title: Learning impairment by minimal cortical injury in a mouse model of Alzheimer's disease.
abstract: Brain injury accelerates amyloid-β (Aβ) deposits and exacerbates Alzheimer's disease (AD). Accumulation of intracellular soluble Aβ impairs cognition prior to emergence of Aβ plaques. However, it is not known whether brain injury affects learning impairment attributable to intracellular soluble Aβ. We made a small injury by injecting glutamate into the parietal cortex in 3xTg AD mice of 4-5 months old, at which age soluble Aβ is accumulated without Aβ deposits. The size of glutamate-induced lesion was significantly larger than that of saline-injected control lesion. We reduced the relative difficulty of Morris water maze (MWM) task by repeating it twice, so that saline-injected 3xTg mice could perform as well as wild-type control mice. Under this condition, glutamate-injected 3xTg mice exhibited learning deficits. DNA microarray analysis revealed that 3 genes are upregulated, with one gene downregulated, more than 2 folds in the hippocampus. These 4 genes do not appear to be involved directly in learning but may be a part of signal cascade triggered by glutamate-induced small injury. Hippocampal content of soluble Aβ1-42 was increased in the glutamate 3xTg group. Facilitation of large-conductance calcium-activated potassium (BK) channel accompanied learning recovery in the saline-control 3xTg group in agreement with our previous reports, in which learning deficits attributable to intracellular Aβ were alleviated by facilitating BK channels. However, BK channel remained suppressed in the glutamate 3xTg group. It is suggested that glutamate-induced injury worsens learning by enhancing the toxicity of soluble Aβ or increasing its content per se.
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; Department of Neurosurgery, Kanazawa Medical University, Ishikawa 920-0293, Japan; First Affiliated Hospital, China Medical University, Shenyang 110001, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Uchiumi
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shui
authors.affiliation: Medical Research Institute, Kanazawa Medical University, Ishikawa 920-0293, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Ishigaki
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan; Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Tajima
authors.affiliation: Department of Neurosurgery, Kanazawa Medical University, Ishikawa 920-0293, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Akai
authors.affiliation: Department of Neurosurgery, Kanazawa Medical University, Ishikawa 920-0293, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Iizuka
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan. Electronic address: kato@kanazawa-med.ac.jp.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kato
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism; D010296:Parietal Lobe / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009498:Neurotoxins; D010446:Peptide Fragments; D018698:Glutamic Acid
keywords: BK channel; Brain injury; DNA microarray; Excitotoxicity; Morris water maze