Amyloid-β25-35 induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2

Toshinari Isono, Naoya Yamashita, Masami Obara, Tomomi Araki, Fumio Nakamura, Yoshinori Kamiya, Tursun Alkam, Atsumi Nitta, Toshitaka Nabeshima, Katsuhiko Mikoshiba, Toshio Ohshima, Yoshio Goshima

    研究成果: Article

    23 引用 (Scopus)

    抄録

    Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) protein and tau deposition in the brain. Numerous studies have reported a central role of Aβ in the development of AD, but the pathogenesis is not well understood. Collapsin response mediator protein 2 (CRMP2), an intracellular protein mediating a repulsive axon guidance molecule, Semaphorin3A, is also accumulated in neurofibrillary tangles in AD brains. To gain insight into the role of CRMP2 phosphorylation in AD pathogenesis, we investigated the effects of Aβ neurotoxicity in CRMP2 phosphorylation-deficient knock-in (crmp2ki/ki) mice, in which the serine residue at 522 was replaced with alanine. Intracerebroventricular (i.c.v.) injection of Aβ25-35 peptide, a neurotoxic fragment of Aβ protein, to wild-type (wt) mice increased hippocampal phosphorylation of CRMP2. Behavioral assessment revealed that i.c.v. injection of Aβ25-35 peptide caused impairment of novel object recognition in wt mice, while the same peptide did not in crmp2ki/ki mice. In electrophysiological recording, wt and crmp2ki/ki mice have similar input-output basal synaptic transmission and paired-pulse ratios. However, long-term potentiation was impaired in hippocampal slices of Aβ25-35 peptide-treated wt but not those of crmp2ki/ki. Our findings indicate that CRMP2 phosphorylation is required for Aβ-induced impairment of cognitive memory and synaptic plasticity.

    元の言語English
    ページ(範囲)180-185
    ページ数6
    ジャーナルNeuroscience Research
    77
    発行部数3
    DOI
    出版物ステータスPublished - 2013 11

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    Long-Term Potentiation
    Amyloid
    Cognition
    Phosphorylation
    Alzheimer Disease
    Peptides
    Serum Amyloid A Protein
    Neurofibrillary Tangles
    Injections
    Neuronal Plasticity
    Brain
    Synaptic Transmission
    Alanine
    Serine
    Proteins
    collapsin response mediator protein-2

    ASJC Scopus subject areas

    • Neuroscience(all)

    これを引用

    Amyloid-β25-35 induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2. / Isono, Toshinari; Yamashita, Naoya; Obara, Masami; Araki, Tomomi; Nakamura, Fumio; Kamiya, Yoshinori; Alkam, Tursun; Nitta, Atsumi; Nabeshima, Toshitaka; Mikoshiba, Katsuhiko; Ohshima, Toshio; Goshima, Yoshio.

    :: Neuroscience Research, 巻 77, 番号 3, 11.2013, p. 180-185.

    研究成果: Article

    Isono, T, Yamashita, N, Obara, M, Araki, T, Nakamura, F, Kamiya, Y, Alkam, T, Nitta, A, Nabeshima, T, Mikoshiba, K, Ohshima, T & Goshima, Y 2013, 'Amyloid-β25-35 induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2', Neuroscience Research, 巻. 77, 番号 3, pp. 180-185. https://doi.org/10.1016/j.neures.2013.08.005
    Isono, Toshinari ; Yamashita, Naoya ; Obara, Masami ; Araki, Tomomi ; Nakamura, Fumio ; Kamiya, Yoshinori ; Alkam, Tursun ; Nitta, Atsumi ; Nabeshima, Toshitaka ; Mikoshiba, Katsuhiko ; Ohshima, Toshio ; Goshima, Yoshio. / Amyloid-β25-35 induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2. :: Neuroscience Research. 2013 ; 巻 77, 番号 3. pp. 180-185.
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    abstract = "Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) protein and tau deposition in the brain. Numerous studies have reported a central role of Aβ in the development of AD, but the pathogenesis is not well understood. Collapsin response mediator protein 2 (CRMP2), an intracellular protein mediating a repulsive axon guidance molecule, Semaphorin3A, is also accumulated in neurofibrillary tangles in AD brains. To gain insight into the role of CRMP2 phosphorylation in AD pathogenesis, we investigated the effects of Aβ neurotoxicity in CRMP2 phosphorylation-deficient knock-in (crmp2ki/ki) mice, in which the serine residue at 522 was replaced with alanine. Intracerebroventricular (i.c.v.) injection of Aβ25-35 peptide, a neurotoxic fragment of Aβ protein, to wild-type (wt) mice increased hippocampal phosphorylation of CRMP2. Behavioral assessment revealed that i.c.v. injection of Aβ25-35 peptide caused impairment of novel object recognition in wt mice, while the same peptide did not in crmp2ki/ki mice. In electrophysiological recording, wt and crmp2ki/ki mice have similar input-output basal synaptic transmission and paired-pulse ratios. However, long-term potentiation was impaired in hippocampal slices of Aβ25-35 peptide-treated wt but not those of crmp2ki/ki. Our findings indicate that CRMP2 phosphorylation is required for Aβ-induced impairment of cognitive memory and synaptic plasticity.",
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    AU - Isono, Toshinari

