Elsevier

Biological Psychiatry

Volume 83, Issue 5, 1 March 2018, Pages 395-405
Biological Psychiatry

Archival Report
A Novel MicroRNA-124/PTPN1 Signal Pathway Mediates Synaptic and Memory Deficits in Alzheimer’s Disease

https://doi.org/10.1016/j.biopsych.2017.07.023Get rights and content

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.

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

References (45)

  • M. Fang et al.

    The miR-124 regulates the expression of BACE1/beta-secretase correlated with cell death in Alzheimer's disease

    Toxicol Lett

    (2012)
  • E.V. Makeyev et al.

    The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing

    Mol Cell

    (2007)
  • V.M. Ho et al.

    GluA2 mRNA distribution and regulation by miR-124 in hippocampal neurons

    Mol Cell Neurosci

    (2014)
  • D.J. Selkoe

    Alzheimer's disease is a synaptic failure

    Science

    (2002)
  • S. Sivanesan et al.

    Pathogenesis of Abeta oligomers in synaptic failure

    Curr Alzheimer Res

    (2013)
  • L. Mucke et al.

    Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction

    Cold Spring Harb Perspect Med

    (2012)
  • V. Cavallucci et al.

    Abeta toxicity in Alzheimer's disease

    Molecular neurobiology

    (2012)
  • E. Marcello et al.

    Synaptic dysfunction in Alzheimer's disease

    Adv Exp Med Biol

    (2012)
  • M. Arbel-Ornath et al.

    Soluble oligomeric amyloid-beta induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain

    Mol Neurodegener

    (2017)
  • G.M. Shankar et al.

    Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory

    Nat Med

    (2008)
  • M. Knobloch et al.

    Abeta oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms

    J Neurosci

    (2007)
  • J.L. Martinez et al.

    Long-term potentiation and learning

    Ann Rev Psychol

    (1996)
  • Cited by (0)

    XW, DL, and H-ZH contributed equally to this work.

    View full text