title: Cognitive deficits in single App knock-in mouse models.
abstract: Transgenic mouse models of Alzheimer's disease (AD) with nonphysiologic overexpression of amyloid precursor protein (APP) exhibit various unnatural symptoms/dysfunctions. To overcome this issue, mice with single humanized App knock-in (KI) carrying Swedish (NL), Beyreuther/Iberian (F), and Arctic (G) mutations in different combinations were recently developed. The validity of these mouse models of AD from a behavioral viewpoint, however, has not been extensively evaluated. Thus, using an automated behavior monitoring system, we analyzed various behavioral domains, including executive function, and learning and memory. The App-KI mice carrying NL-G-F mutations showed clear deficits in spatial memory and flexible learning, enhanced compulsive behavior, and reduced attention performance. Mice carrying NL-F mutations exhibited modest abnormalities. The NL-G-F mice had a greater and more rapid accumulation of Aβ deposits and glial responses. These findings reveal that single pathologic App-KI is sufficient to produce deficits in broad cognitive domains and that App-KI mouse lines with different levels of pathophysiology are useful models of AD.
authors.affiliation: Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: masuda-akira@brain.riken.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: snow-k@brain.riken.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: naomi_kogo@brain.riken.jp.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kogo
authors.affiliation: Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: takasai@brain.riken.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: saido@brain.riken.jp.
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.affiliation: Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: sitohara@brain.riken.jp.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D060825:Cognitive Dysfunction / Q000503:physiopathology*; D004195:Disease Models, Animal; D056344:Executive Function / Q000502:physiology*; D005260:Female; D007858:Learning / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D065852:Spatial Memory / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor
keywords: Alzheimer’s disease; Amyloid precursor protein; Cognition; IntelliCage; Model mouse; Sex