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The Journal of Neuroscience, March 1, 2002, 22(5):1858-1867

The Relationship between A and Memory in the Tg2576 Mouse Model of Alzheimer's Disease

Marcus A. Westerman¹, Deirdre Cooper-Blacketer¹, Ami Mariash¹, Linda Kotilinek¹, Takeshi Kawarabayashi², Linda H. Younkin², George A. Carlson³, Steven G. Younkin², and Karen H. Ashe¹

¹ Departments of Neurology and Neuroscience, Center for Clinical and Molecular Neurobiology, University of Minnesota, Minneapolis, Minnesota 55455, ² Mayo Clinic Jacksonville, Jacksonville, Florida 32224, and ³ McLaughlin Research Institute, Great Falls, Montana 59405

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 APP. 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 A aggregates (A_insol). Genetically accelerating the formation of A_insol resulted in an earlier onset of memory decline. A facile interpretation of these results, namely that memory loss and A_insol were closely connected, was rejected when we extended our analysis to include older mice. No obvious correspondence between memory and A_insol was apparent in a combined group of old and young mice unless the mice were stratified by age, whereupon inverse correlations between memory and A_insol became evident. These results suggested that A_insol is a surrogate marker for small assemblies of A that disrupt cognition and occur as intermediates during A_insol 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 A assemblies in vivo.

Key words: Alzheimer's disease; transgenic; behavior; A; SDS-soluble; insoluble; learning; memory

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2251858-10$05.00/0

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