Department of Neurology, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, China.
Department of Critical Care Medicine, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, China.
J Alzheimers Dis. 2019;67(2):571-581. doi: 10.3233/JAD-181053.
Alzheimer's disease (AD) is a neurodegenerative disease prevalent in aged people, clinically characterized by progressive memory loss, behavioral and learning dysfunction, and cognitive deficits. The pathogenesis of AD is hallmarked by formation of amyloid-β peptide aggregates (Aβ) and intraneuronal neurofibrillary tangles (NFTs), which are induced by hyperphosphorylation of amyloid-β protein precursor and tau protein, respectively. The hyperphosphorylation is controlled by cyclin-dependent kinase-5 (CDK5), the aberrant activation of which is mediated by calpain (CAPN)-induced cleavage of p35 into p25. However, the regulation of CAPN in AD remains largely unknown. Here, we studied the post-transcriptional control of CAPN1 by microRNAs (miRNAs) in the setting of AD. We found that miR-124-3p, previously reported as a miRNA that was downregulated in AD, was a CAPN1-targeting miRNA that functionally inhibited the protein translation of CAPN1 in a human neural cell line, HCN-2. In vitro, transfection with miR-124-3p reduced the levels of CAPN1 protein, the cleavage of p35 into p25, and cell apoptosis dose-dependently in HCN-2 cells. Moreover, a significant inverse correlation was detected between the levels of miR-124-3p and CAPN1 in AD specimens. Furthermore, intracranial injection of adeno-associated virus expressing miR-124-3p into APP/PS1-AD mice significantly reduced Aβ deposition and significantly improved the AD-mouse behavior in the social recognition test and plus-maze discriminative avoidance task. Together, our data suggest that post-transcriptional control of calpain by miR-124-3p plays an essential role in the development of AD.
阿尔茨海默病（AD）是一种在老年人中流行的神经退行性疾病，临床上以进行性记忆丧失、行为和学习功能障碍以及认知缺陷为特征。AD 的发病机制以淀粉样β肽聚集物（Aβ）和神经元内神经原纤维缠结（NFTs）的形成为标志，分别由淀粉样β蛋白前体和 tau 蛋白的过度磷酸化诱导。过度磷酸化受细胞周期蛋白依赖性激酶 5（CDK5）的控制，CDK5 的异常激活由钙蛋白酶（CAPN）诱导的 p35 切割为 p25 介导。然而，AD 中 CAPN 的调节在很大程度上尚不清楚。在这里，我们研究了 AD 中 microRNAs（miRNAs）对 CAPN1 的转录后调控。我们发现，miR-124-3p，先前被报道为 AD 中下调的 miRNA，是 CAPN1 的靶向 miRNA，它在人神经细胞系 HCN-2 中功能性地抑制 CAPN1 的蛋白翻译。在体外，miR-124-3p 的转染以剂量依赖性方式降低了 HCN-2 细胞中 CAPN1 蛋白、p35 切割为 p25 的水平和细胞凋亡。此外，在 AD 标本中检测到 miR-124-3p 的水平与 CAPN1 的水平呈显著负相关。此外，将表达 miR-124-3p 的腺相关病毒颅内注射到 APP/PS1-AD 小鼠中，显著减少了 Aβ 沉积，并显著改善了 AD 小鼠在社会识别测试和加迷宫辨别回避任务中的行为。总之，我们的数据表明，miR-124-3p 对钙蛋白酶的转录后调控在 AD 的发展中起着重要作用。
