTRACT

Alzheimer’s disease is a progressive neurodegenerative disorder, with the strongest disease-associated changes observed at clinical or end-stage disease. Transcriptomic deregulation of miRNA expression can spread via “horizontal” RNA transfer through extracellular vesicles (EVs) to act in conjunction with proteins, leading to changes in mRNA, which can provide early signals to indicate forthcoming neuropathological changes in the brain. Here, we analysed the small RNA content, in particular, miRNA, contained in brain-derived EVs isolated from the frontal cortex of Alzheimer’s subjects (n = 8) and neurological control subjects (n = 9). Brain-derived EVs were found to contain an upregulation of disease-associated miRNA. RNA species from brain-derived EVs were correlated with miRNA profiles obtained from matching total brain homogenate. These results provide a blueprint into the biological pathways potentially effected during disease that may be assisted by brain-derived EV RNA horizontal transfer.We also correlated the miRNA changes in the brain with those detected in peripheral EVs collected from serum of Alzheimer’s disease patients (n = 23, and healthy controls, n = 23) and revealed a panel of miRNA that could be used as a liquid brain biopsy. Overall, our study provides the first interrogation of the small RNA contents in brain-derived EVs and how they could be used to understand the early pathological changes in Alzheimer’s disease which will benefit the development of an early diagnostic blood test.

摘要

阿尔茨海默氏病是一种进行性神经退行性疾病，在临床或末期疾病中观察到最强的疾病相关变化。miRNA表达的转录组失调可以通过“水平” RNA转移通过细胞外囊泡（EV）传播，从而与蛋白质协同作用，从而导致mRNA的变化，从而可以提供早期信号来指示大脑中即将发生的神经病理学变化。在这里，我们分析了从阿尔茨海默氏症受试者（n = 8）和神经系统控制受试者（n）的额叶皮层分离的脑源性电动汽车中所含的小RNA含量，尤其是miRNA。= 9）。发现脑源电动车含有与疾病相关的miRNA上调。来自大脑的电动汽车的RNA种类与从匹配的总脑匀浆获得的miRNA谱图相关。这些结果提供了一个蓝图变成疾病中潜在影响的生物学途径可通过脑衍生EV RNA水平transfer.We来辅助相关也与miRNA在脑中与在阿尔茨海默氏病的患者的血清采集的末梢电动汽车检测到的变化（Ñ = 23，健康对照者，n= 23），并揭示了一组可用作液体脑活检的miRNA。总体而言，我们的研究首次询问了脑源电动汽车中小RNA的含量，以及如何将其用于了解阿尔茨海默氏病的早期病理变化，这将有利于早期诊断性血液测试的发展。