Kim Jaekwang, Yoon Hyejin, Chung Dah-Eun, Brown Jennifer L, Belmonte Krystal C, Kim Jungsu
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.
J Neurochem. 2016 May;137(3):436-45. doi: 10.1111/jnc.13507. Epub 2016 Mar 30.
Accumulation of amyloid β (Aβ) in the brain is a key pathological hallmark of Alzheimer's disease (AD). Because aging is the most prominent risk factor for AD, understanding the molecular changes during aging is likely to provide critical insights into AD pathogenesis. However, studies on the role of miRNAs in aging and AD pathogenesis have only recently been initiated. Identifying miRNAs dysregulated by the aging process in the brain may lead to novel understanding of molecular mechanisms of AD pathogenesis. Here, we identified that miR-186 levels are gradually decreased in cortices of mouse brains during aging. In addition, we demonstrated that miR-186 suppresses β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) expression by directly targeting the 3'UTR of Bace1 mRNA in neuronal cells. In contrast, inhibition of endogenous miR-186 significantly increased BACE1 levels in neuronal cells. Importantly, miR-186 over-expression significantly decreased Aβ level by suppressing BACE1 expression in cells expressing human pathogenic mutant amyloid precursor protein. Taken together, our data demonstrate that miR-186 is a potent negative regulator of BACE1 in neuronal cells and it may be one of the molecular links between brain aging and the increased risk for AD during aging. We identified that miR-186 levels are gradually decreased in mouse cortices during aging. Furthermore, we demonstrated that miR-186 is a novel negative regulator of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) expression in neuronal cells. Therefore, we proposed that reduction in miR-186 levels during aging may lead to the up-regulation of BACE1 in the brain, thereby increasing a risk for Alzheimer's disease in aged individuals. Read the Editorial Highlight for this article on page 308.
淀粉样β蛋白（Aβ）在大脑中的积累是阿尔茨海默病（AD）的关键病理标志。由于衰老为AD最显著的风险因素，了解衰老过程中的分子变化可能为AD发病机制提供关键见解。然而，关于微小RNA（miRNA）在衰老和AD发病机制中的作用的研究直到最近才开始。鉴定大脑中受衰老过程失调的miRNA可能会带来对AD发病机制分子机制的新认识。在此，我们发现衰老过程中小鼠大脑皮质中miR-186水平逐渐降低。此外，我们证明miR-186通过直接靶向神经元细胞中Bace1 mRNA的3'非翻译区（3'UTR）来抑制β-位点淀粉样前体蛋白裂解酶1（BACE1）的表达。相反，抑制内源性miR-186可显著提高神经元细胞中BACE1的水平。重要的是，在表达人类致病性突变淀粉样前体蛋白的细胞中，miR-186过表达通过抑制BACE1表达显著降低了Aβ水平。综上所述，我们的数据表明miR-186是神经元细胞中BACE1的有效负调节因子，它可能是大脑衰老与衰老过程中AD风险增加之间的分子联系之一。我们发现衰老过程中小鼠皮质中miR-186水平逐渐降低。此外，我们证明miR-186是神经元细胞中β-位点淀粉样前体蛋白裂解酶1（BACE1）表达的新型负调节因子。因此，我们提出衰老过程中miR-186水平的降低可能导致大脑中BACE1上调，从而增加老年个体患阿尔茨海默病的风险。阅读本文第308页的编辑推荐。
