title: Targeted introduction of V642I mutation in amyloid precursor protein gene causes functional abnormality resembling early stage of Alzheimer's disease in aged mice.
abstract: While the exact aetiology of Alzheimer's disease (AD) is unknown, distinct genetic mutations have been identified for the rare cases of familial AD (FAD). V642I mutation in amyloid precursor protein (APP) co-segregates with FAD with perfect penetration, and the clinicopathological characteristics of patients with this mutation resemble that of sporadic AD. To examine the pathogenic process of this FAD-linked trait in vivo, we produced a mouse with the corresponding point mutation in the APP gene using homologous recombination and Cre-loxP site-specific recombination ('knock-in' technique). Mice with the heterozygous V642I-APP allele most precisely reflected the genotype of humans bearing this mutation. For the observation period of 2.5 years the mutants stayed apparently indistinguishable from the wild-type littermates. However, behavioural analysis revealed significantly deteriorated long-term memory in mutants when examined for the retention of spatial attention. Interestingly, acquisition of spatial memory was slightly affected but short-term working memory was not deteriorated at all. Histological examination was negative for formation of neuritic plaques or neurofibrillary tangles, whereas the relative amount of longer form of beta-amyloid species A beta 42(43) was significantly increased against that of the shorter form (A beta 40) in the mutant brain homogenates. We conclude that a V642I-APP mutant allele in aged mice confers functional components, but not organic components, of the AD-related phenotype that are observed in the early stage of AD. This V642I-APP knock-in mutant line may serve as a model to study the early pathogenic processes of AD in vivo and to develop therapeutics for this stage.
authors.affiliation: Department of Pharmacology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masaoki
authors.initials: M
authors.lastname: Kawasumi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Chiba
authors.forename: Marina
authors.initials: M
authors.lastname: Yamada
authors.forename: Makiko
authors.initials: M
authors.lastname: Miyamae-Kaneko
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Jin
authors.initials: J
authors.lastname: Nakahara
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Sadakazu
authors.initials: S
authors.lastname: Aiso
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nishimoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kouyama
mesh_terms: D000367:Age Factors; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal; D015139:Blotting, Southern / Q000379:methods; D001923:Brain Chemistry; D002755:Choice Behavior / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007532:Isoleucine / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000235:genetics; D009154:Mutation; D016874:Neurofibrillary Tangles; D010446:Peptide Fragments / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011930:Reaction Time / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012737:Sex Factors; D015996:Survival Rate; D014633:Valine / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D007532:Isoleucine; D014633:Valine