MicroRNA-149 is downregulated in Alzheimer’s disease and inhibits β-amyloid accumulation and ameliorates neuronal viability through targeting BACE1

Abstract Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a critical role in Alzheimer’s disease (AD) pathogenesis. This study aimed to investigate the relationship between microRNA-149 (miR-149) and BACE1, and evaluate the clinical significance and biological function of miR-149 in AD progression. Bioinformatics analysis and a luciferase reporter assay were used to confirm the interaction between miR-149 and BACE1. Expression of miR-149 and BACE1 was estimated using quantitative real-time PCR. The clinical significance of miR-149 in AD diagnosis and severity determination was evaluated using ROC analysis. The effect of miR-149 on Aβ accumulation and neuronal viability was analyzed in Aβ-treated SH-SY5Y cells. miR-149 was found directly binding the 3’-UTR of BACE1 and was negatively correlated with BACE1 in AD patients and cell model. Serum miR-149 expression was downregulated in AD patients and served as a potential diagnostic biomarker. The overexpression of miR-149 in Aβ-treated SH-SY5Y cells resulted in inhibited Aβ accumulation and enhanced neuronal viability. This study demonstrated that serum miR-149 is decreased in AD patients and serves as a candidate diagnostic biomarker, and that the overexpression of miR-149 may suppress Aβ accumulation and promote neuronal viability by targeting BACE1 in AD model cells.摘要 β位淀粉样前体蛋白裂解酶1（Beta-site amyloid precursor protein cleaving enzyme 1, BACE1）在阿尔茨海默病（Alzheimer’s disease, AD）的发病机制中发挥关键作用。本研究旨在探讨微小RNA-149（microRNA-149, miR-149）与BACE1的相互调控关系，并评估miR-149在AD进展中的临床意义与生物学功能。研究采用生物信息学分析与荧光素酶报告基因测定（luciferase reporter assay）验证了miR-149与BACE1的靶向结合作用；通过实时定量PCR（quantitative real-time PCR）检测miR-149与BACE1的转录表达水平；利用受试者工作特征曲线（Receiver Operating Characteristic, ROC）分析评估miR-149在AD诊断与病情严重程度判定中的临床价值；在经β淀粉样蛋白（Amyloid-β, Aβ）处理的SH-SY5Y细胞模型中，分析miR-149对Aβ积累与神经元存活率的影响。研究结果显示，miR-149可直接结合BACE1的3'非翻译区（3'-untranslated region, 3’-UTR），且在AD患者及细胞模型中，miR-149的表达水平与BACE1呈显著负相关。AD患者血清中的miR-149表达水平显著下调，其可作为潜在的AD诊断生物标志物。在Aβ处理的SH-SY5Y细胞中过表达miR-149，可有效抑制Aβ积累并提升神经元存活率。本研究证实，AD患者血清miR-149表达降低，可作为候选诊断生物标志物；且在AD模型细胞中，miR-149过表达可通过靶向调控BACE1，进而抑制Aβ积累并促进神经元存活。