Advertisement

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

  • Xiong Wang
    Affiliations
    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
    Search for articles by this author
  • Dan Liu
    Affiliations
    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
    Search for articles by this author
  • He-Zhou Huang
    Affiliations
    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
    Search for articles by this author
  • Zhi-Hao Wang
    Affiliations
    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
    Search for articles by this author
  • Tong-Yao Hou
    Affiliations
    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
    Search for articles by this author
  • Xin Yang
    Affiliations
    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
    Search for articles by this author
  • Pei Pang
    Affiliations
    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
    Search for articles by this author
  • Na Wei
    Affiliations
    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
    Search for articles by this author
  • Ya-Fan Zhou
    Affiliations
    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
    Search for articles by this author
  • Marie-Josée Dupras
    Affiliations
    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
    Search for articles by this author
  • Frédéric Calon
    Affiliations
    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
    Search for articles by this author
  • Yu-Tian Wang
    Affiliations
    Brain Research Centre and Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
    Search for articles by this author
  • Heng-Ye Man
    Affiliations
    Department of Biology, Boston University, Boston, Massachusetts
    Search for articles by this author
  • Jian-Guo Chen
    Affiliations
    Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China
    Search for articles by this author
  • Jian-Zhi Wang
    Affiliations
    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
    Search for articles by this author
  • Sébastien S. Hébert
    Affiliations
    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
    Search for articles by this author
  • Youming Lu
    Affiliations
    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
    Search for articles by this author
  • Ling-Qiang Zhu
    Correspondence
    Address correspondence to Ling-Qiang Zhu, Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, No. 13, Hangkong Road, Wuhan, 430030, P. R. China.
    Affiliations
    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
    Search for articles by this author

