Days to criterion as an indicator of toxicity associated with human Alzheimer amyloid-β oligomers

Authors

  • Sam Gandy MD, PhD,

    Corresponding author
    1. Department of Neurology, Mount Sinai School of Medicine, New York, NY
    2. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY
    3. Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY
    4. James J. Peters VA Medical Center, Bronx, NY
    • Departments of Neurology and Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1137, New York, NY 10029
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  • Adam J. Simon PhD,

    1. AJ Simon Enterprises LLC, Yardley, PA
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  • John W. Steele BA,

    1. Department of Neurology, Mount Sinai School of Medicine, New York, NY
    2. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY
    3. Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY
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  • Alex L. Lublin PhD,

    1. Department of Neurology, Mount Sinai School of Medicine, New York, NY
    2. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY
    3. Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY
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  • James J. Lah MD, PhD,

    1. Department of Neurology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA
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  • Lary C. Walker PhD,

    1. Department of Neurology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA
    2. Yerkes National Primate Research Center, Emory University, Atlanta, GA
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  • Allan I. Levey MD, PhD,

    1. Department of Neurology, Center for Neurodegenerative Disease, Emory University, Atlanta, GA
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  • Grant A. Krafft PhD,

    1. Acumen Pharmaceuticals, Inc., Livermore, CA
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  • Efrat Levy PhD,

    1. Departments of Psychiatry and Pharmacology, New York University School of Medicine, New York, NY
    2. Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY
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  • Frédéric Checler PhD,

    1. Fondation pour le Recherche Médicale, Institute of Molecular and Cellular Pharmacology, Valbonne, France
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  • Charles Glabe PhD,

    1. Department of Neurology, University of California at Irvine School of Medicine, Irvine, CA
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  • Warren B. Bilker PhD,

    1. Department of Biostatistics and Epidemiology, Philadelphia PA
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  • Ted Abel PhD,

    1. Department of Biology, University of Pennsylvania, Philadelphia PA
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  • James Schmeidler PhD,

    1. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY
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  • Michelle E. