Cognitive deficits in single App knock-in mouse models

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

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.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Protein Precursor / genetics*
  • Animals
  • Behavior, Animal / physiology*
  • Cognitive Dysfunction / physiopathology*
  • Disease Models, Animal
  • Executive Function / physiology*
  • Female
  • Learning / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Spatial Memory / physiology

Substances

  • Amyloid beta-Protein Precursor