Archival ReportA Novel MicroRNA-124/PTPN1 Signal Pathway Mediates Synaptic and Memory Deficits in Alzheimer’s Disease
Section snippets
AD Transgenic Mice
Male Tg2576 transgenic mice and nontransgenic littermates, which express the human 695-amino acid isoform of APP containing the Swedish double mutation, were used. These mice were purchased from the Jackson Laboratory (Bar Harbor, ME) and bred in the Experimental Animal Central of Tongji Medical College, Huazhong University of Science and Technology. This study was approved by Animal Care and Use Committee of Tongji Medical College.
Human Brain Samples
Brain tissues of nondementia control subjects and AD cases
Impaired miR-124/PTPN1 Pathway in AD Patients and Mouse Models
To identify miRNAs involved in AD-related synaptic alterations and memory impairment, the miRNA microarray was performed on the hippocampus of 12-month-old Tg2576 mice in which synaptic plasticity was severely impaired and cellular Aβ was highly accumulated (25). As indicated by the microarray heatmap (Figure 1A) and validated by quantitative reverse transcription polymerase chain reaction, we detected a number of brain-enriched miRNAs (26) that were significantly abnormally expressed in Tg2576
Discussion
Our study uncovers a novel signaling pathway of Aβ-induced pathological alterations in AD, implicating both upstream and downstream effectors of miR-124. Based on these findings, a peptide inhibitor, R-124P, that specifically disrupts the miR-124-PTPN1 interaction was designed. We have demonstrated that administration of R-124P in AD mice effectively reverses the deficits of both synaptic transmission and memory. Thus, this study provides a potential novel therapeutic strategy for the
Acknowledgments and Disclosures
This work was supported by National Natural Science Foundation of China Grant Nos. 91632114, 31571039, and 81771150 (to L-QZ) and 31721002 (to YL); National Program for Support of Top-Notch Young Professionals and Academic Frontier Youth Team of Huazhong University of Science and Technology (to L-QZ); Program for Changjiang Scholars and Innovative Research Team in University Grant No. IRT13016 (to J-GC); and joint Fonds de recherché du Québec–Santé and National Natural Science Foundation of
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Cited by (0)
XW, DL, and H-ZH contributed equally to this work.