Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APPSWE

Alena V. Savonenko, Guilian M. Xu, Donald L. Price, David R. Borchelt, Alicja L. Markowska

Research output: Contribution to journalArticle

Abstract

Amyloid deposition appears to be an early and crucial event in Alzheimer's disease (AD). To generate animal models of AD, mice expressing full-length amyloid precursor protein (APP), with mutations linked to FAD, have been created. These animals exhibit abnormalities characteristic of AD, including deposits of β-amyloid (Aβ), neuritic plaques, and glial responses. In studies of cognition in these animals, there have been several reports of memory disturbances well before the appearance of amyloid deposits. We have developed two distinct lines of transgenic mice (C3-3 and E1-2) that express the "Swedish" variant of APP (APPSWE) at levels that are approximately three-fold higher than endogenous mouse APP. Both lines have been backcrossed to C57BL/6J mice for 10 generations. Here, we use longitudinal and cross-sectional studies to evaluate the cognitive performance of our animals, where the concentration of Aβ1-42 in brain increases with aging from low levels (2-10 pmol/g) at 6-14 months of age to relatively high levels (60-100 pmol/g) at 24-26 months, when deposits of Aβ were beginning to form. When 12-month-old mice were tested in tasks that assess reference and working memory, transgenic mice from both lines could not be distinguished from nontransgenic littermates. Further study of 24- to 26-month-old transgenic mice (C3-3 line) found no evidence of memory impairment despite the presence of high levels of human Aβ (60-100 pmol/g). Thus, the expression of APPSWE at approximately three-fold over endogenous levels, which is sufficient to induce amyloid deposition at advanced ages, does not significantly erode cognitive performance in aged mice.

Original languageEnglish (US)
Pages (from-to)194-211
Number of pages18
JournalNeurobiology of Disease
Volume12
Issue number3
DOIs
StatePublished - Apr 2003

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Keywords

  • Aging
  • Cross-sectional
  • Longitudinal
  • Memory
  • Place discrimination
  • Water maze
  • β-Amyloid

ASJC Scopus subject areas

  • Neurology

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