Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment

Naoto Watamura, Junya Toba, Aya Yoshii, Miyu Nikkuni, Toshio Ohshima

    Research output: Contribution to journalArticle

    8 Citations (Scopus)

    Abstract

    Alzheimer's disease (AD) is the most common type of dementia among the elderly. Neurofibrillary tangles (NFTs), a major pathological hallmark of AD, are composed of tau protein that is hyperphosphorylated by cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK3β). NFTs also contain Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) and collapsin response-mediator protein 2 (CRMP2). Although Cdk5 is known to phosphorylate tau, WAVE1, and CRMP2, the significance of this with respect to NFT formation remains to be elucidated. This study examines the involvement of phosphorylated (p-) CRMP2 and WAVE1 in p-tau aggregates using a triple-transgenic (3×Tg; APPswe/PS1M146V/tauP301L) AD mouse model. First, we verified the colocalization of p-WAVE1 and p-CRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates. To test the significance of phosphorylation of these proteins further, we administered all-trans-retinoic acid (ATRA) to the 3×Tg mice, which downregulates Cdk5 and GSK3β activity. In ATRA-treated mice, fewer and smaller tau aggregates were observed compared with non-ATRA-treated mice. These results suggest the possibility of novel therapeutic target molecules for preventing tau pathology.

    Original languageEnglish
    Pages (from-to)15-26
    Number of pages12
    JournalJournal of Neuroscience Research
    Volume94
    Issue number1
    DOIs
    Publication statusPublished - 2016 Jan 1

    Fingerprint

    Tretinoin
    Cyclin-Dependent Kinase 5
    Alzheimer Disease
    Phosphorylation
    Neurofibrillary Tangles
    Wiskott-Aldrich Syndrome Protein Family
    Glycogen Synthase Kinase 3
    Therapeutics
    tau Proteins
    Dementia
    Hippocampus
    Down-Regulation
    collapsin response mediator protein-2
    Mouse Cdk5 protein
    Pathology
    Proteins

    Keywords

    • Alzheimer's disease
    • ATRA
    • CRMP2
    • Neurofibrillary tangle
    • Tau
    • WAVE1

    ASJC Scopus subject areas

    • Cellular and Molecular Neuroscience

    Cite this

    Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice : Involvement of Cdk5 phosphorylation and the effect of ATRA treatment. / Watamura, Naoto; Toba, Junya; Yoshii, Aya; Nikkuni, Miyu; Ohshima, Toshio.

    In: Journal of Neuroscience Research, Vol. 94, No. 1, 01.01.2016, p. 15-26.

    Research output: Contribution to journalArticle

    @article{d887d695dba04cdf9e32af4a5a367b29,
    title = "Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment",
    abstract = "Alzheimer's disease (AD) is the most common type of dementia among the elderly. Neurofibrillary tangles (NFTs), a major pathological hallmark of AD, are composed of tau protein that is hyperphosphorylated by cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK3β). NFTs also contain Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) and collapsin response-mediator protein 2 (CRMP2). Although Cdk5 is known to phosphorylate tau, WAVE1, and CRMP2, the significance of this with respect to NFT formation remains to be elucidated. This study examines the involvement of phosphorylated (p-) CRMP2 and WAVE1 in p-tau aggregates using a triple-transgenic (3×Tg; APPswe/PS1M146V/tauP301L) AD mouse model. First, we verified the colocalization of p-WAVE1 and p-CRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates. To test the significance of phosphorylation of these proteins further, we administered all-trans-retinoic acid (ATRA) to the 3×Tg mice, which downregulates Cdk5 and GSK3β activity. In ATRA-treated mice, fewer and smaller tau aggregates were observed compared with non-ATRA-treated mice. These results suggest the possibility of novel therapeutic target molecules for preventing tau pathology.",
    keywords = "Alzheimer's disease, ATRA, CRMP2, Neurofibrillary tangle, Tau, WAVE1",
    author = "Naoto Watamura and Junya Toba and Aya Yoshii and Miyu Nikkuni and Toshio Ohshima",
    year = "2016",
    month = "1",
    day = "1",
    doi = "10.1002/jnr.23674",
    language = "English",
    volume = "94",
    pages = "15--26",
    journal = "Journal of Neuroscience Research",
    issn = "0360-4012",
    publisher = "Wiley-Liss Inc.",
    number = "1",

    }

    TY - JOUR

    T1 - Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice

    T2 - Involvement of Cdk5 phosphorylation and the effect of ATRA treatment

    AU - Watamura, Naoto

    AU - Toba, Junya

    AU - Yoshii, Aya

    AU - Nikkuni, Miyu

    AU - Ohshima, Toshio

    PY - 2016/1/1

    Y1 - 2016/1/1

    N2 - Alzheimer's disease (AD) is the most common type of dementia among the elderly. Neurofibrillary tangles (NFTs), a major pathological hallmark of AD, are composed of tau protein that is hyperphosphorylated by cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK3β). NFTs also contain Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) and collapsin response-mediator protein 2 (CRMP2). Although Cdk5 is known to phosphorylate tau, WAVE1, and CRMP2, the significance of this with respect to NFT formation remains to be elucidated. This study examines the involvement of phosphorylated (p-) CRMP2 and WAVE1 in p-tau aggregates using a triple-transgenic (3×Tg; APPswe/PS1M146V/tauP301L) AD mouse model. First, we verified the colocalization of p-WAVE1 and p-CRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates. To test the significance of phosphorylation of these proteins further, we administered all-trans-retinoic acid (ATRA) to the 3×Tg mice, which downregulates Cdk5 and GSK3β activity. In ATRA-treated mice, fewer and smaller tau aggregates were observed compared with non-ATRA-treated mice. These results suggest the possibility of novel therapeutic target molecules for preventing tau pathology.

    AB - Alzheimer's disease (AD) is the most common type of dementia among the elderly. Neurofibrillary tangles (NFTs), a major pathological hallmark of AD, are composed of tau protein that is hyperphosphorylated by cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK3β). NFTs also contain Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) and collapsin response-mediator protein 2 (CRMP2). Although Cdk5 is known to phosphorylate tau, WAVE1, and CRMP2, the significance of this with respect to NFT formation remains to be elucidated. This study examines the involvement of phosphorylated (p-) CRMP2 and WAVE1 in p-tau aggregates using a triple-transgenic (3×Tg; APPswe/PS1M146V/tauP301L) AD mouse model. First, we verified the colocalization of p-WAVE1 and p-CRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates. To test the significance of phosphorylation of these proteins further, we administered all-trans-retinoic acid (ATRA) to the 3×Tg mice, which downregulates Cdk5 and GSK3β activity. In ATRA-treated mice, fewer and smaller tau aggregates were observed compared with non-ATRA-treated mice. These results suggest the possibility of novel therapeutic target molecules for preventing tau pathology.

    KW - Alzheimer's disease

    KW - ATRA

    KW - CRMP2

    KW - Neurofibrillary tangle

    KW - Tau

    KW - WAVE1

    UR - http://www.scopus.com/inward/record.url?scp=84945307161&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84945307161&partnerID=8YFLogxK

    U2 - 10.1002/jnr.23674

    DO - 10.1002/jnr.23674

    M3 - Article

    C2 - 26400044

    AN - SCOPUS:84945307161

    VL - 94

    SP - 15

    EP - 26

    JO - Journal of Neuroscience Research

    JF - Journal of Neuroscience Research

    SN - 0360-4012

    IS - 1

    ER -