Department of Pathophysiology, Key Lab of Neurological Disorder of Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China; Sino-Canada Collaborative Platform on Molecular Biology of Neurological Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
Department of Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China; Sino-Canada Collaborative Platform on Molecular Biology of Neurological Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
Biol Psychiatry. 2018 Mar 1;83(5):395-405. doi: 10.1016/j.biopsych.2017.07.023. Epub 2017 Aug 10.
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.
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.
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.
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.
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不清楚。最近，microRNAs（miRNAs）已成为调节突触功能和记忆的重要调控因子。
我们使用 miRNA 阵列和定量聚合酶链反应来检测 AD 小鼠和患者中 miRNAs 的变化，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酪氨酸蛋白磷酸酶非受体型 1（PTPN1）表达的沉默 RNA。长时程增强和高尔基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。
在这里，我们报告神经元 miR-124 在 Tg2576 小鼠（一种公认的 AD 小鼠模型）的海马体中显著增加。在受影响的 AD 个体的特定大脑区域也观察到了类似的变化。我们进一步确定 PTPN1 是 miR-124 的直接靶标。miR-124 的过表达或 PTPN1 的敲低在小鼠中再现了 AD 样表型，包括突触传递和可塑性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 途径，可以恢复突触功能障碍和记忆缺陷。
综上所述，这些结果确定了 miR-124/PTPN1 途径是 AD 中突触功能障碍和记忆丧失的关键介质，miR-124/PTPN1 途径可被视为 AD 患者有前途的新型治疗靶标。
