MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties.
MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties.
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DOI：
10.1038/s41380-019-0610-2
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发表时间：
2021-10
影响因子：
11
通讯作者：
Lahiri DK
中科院分区：
文献类型：
--
作者：
Chopra N;Wang R;Maloney B;Nho K;Beck JS;Pourshafie N;Niculescu A;Saykin AJ;Rinaldi C;Counts SE;Lahiri DK
阿尔茨海默病（AD）是最常见的与年龄相关的痴呆形式，与主要由过度磷酸化的微管相关蛋白tau（p-tau）组成的细胞内神经元缠结和主要包含淀粉样蛋白β（Aβ）肽的细胞外斑块的沉积相关。p-tau缠结单位是正常tau蛋白的翻译后修饰。Aβ是一种神经毒性肽，通过β-位点APP裂解酶1（BACE 1）和γ-分泌酶复合物从淀粉样蛋白-β前体蛋白（APP）中切除。microRNA（miRNAs）是短的单链RNA，其作为RNA诱导的沉默复合物（RISC）的一部分调节蛋白质表达。我们在原代人类细胞培养模型中鉴定了miR-298作为APP、BACE 1和两种主要形式Aβ（Aβ40和Aβ42）的阻遏物。此外，我们发现了miR-298对两个特定tau部分的翻译后水平的新作用。值得注意的是，miR-298显著降低了约55和50 kDa形式的tau蛋白的水平，而没有显著改变总tau或其他形式。人miR-298的体内过表达导致小鼠中APP、BACE 1和tau的非显著减少。此外，我们在一组人类AD患者中发现了两种与脑脊液（CSF）p-tau水平升高和CSF Aβ42水平降低相关的miR-298 SNP。最后，在AD患者和年龄匹配的非AD对照之间，miR-298的水平在死后人类颞叶中变化。我们的研究结果表明，miR-298可能是AD治疗的合适靶点。
Alzheimer’s disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aβ42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.
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