Tan Yi Jayne, Wong Benjamin Y X, Vaidyanathan Ramanathan, Sreejith Sivaramapanicker, Chia Sook Yoong, Kandiah Nagaendran, Ng Adeline S L, Zeng Li
Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.
Department of Biomedical Engineering, National University of Singapore, Singapore.
J Alzheimers Dis Rep. 2021 Oct 28;5(1):805-813. doi: 10.3233/ADR-210311. eCollection 2021.
micro-RNAs (miRNAs) are stable, small, non-coding RNAs enriched in exosomes. Their variation in levels according to different disease etiologies have made them a promising diagnostic biomarker for neurodegenerative diseases such as Alzheimer's disease (AD). Altered expression of miR-320a, miR-328-3p, and miR-204-5p have been reported in AD and frontotemporal dementia (FTD).
To determine their reliability, we aimed to examine the expression of three exosomal miRNAs isolated from cerebrospinal fluid (CSF) of patients with young-onset AD and FTD (< 65 years), correlating with core AD biomarkers and cognitive scores.
Exosomes were first isolated from CSF samples of 48 subjects (8 controls, 28 AD, and 12 FTD), followed by RNA extraction and quantitative PCR to measure the expression of miR-320a, miR-328-3p, and miR-204-5p.
Expression of all three markers (miR-320a ( = 0.005), miR-328-3p ( = 0.049), and miR-204-5p ( = 0.036)) were significantly lower in AD versus controls. miR-320a was reduced in FTD versus controls ( = 0.049) and miR-328-3p was lower in AD versus FTD ( = 0.054). Notably, lower miR-328-3p levels could differentiate AD from FTD and controls with an AUC of 0.702, 95% CI: 0.534- 0.870, and showed significant correlation with lower CSF Aβ levels ( = 0.359, = 0.029). Pathway enrichment analysis identified potential targets of miR-328-3p implicated in the AMPK signaling pathway linked to amyloid-β and tau metabolism in AD.
Overall, we demonstrated miR-320a and miR-204-5p as reliable biomarkers for AD and FTD and report miR-328-3p as a novel AD biomarker.
微小RNA（miRNA）是稳定的、小的非编码RNA，在外泌体中含量丰富。它们根据不同疾病病因的水平变化使其成为阿尔茨海默病（AD）等神经退行性疾病有前景的诊断生物标志物。已有报道称，AD和额颞叶痴呆（FTD）中miR-320a、miR-328-3p和miR-204-5p的表达发生改变。
为了确定它们的可靠性，我们旨在检测从早发性AD和FTD（<65岁）患者脑脊液（CSF）中分离出的三种外泌体miRNA的表达，并将其与AD核心生物标志物和认知评分相关联。
首先从48名受试者（8名对照、28名AD患者和12名FTD患者）的CSF样本中分离出外泌体，然后进行RNA提取和定量PCR，以测量miR-320a、miR-328-3p和miR-204-5p的表达。
与对照组相比，AD患者中所有三种标志物（miR-320a（=0.005）、miR-328-3p（=0.049）和miR-204-5p（=0.036））的表达均显著降低。与对照组相比，FTD患者中miR-320a降低（=0.049），与FTD患者相比，AD患者中miR-328-3p降低（=0.054）。值得注意的是，较低的miR-328-3p水平可将AD与FTD及对照组区分开来，曲线下面积（AUC）为0.702，95%置信区间：0.534-0.870，且与较低的CSF Aβ水平显著相关（=0.359，=0.029）。通路富集分析确定了miR-328-3p的潜在靶点，这些靶点与AD中与淀粉样蛋白-β和tau代谢相关的AMPK信号通路有关。
总体而言，我们证明了miR-320a和miR-204-5p是AD和FTD的可靠生物标志物，并报告miR-328-3p是一种新型的AD生物标志物。
