Developmental Expression and Dysregulation of miR-146a and miR-155 in Down's Syndrome and Mouse Models of Down's Syndrome and Alzheimer's Disease
Developmental Expression and Dysregulation of miR-146a and miR-155 in Down's Syndrome and Mouse Models of Down's Syndrome and Alzheimer's Disease
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DOI：
10.2174/1567205014666170706112701
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发表时间：
2017-01-01
影响因子：
2.1
通讯作者：
Aronica, E.
中科院分区：
文献类型：
--
作者：
Arena, A.;Iyer, A. M.;Aronica, E.
背景：miR-146a和miR-155是先天免疫应答的关键调节因子。我们假设炎症介导的这些mirna失调可能发生在唐氏综合征（DS）和阿尔茨海默病（AD）患者中。方法：采用原位杂交方法研究了对照组、DS患者和AD病理成人（DS和散发性AD； sAD）发育中的海马miRNA表达谱。采用实时荧光定量PCR法检测sAD海马及DS和AD小鼠模型中miRNA水平。这两种mirna均在产前人海马中表达。在DS中，我们检测到反应性星形胶质细胞中miR-146a表达增加。miR-146a在sAD海马中表达升高，且与其靶点IRAK-1呈负相关。APP/PS1小鼠在11-13月龄时，与WT和3月龄小鼠相比，这两种mirna的表达均显著增加。在Ts65Dn和APP/PS1小鼠中均观察到miR-146a水平与其靶标TRAF6呈负相关。结论：这些发现提示miR-146a和miR-155可能参与脑发育和神经变性。特别是，我们提供了这两种免疫调节mirna在AD中失调的证据，具有潜在的治疗意义，值得进一步研究。
Background: miR-146a and miR-155 are key regulators of the innate immune response. We hypothesized that an inflammation-mediated dysregulation of these miRNAs may occur in patients with Down syndrome (DS) and Alzheimer's disease (AD).Methods: The miRNA expression patterns were investigated by in situ hybridization in developing hippocampus from controls, patients with DS and in adults with AD pathology (DS and sporadic AD; sAD). Quantitative real-time PCR was employed to evaluate the miRNA levels in the hippocampus of sAD and in mouse models of DS and AD. Both miRNAs were expressed in prenatal human hippocampus. In DS we detected increased miR-146a expression in reactive astrocytes. Increased expression of miR-146a was found in the hippocampus of sAD and negatively correlated with its target IRAK-1. APP/PS1 mice showed a significant increase in the expression of both miRNAs at 11-13 months of age as compared to WT and mice at 3 months. A negative correlation between miR-146a levels and its target TRAF6 was observed in both Ts65Dn and APP/PS1 mice.Conclusion: These findings suggest a possible involvement of miR-146a and miR-155 in brain development and neurodegeneration. In particular, we provide evidence of a dysregulation of these two immunomodulatory miRNAs in AD with a potential therapeutical implication, deserving further investigation.