Delayed amyloid plaque deposition and behavioral deficits in outcrossed AβPP/PS1 mice

Authors

  • Brian A. Couch,

    1. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520
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    • The first two authors contributed equally to this work.

  • Meghan E. Kerrisk,

    1. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520
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    • The first two authors contributed equally to this work.

  • Adam C. Kaufman,

    1. Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520
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  • Haakon B. Nygaard,

    1. Department of Neurology, Yale University, New Haven, Connecticut 06520
    2. Department of Neurobiology, Yale University, New Haven, Connecticut 06520
    3. Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University, New Haven, Connecticut 06536
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  • Stephen M. Strittmatter,

    1. Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520
    2. Department of Neurology, Yale University, New Haven, Connecticut 06520
    3. Department of Neurobiology, Yale University, New Haven, Connecticut 06520
    4. Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University, New Haven, Connecticut 06536
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  • Anthony J. Koleske

    Corresponding author
    1. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520
    2. Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520
    3. Department of Neurobiology, Yale University, New Haven, Connecticut 06520
    4. Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University, New Haven, Connecticut 06536
    • Department of Molecular Biophysics and Biochemistry, Yale University, 333 Cedar St., SHM CE-31, New Haven, CT 06520
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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative dementia characterized by amyloid plaque accumulation, synapse/dendrite loss, and cognitive impairment. Transgenic mice expressing mutant forms of amyloid-β precursor protein (AβPP) and presenilin-1 (PS1) recapitulate several aspects of this disease and provide a useful model system for studying elements of AD progression. AβPP/PS1 mice have been previously shown to exhibit behavioral deficits and amyloid plaque deposition between 4–9 months of age. We crossed AβPP/PS1 animals with mice of a mixed genetic background (C57BL/6 × 129/SvJ) and investigated the development of AD-like features in the resulting outcrossed mice. The onset of memory-based behavioral impairment is delayed considerably in outcrossed AβPP/PS1 mice relative to inbred mice on a C57BL/6 background. While inbred AβPP/PS1 mice develop deficits in radial-arm water maze performance and novel object recognition as early as 8 months, outcrossed AβPP/PS1 mice do not display defects until 18 months. Within the forebrain, we find that inbred AβPP/PS1 mice have significantly higher amyloid plaque burden at 12 months than outcrossed AβPP/PS1 mice of the same age. Surprisingly, inbred AβPP/PS1 mice at 8 months have low plaque burden, suggesting that plaque burden alone cannot explain the accompanying behavioral deficits. Analysis of AβPP processing revealed that elevated levels of soluble Aβ correlate with the degree of behavioral impairment in both strains. Taken together, these findings suggest that animal behavior, amyloid plaque deposition, and AβPP processing are sensitive to genetic differences between mouse strains. J. Comp. Neurol., 521:1395–1408, 2013. © 2012 Wiley Periodicals, Inc.

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