    AU - Yamashita, Naoya

    AU - Obara, Masami

    AU - Araki, Tomomi

    AU - Nakamura, Fumio

    AU - Kamiya, Yoshinori

    AU - Alkam, Tursun

    AU - Nitta, Atsumi

    AU - Nabeshima, Toshitaka

    AU - Mikoshiba, Katsuhiko

    AU - Ohshima, Toshio

    AU - Goshima, Yoshio

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    N2 - Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) protein and tau deposition in the brain. Numerous studies have reported a central role of Aβ in the development of AD, but the pathogenesis is not well understood. Collapsin response mediator protein 2 (CRMP2), an intracellular protein mediating a repulsive axon guidance molecule, Semaphorin3A, is also accumulated in neurofibrillary tangles in AD brains. To gain insight into the role of CRMP2 phosphorylation in AD pathogenesis, we investigated the effects of Aβ neurotoxicity in CRMP2 phosphorylation-deficient knock-in (crmp2ki/ki) mice, in which the serine residue at 522 was replaced with alanine. Intracerebroventricular (i.c.v.) injection of Aβ25-35 peptide, a neurotoxic fragment of Aβ protein, to wild-type (wt) mice increased hippocampal phosphorylation of CRMP2. Behavioral assessment revealed that i.c.v. injection of Aβ25-35 peptide caused impairment of novel object recognition in wt mice, while the same peptide did not in crmp2ki/ki mice. In electrophysiological recording, wt and crmp2ki/ki mice have similar input-output basal synaptic transmission and paired-pulse ratios. However, long-term potentiation was impaired in hippocampal slices of Aβ25-35 peptide-treated wt but not those of crmp2ki/ki. Our findings indicate that CRMP2 phosphorylation is required for Aβ-induced impairment of cognitive memory and synaptic plasticity.

    AB - Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) protein and tau deposition in the brain. Numerous studies have reported a central role of Aβ in the development of AD, but the pathogenesis is not well understood. Collapsin response mediator protein 2 (CRMP2), an intracellular protein mediating a repulsive axon guidance molecule, Semaphorin3A, is also accumulated in neurofibrillary tangles in AD brains. To gain insight into the role of CRMP2 phosphorylation in AD pathogenesis, we investigated the effects of Aβ neurotoxicity in CRMP2 phosphorylation-deficient knock-in (crmp2ki/ki) mice, in which the serine residue at 522 was replaced with alanine. Intracerebroventricular (i.c.v.) injection of Aβ25-35 peptide, a neurotoxic fragment of Aβ protein, to wild-type (wt) mice increased hippocampal phosphorylation of CRMP2. Behavioral assessment revealed that i.c.v. injection of Aβ25-35 peptide caused impairment of novel object recognition in wt mice, while the same peptide did not in crmp2ki/ki mice. In electrophysiological recording, wt and crmp2ki/ki mice have similar input-output basal synaptic transmission and paired-pulse ratios. However, long-term potentiation was impaired in hippocampal slices of Aβ25-35 peptide-treated wt but not those of crmp2ki/ki. Our findings indicate that CRMP2 phosphorylation is required for Aβ-induced impairment of cognitive memory and synaptic plasticity.

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    KW - Cyclin-dependent kinase 5

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    KW - Neurotoxicity

    KW - Novel object recognition

    KW - Phosphorylation

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