Alzheimer's disease (AD) is the most common form of dementia with irreversible neurodegeneration. Accumulation of amyloid beta (Aβ) in the brain is considered to be a major cause of neuronal cell death in AD, but the neurotoxic mechanism of Aβ is not yet fully understood. Here, we focused on the role of microRNAs (miRNAs) in Aβ-induced neuronal cell death. In microarray and RT-qPCR analysis of plasma miRNAs obtained from 5 familiar AD mutations (5xFAD) and wild-type (WT) mice of various ages, miR-16-5p showed a significant age-related change that was accompanied by neuronal cell death in the brain tissue of 5xFAD mice. In addition, increased miR-16-5p was prominent near Aβ plaque-deposition sites in 5xFAD mouse brains. Aβ treatment induced miR-16-5p upregulation and apoptosis in primary cultured mouse cortical neurons and the SH-SY5Y human neuroblastoma cell line. In silico analysis and reporter gene assays indicated that miR-16-5p directly targets the mRNA encoding the anti-apoptotic factor, B cell lymphoma-2 (BCL-2), in the neuronal cell line. Overexpression of miR-16-5p in SH-SY5Y cells downregulated BCL-2 expression and induced apoptosis. These results collectively suggest that the miR-16-5p/BCL-2 axis plays an important role for neuronal cell apoptosis in AD.

中文翻译：

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miR-16-5p 在阿尔茨海默病模型中被淀粉样蛋白 β 沉积上调，并通过直接靶向和抑制 BCL-2 诱导神经元细胞凋亡。

阿尔茨海默病 (AD) 是最常见的痴呆形式，具有不可逆的神经变性。大脑中β-淀粉样蛋白 (Aβ) 的积累被认为是 AD 中神经元细胞死亡的主要原因，但 Aβ 的神经毒性机制尚不完全清楚。在这里，我们专注于 microRNA (miRNA) 在 Aβ 诱导的神经元细胞死亡中的作用。在从 5 只熟悉的 AD 突变 (5xFAD) 和不同年龄的野生型 (WT) 小鼠获得的血浆 miRNA 的微阵列和 RT-qPCR 分析中，miR-16-5p 显示出与年龄相关的显着变化，并伴有神经元细胞死亡在 5xFAD 小鼠的脑组织中。此外，增加的 miR-16-5p 在 5xFAD 小鼠大脑中的 Aβ 斑块沉积位点附近很显着。在原代培养的小鼠皮质神经元和 SH-SY5Y 人神经母细胞瘤细胞系中，Aβ 处理诱导 miR-16-5p 上调和凋亡。计算机分析和报告基因分析表明，miR-16-5p 直接靶向神经元细胞系中编码抗凋亡因子 B 细胞淋巴瘤-2 (BCL-2) 的 mRNA。SH-SY5Y 细胞中 miR-16-5p 的过表达下调 BCL-2 的表达并诱导细胞凋亡。这些结果共同表明 miR-16-5p/BCL-2 轴在 AD 中的神经元细胞凋亡中起重要作用。