Correcting abnormalities in miR-124/PTPN1 signaling rescues tau pathology in Alzheimer's disease
Correcting abnormalities in miR-124/PTPN1 signaling rescues tau pathology in Alzheimer's disease
复制标题
纠正 miR-124/PTPN1 信号传导异常可挽救阿尔茨海默病中的 tau 病理学。
DOI：
10.1111/jnc.14961
复制
发表时间：
2020-02-07
影响因子：
4.7
通讯作者：
Liu, Dan
中科院分区：
文献类型：
--
作者：
Hou, Tong-Yao;Zhou, Yang;Liu, Dan
MicroRNA参与了多种生理和病理过程。我们先前报道了异常的microRNA-124（miR-124）/非受体型蛋白磷酸酶1（PTPN 1）信号在与阿尔茨海默病（AD）相关的突触障碍中起重要作用。在这项研究中，我们进一步研究了miR-124/PTPN 1在AD的tau病理学中的潜在作用。我们首先用海马内立体定向注射治疗小鼠。采用实时荧光定量逆转录PCR（qRT-PCR）检测microRNA的表达。蛋白质印迹法用于测量PTPN 1水平、tau蛋白水平、AD相关位点的tau磷酸化以及糖原合成酶激酶3 β（GSK-3 β）和蛋白磷酸酶2（PP 2A）活性的改变。免疫组织化学也被用来检测在AD相关网站和体细胞腺样体聚集的tau蛋白磷酸化水平的变化。通过70%甲酸（FA）提取分离可溶性和不溶性tau蛋白以检查tau溶解度。最后，进行行为学实验（包括Morris水迷宫、恐惧条件化和高架十字迷宫）以检测学习记忆能力和情绪相关行为。我们发现，人工复制miR-124/PTPN 1信号传导的异常在野生型小鼠海马中诱导AD样tau病理学，包括多个位点的过度磷酸化、不溶性和体细胞腺样体聚集以及学习/记忆缺陷。我们还发现，miR-124/PTPN 1信号传导的中断是由RE 1沉默转录因子蛋白的丢失引起的，这可以由A β损伤或氧化应激引发，如在P301 S小鼠的大脑中观察到的。纠正miR-124/PTPN 1信号的失调挽救了P301 S小鼠中的tau病理学和学习/记忆障碍。我们还发现miR-124/PTPN 1异常通过促进酪氨酸磷酸化诱导糖原合成酶激酶3（GSK-3）的激活和蛋白磷酸酶2A（PP 2A）的失活，暗示tau激酶/磷酸酶的失衡。因此，靶向miR-124/PTPN 1信号通路是AD的一种有前景的治疗策略。
MicroRNAs have been implicated in diverse physiological and pathological processes. We previously reported that aberrant microRNA-124 (miR-124)/non-receptor-type protein phosphatase 1 (PTPN1) signaling plays an important role in the synaptic disorders associated with Alzheimer's disease (AD). In this study, we further investigated the potential role of miR-124/PTPN1 in the tau pathology of AD. We first treated the mice with intra-hippocampal stereotactic injections. Then, we used quantitative real-time reverse transcription PCR (qRT-PCR) to detect the expression of microRNAs. Western blotting was used to measure the level of PTPN1, the level of tau protein, the phosphorylation of tau at AD-related sites, and alterations in the activity of glycogen synthase kinase 3 beta (GSK-3 beta) and protein phosphatase 2 (PP2A). Immunohistochemistry was also used to detect changes in tau phosphorylation levels at AD-related sites and somadendritic aggregation. Soluble and insoluble tau protein was separated by 70% formic acid (FA) extraction to examine tau solubility. Finally, behavioral experiments (including the Morris water maze, fear conditioning, and elevated plus maze) were performed to examine learning and memory ability and emotion-related behavior. We found that artificially replicating the abnormalities in miR-124/PTPN1 signaling induced AD-like tau pathology in the hippocampus of wild-type mice, including hyperphosphorylation at multiple sites, insolubility and somadendritic aggregation, as well as learning/memory deficits. We also found that disruption of miR-124/PTPN1 signaling was caused by the loss of RE1-silencing transcription factor protein, which can be initiated by A beta insults or oxidative stress, as observed in the brains of P301S mice. Correcting the deregulation of miR-124/PTPN1 signaling rescued the tau pathology and learning/memory impairments in the P301S mice. We also found that miR-124/PTPN1 abnormalities induced activation of glycogen synthase kinase 3 (GSK-3) and inactivation of protein phosphatase 2A (PP2A) by promoting tyrosine phosphorylation, implicating an imbalance in tau kinase/phosphatase. Thus, targeting the miR-124/PTPN1 signaling pathway is a promising therapeutic strategy for AD.