      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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Selkoe D.J.
        Alzheimer's disease is a synaptic failure.
        Science. 2002; 298: 789-791
        • Sivanesan S.
        • Tan A.
        • Rajadas J.
        Pathogenesis of Abeta oligomers in synaptic failure.
        Curr Alzheimer Res. 2013; 10: 316-323
        • Mucke L.
        • Selkoe D.J.
        Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction.
        Cold Spring Harb Perspect Med. 2012; 2: a006338
        • Cavallucci V.
        • D'Amelio M.
        • Cecconi F.
        Abeta toxicity in Alzheimer's disease.
        Molecular neurobiology. 2012; 45: 366-378
        • Marcello E.
        • Epis R.
        • Saraceno C.
        • Di Luca M.
        Synaptic dysfunction in Alzheimer's disease.
        Adv Exp Med Biol. 2012; 970: 573-601
        • Arbel-Ornath M.
        • Hudry E.
        • Boivin J.R.
        • Hashimoto T.
        • Takeda S.
        • Kuchibhotla K.V.
        • et al.
        Soluble oligomeric amyloid-beta induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain.
        Mol Neurodegener. 2017; 12: 27
        • Selkoe D.J.
        Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior.
        Behav Brain Res. 2008; 192: 106-113
        • Shankar G.M.
        • Li S.
        • Mehta T.H.
        • Garcia-Munoz A.
        • Shepardson N.E.
        • Smith I.
        • et al.
        Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
        Nat Med. 2008; 14: 837-842
        • Knobloch M.
        • Farinelli M.
        • Konietzko U.
        • Nitsch R.M.
        • Mansuy I.M.
        Abeta oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms.
        J Neurosci. 2007; 27: 7648-7653
        • Martinez Jr., J.L.
        • Derrick B.E.
        Long-term potentiation and learning.
        Ann Rev Psychol. 1996; 47: 173-203
        • Roselli F.
        • Tirard M.
        • Lu J.
        • Hutzler P.
        • Lamberti P.
        • Livrea P.
        • et al.
        Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses.
        J Neurosci. 2005; 25: 11061-11070
        • D'Amelio M.
        • Cavallucci V.
        • Middei S.
        • Marchetti C.
        • Pacioni S.
        • Ferri A.
        • et al.
        Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease.
        Nat Neurosci. 2011; 14: 69-76
        • Hoover B.R.
        • Reed M.N.
        • Su J.
        • Penrod R.D.
        • Kotilinek L.A.
        • Grant M.K.
        • et al.
        Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration.
        Neuron. 2010; 68: 1067-1081
        • Siegel G.
        • Saba R.
        • Schratt G.
        microRNAs in neurons: manifold regulatory roles at the synapse.
        Curr Opin Genet Dev. 2011; 21: 491-497
        • Schratt G.
        microRNAs at the synapse.
        Nat Rev Neurosci. 2009; 10: 842-849
        • Femminella G.D.
        • Ferrara N.
        • Rengo G.
        The emerging role of microRNAs in Alzheimer's disease.
        Front Physiol. 2015; 6: 40
        • Delay C.
        • Mandemakers W.
        • Hebert S.S.
        MicroRNAs in Alzheimer's disease.
        Neurobiol Dis. 2012; 46: 285-290
        • Hebert S.S.
        • Horre K.
        • Nicolai L.
        • Papadopoulou A.S.
        • Mandemakers W.
        • Silahtaroglu A.N.
        • et al.
        Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression.
        Proc Natl Acad Sci U S A. 2008; 105: 6415-6420
        • Hebert S.S.
        • Horre K.
        • Nicolai L.
        • Bergmans B.
        • Papadopoulou A.S.
        • Delacourte A.
        • et al.
        MicroRNA regulation of Alzheimer's Amyloid precursor protein expression.
        Neurobiol Dis. 2009; 33: 422-428
        • Smith P.Y.
        • Hernandez-Rapp J.
        • Jolivette F.
        • Lecours C.
        • Bisht K.
        • Goupil C.
        • et al.
        miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo.
        Hum Mol Genet. 2015; 24: 6721-6735
        • Smith P.Y.
        • Delay C.
        • Girard J.
        • Papon M.A.
        • Planel E.
        • Sergeant N.
        • et al.
        MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy.
        Hum Mol Genet. 2011; 20: 4016-4024
        • Julien C.
        • Tremblay C.
        • Bendjelloul F.
        • Phivilay A.
        • Coulombe M.A.
        • Emond V.
        • et al.
        Decreased drebrin mRNA expression in Alzheimer disease: correlation with tau pathology.
        J Neurosci Res. 2008; 86: 2292-2302
        • He N.
        • Jin W.L.
        • Lok K.H.
        • Wang Y.
        • Yin M.
        • Wang Z.J.
        Amyloid-beta(1-42) oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2.
        Cell Death Dis. 2013; 4: e924
        • Wang S.H.
        • Liao X.M.
        • Liu D.
        • Hu J.
        • Yin Y.Y.
        • Wang J.Z.
        • et al.
        NGF promotes long-term memory formation by activating poly(ADP-ribose)polymerase-1.
        Neuropharmacology. 2012; 63: 1085-1092
        • Jacobsen J.S.
        • Wu C.C.
        • Redwine J.M.
        • Comery T.A.
        • Arias R.
        • Bowlby M.
        • et al.
        Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease.
        Proc Natl Acad Sci U S A. 2006; 103: 5161-5166
        • Sempere L.F.
