Xiong Wang1, Dan Liu2, He-Zhou Huang1, Zhi-Hao Wang3, Tong-Yao Hou1, Xin Yang3, Pei Pang3, Na Wei3, Ya-Fan Zhou3, Marie-Josée Dupras4, Frédéric Calon4, Yu-Tian Wang5, Heng-Ye Man6, Jian-Guo Chen7, Jian-Zhi Wang3, Sébastien S Hébert8, Youming Lu9, Ling-Qiang Zhu10. 1. 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. 2. 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. 3. 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. 4. 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 Psychiatry and Neuroscience, Université Laval, Québec City, Québec, Canada. 5. Brain Research Centre and Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 6. Department of Biology, Boston University, Boston, Massachusetts. 7. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China. 8. 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 Psychiatry and Neuroscience, Université Laval, Québec City, Québec, Canada; Centre de recherche du CHU de Québec, Axe Neurosciences, Québec City, Québec, Canada. 9. Department of Physiology, 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; Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, P. R. China. 10. 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; Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, P. R. China. Electronic address: zhulq@mail.hust.edu.cn.
Abstract
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.
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 ADmice 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 ADmouse 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 ADpatients.