The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer's disease

Marcus A. Westerman, Deirdre Cooper-Blacketer, Ami Mariash, Linda Kotilinek, Takeshi Kawarabayashi, Linda H. Younkin, George A. Carlson, Steven G. Younkin, Karen H. Ashe

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Transgenic mice expressing mutant amyloid precursor proteins (APPs) have provided important new information about the pathogenesis of Alzheimer's disease (AD) histopathology. However, the molecular basis of memory loss in these mice is poorly understood. One of the major impediments has been the difficulty of distinguishing between age-dependent and age-independent behavioral changes. To address this issue we studied in parallel two lines of APP transgenic mice expressing comparable levels of mutant and wild-type human APR. This enabled us to identify age-independent behavioral deficits that were not specifically related to mutant APP expression. When mice with age-independent deficits were eliminated, we detected memory loss in transgenic mice expressing mutant APP (Tg2576 mice) starting at ∼6 months, which coincided with the appearance of detergent-insoluble Aβ aggregates (Aβinsol) Genetically accelerating the formation of Aβinsol resulted in an earlier onset of memory decline. A facile interpretation of these results, namely that memory loss and Aβinsol were closely connected, was rejected when we extended our analysis to include older mice. No obvious correspondence between memory and Aβinsol was apparent in a combined group of old and young mice unless the mice were stratified by age, whereupon inverse correlations between memory and Aβinsol became evident. These results suggested that Aβinsol is a surrogate marker for small assemblies of Aβ that disrupt cognition and occur as intermediates during Aβinsol formation, and they are the first descriptive in vivo data supporting their role in impairing memory. These studies also provide a methodological framework within which to investigate these Aβ assemblies in vivo.

Original languageEnglish (US)
Pages (from-to)1858-1867
Number of pages10
JournalJournal of Neuroscience
Issue number5
StatePublished - Mar 1 2002


  • Alzheimer's disease
  • Behavior
  • Insoluble
  • Learning
  • Memory
  • SDS-soluble
  • Transgenic


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