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Neurobiol Learn Mem. 2016 Nov;135:73-82. doi: 10.1016/j.nlm.2016.07.001. Epub 2016 Jul 1.

Cognitive deficits in single App knock-in mouse models.

Author information

1
Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: masuda-akira@brain.riken.jp.
2
Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: snow-k@brain.riken.jp.
3
Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: naomi_kogo@brain.riken.jp.
4
Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: takasai@brain.riken.jp.
5
Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: saido@brain.riken.jp.
6
Laboratory for Behavioral Genetics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: sitohara@brain.riken.jp.

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.

KEYWORDS:

Alzheimer’s disease; Amyloid precursor protein; Cognition; IntelliCage; Model mouse; Sex

PMID:
27377630
DOI:
10.1016/j.nlm.2016.07.001
[Indexed for MEDLINE]
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