        • Freemantle S.
        • Pitha-Rowe I.
        • Moss E.
        • Dmitrovsky E.
        • Ambros V.
        Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation.
        Genome Biol. 2004; 5: R13
        • Rajasethupathy P.
        • Fiumara F.
        • Sheridan R.
        • Betel D.
        • Puthanveettil S.V.
        • Russo J.J.
        • et al.
        Characterization of small RNAs in Aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB.
        Neuron. 2009; 63: 803-817
        • Garcia D.M.
        • Baek D.
        • Shin C.
        • Bell G.W.
        • Grimson A.
        • Bartel D.P.
        Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs.
        Nat Struct Mol Biol. 2011; 18: 1139-1146
        • Huang da W.
        • Sherman B.T.
        • Lempicki R.A.
        Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.
        Nat Protoc. 2009; 4: 44-57
        • Bourdeau A.
        • Dube N.
        • Tremblay M.L.
        Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP.
        Curr Opin Cell Biol. 2005; 17: 203-209
        • Van Vactor D.
        Protein tyrosine phosphatases in the developing nervous system.
        Curr Opin Cell Biol. 1998; 10: 174-181
        • Uetani N.
        • Kato K.
        • Ogura H.
        • Mizuno K.
        • Kawano K.
        • Mikoshiba K.
        • et al.
        Impaired learning with enhanced hippocampal long-term potentiation in PTPdelta-deficient mice.
        EMBO J. 2000; 19: 2775-2785
        • Moult P.R.
        • Gladding C.M.
        • Sanderson T.M.
        • Fitzjohn S.M.
        • Bashir Z.I.
        • Molnar E.
        • et al.
        Tyrosine phosphatases regulate AMPA receptor trafficking during metabotropic glutamate receptor-mediated long-term depression.
        J Neurosci. 2006; 26: 2544-2554
        • Lim S.H.
        • Kwon S.K.
        • Lee M.K.
        • Moon J.
        • Jeong D.G.
        • Park E.
        • et al.
        Synapse formation regulated by protein tyrosine phosphatase receptor T through interaction with cell adhesion molecules and Fyn.
        EMBO J. 2009; 28: 3564-3578
        • Fuentes F.
        • Zimmer D.
        • Atienza M.
        • Schottenfeld J.
        • Penkala I.
        • Bale T.
        • et al.
        Protein tyrosine phosphatase PTP1B is involved in hippocampal synapse formation and learning.
        PLoS One. 2012; 7: e41536
        • Yang Y.
        • Shu X.
        • Liu D.
        • Shang Y.
        • Wu Y.
        • Pei L.
        • et al.
        EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation.
        Neuron. 2012; 73: 774-788
        • Hayashi T.
        • Huganir R.L.
        Tyrosine phosphorylation and regulation of the AMPA receptor by SRC family tyrosine kinases.
        J Neurosci. 2004; 24: 6152-6160
        • Filipovska A.
        • Razif M.F.
        • Nygard K.K.
        • Rackham O.
        A universal code for RNA recognition by PUF proteins.
        Nat Chem Biol. 2011; 7: 425-427
        • Smith P.
        • Al Hashimi A.
        • Girard J.
        • Delay C.
        • Hebert S.S.
        In vivo regulation of amyloid precursor protein neuronal splicing by microRNAs.
        J Neurochem. 2011; 116: 240-247
        • Lukiw W.J.
        Micro-RNA speciation in fetal, adult and Alzheimer's disease hippocampus.
        Neuroreport. 2007; 18: 297-300
        • Fang M.
        • Wang J.
        • Zhang X.
        • Geng Y.
        • Hu Z.
        • Rudd J.A.
        • et al.
        The miR-124 regulates the expression of BACE1/beta-secretase correlated with cell death in Alzheimer's disease.
        Toxicol Lett. 2012; 209: 94-105
        • Makeyev E.V.
        • Zhang J.
        • Carrasco M.A.
        • Maniatis T.
        The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.
        Mol Cell. 2007; 27: 435-448
        • Cheng L.C.
        • Pastrana E.
        • Tavazoie M.
        • Doetsch F.
        miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche.
        Nat Neurosci. 2009; 12: 399-408
        • Liu X.S.
        • Chopp M.
        • Zhang R.L.
        • Tao T.
        • Wang X.L.
        • Kassis H.
        • et al.
        MicroRNA profiling in subventricular zone after stroke: MiR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway.
        PLoS One. 2011; 6: e23461
        • Ho V.M.
        • Dallalzadeh L.O.
        • Karathanasis N.
        • Keles M.F.
        • Vangala S.
        • Grogan T.
        • et al.
        GluA2 mRNA distribution and regulation by miR-124 in hippocampal neurons.
        Mol Cell Neurosci. 2014; 61: 1-12

      Linked Article

      • Micromanaging Memory
        Biological PsychiatryVol. 83Issue 5
        • Preview
          Making human memories involves a complicated orchestration of genetic, biochemical, and cellular processes. Although much remains unknown, considerable progress has been made in the study of memory processing, consolidation, storage, and retention. In addition, molecular pathways underlying memory impairments in neurodegenerative and other neurological diseases are beginning to be revealed. In this issue of Biological Psychiatry, Wang et al. (1) contribute to this ever-growing field of research by uncovering a novel molecular signaling pathway that mediates memory deficits in Alzheimer’s disease (AD).
        • Full-Text
        • PDF