title: Amyloid-β₂₅₋₃₅ induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2.
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 (crmp2(ki/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 crmp2(ki/ki) mice. In electrophysiological recording, wt and crmp2(ki/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 crmp2(ki/ki). Our findings indicate that CRMP2 phosphorylation is required for Aβ-induced impairment of cognitive memory and synaptic plasticity.
authors.affiliation: Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; Division of Physics, Electrical and Computer Engineering, Yokohama National University Graduate School of Engineering, Yokohama 240-8501, Japan.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Isono
authors.forename: Naoya
authors.initials: N
authors.lastname: Yamashita
authors.forename: Masami
authors.initials: M
authors.lastname: Obara
authors.forename: Tomomi
authors.initials: T
authors.lastname: Araki
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakamura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kamiya
authors.forename: Tursun
authors.initials: T
authors.lastname: Alkam
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Goshima
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D006624:Hippocampus / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity; D010766:Phosphorylation; D021641:Recognition, Psychology / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C095114:collapsin response mediator protein-2
keywords: 3,3′-Diaminobenzidine; AD; Alzheimer's disease; Aβ; CRMP2; Cdk5; Cyclin-dependent kinase 5; DAB; GSK-3β; IP; Knock-in mice; LTP; Neurotoxicity; Novel object recognition; PBS; Phosphorylation; Sema3A; amyloid-β; collapsin response mediator protein 2; cyclin-dependent kinase 5; fEPSP; field excitatory postsynaptic potentials; glycogen synthase kinase-3β; i.c.v.; immunoprecipitation; intracerebroventricular; long term potentiation; phosphate buffered saline; semaphorin3A