BACKGROUND Synaptic loss is an early pathological event in Alzheimer's disease (AD), but its underlying molecular mechanisms remain largely unknown. Recently, microRNAs (miRNAs) have emerged as important modulators of synaptic function and memory. METHODS We used miRNA array and quantitative polymerase chain reaction to examine the alteration of miRNAs in AD mice and patients as well as the Morris water maze to evaluate learning and memory in the mice. We also used adeno-associated virus or lentivirus to introduce tyrosine-protein phosphatase non-receptor type 1 (PTPN1) expression of silencing RNAs. Long-term potentiation and Golgi staining were used to evaluate the synaptic function and structure. We designed a peptide to interrupt miR-124/PTPN1 interaction. RESULTS Here we report that neuronal miR-124 is dramatically increased in the hippocampus of Tg2576 mice, a recognized AD mouse model. Similar changes were observed in specific brain regions of affected AD individuals. We further identified PTPN1 as a direct target of miR-124. Overexpression of miR-124 or knockdown of PTPN1 recapitulated AD-like phenotypes in mice, including deficits in synaptic transmission and plasticity as well as memory by impairing the glutamate receptor 2 membrane insertion. Most importantly, rebuilding the miR-124/PTPN1 pathway by suppression of miR-124, overexpression of PTPN1, or application of a peptide that disrupts the miR-124/PTPN1 interaction could restore synaptic failure and memory deficits. CONCLUSIONS Taken together, these results identified the miR-124/PTPN1 pathway as a critical mediator of synaptic dysfunction and memory loss in AD, and the miR-124/PTPN1 pathway could be considered as a promising novel therapeutic target for AD patients.

中文翻译：

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一种新型 miR-124/PTPN1 信号通路介导阿尔茨海默病的突触和记忆缺陷

背景突触丢失是阿尔茨海默病 (AD) 的早期病理事件，但其潜在的分子机制在很大程度上仍然未知。最近，microRNA (miRNA) 已成为突触功能和记忆的重要调节剂。方法我们使用miRNA阵列和定量聚合酶链反应检测AD小鼠和患者中miRNA的改变，以及Morris水迷宫来评估小鼠的学习和记忆。我们还使用腺相关病毒或慢病毒来引入沉默 rna 的酪氨酸蛋白磷酸酶非受体 1 型 (PTPN1) 表达。长时程增强和高尔基体染色用于评估突触功能和结构。我们设计了一种肽来中断 miR-124/PTPN1 相互作用。结果 在此我们报告称，Tg2576 小鼠（一种公认的 AD 小鼠模型）的海马神经元 miR-124 显着增加。在受影响的 AD 个体的特定大脑区域中观察到类似的变化。我们进一步将 PTPN1 确定为 miR-124 的直接靶标。miR-124 的过表达或 PTPN1 的敲低重现了小鼠的 AD 样表型，包括突触传递和可塑性的缺陷以及通过损害谷氨酸受体 2 膜插入的记忆。最重要的是，通过抑制 miR-124、过表达 PTPN1 或应用破坏 miR-124/PTPN1 相互作用的肽来重建 miR-124/PTPN1 通路可以恢复突触失败和记忆缺陷。结论 综合起来，