Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice

Authors

  • Fabrizio Trinchese MD,

    1. Department of Psychiatry, New York University School of Medicine, New York
    2. The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY
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  • Shumin Liu MD,

    1. Department of Psychiatry, New York University School of Medicine, New York
    2. The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY
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  • Fortunato Battaglia MD, PhD,

    1. Department of Psychiatry, New York University School of Medicine, New York
    2. The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY
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  • Sean Walter MA,

    1. Department of Psychiatry, New York University School of Medicine, New York
    2. The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY
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  • Paul M. Mathews PhD,

    1. Department of Psychiatry, New York University School of Medicine, New York
    2. The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY
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  • Ottavio Arancio MD, PhD

    Corresponding author
    1. Department of Psychiatry, New York University School of Medicine, New York
    2. The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY
    3. Department of Physiology and Neuroscience, New York University School of Medicine, New York
    • Department of Pathology and Taub Institute, P&S Building #12-442, 630 W 168th Street, New York, NY 10032
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Abstract

Increasing evidence points to synaptic plasticity impairment as one of the first events in Alzheimer's disease (AD). However, studies on synaptic dysfunction in different transgenic AD models that overexpress familial AD mutant forms of amyloid precursor protein (APP) and/or presenilin (PS) have provided conflicting results. Both long-term potentiation (LTP) and basal synaptic transmission (BST) have been found to be both unchanged and altered in different models and under differing experimental conditions. Because of their more robust amyloid-β (Aβ) deposition, double transgenic mice currently are used by several laboratories as an AD model. Here, we report that mice overexpressing APP (K670N:M671L) together with PS1 (M146L) have abnormal LTP as early as 3 months of age. Interestingly, reduced LTP paralleled plaque appearance and increased Aβ levels and abnormal short-term memory (working memory). BST and long-term memory (reference memory) are impaired only later (approximately 6 months) as amyloid burden increases. Aβ pathology across different ages did not correlate with synaptic and cognitive deficits, suggesting that Aβ levels are not a marker of memory decline. In contrast, progression of LTP impairment correlated with the deterioration of working memory, suggesting that percentage of potentiation might be an indicator of the cognitive decline and disease progression in the APP/PS1 mice. Ann Neurol 2004;55:801–814

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