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

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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.

Original languageEnglish
Pages (from-to)180-185
Number of pages6
JournalNeuroscience Research
Volume77
Issue number3
DOIs
Publication statusPublished - 01-11-2013
Externally publishedYes

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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

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

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. In: Neuroscience Research. 2013 ; Vol. 77, No. 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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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, vol. 77, no. 3, pp. 180-185. https://doi.org/10.1016/j.neures.2013.08.005

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.

In: Neuroscience Research, Vol. 77, No. 3, 01.11.2013, p. 180-185.

Research output: Contribution to journalArticle

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T1 - Amyloid-β25-35 induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2

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

PY - 2013/11/1

Y1 - 2013/11/1

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.

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