TY - JOUR
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
Y1 - 2013/11
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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U2 - 10.1016/j.neures.2013.08.005
DO - 10.1016/j.neures.2013.08.005
M3 - Article
C2 - 23994236
AN - SCOPUS:84886598885
SN - 0168-0102
VL - 77
SP - 180
EP - 185
JO - Neuroscience Research
JF - Neuroscience Research
IS - 3
ER -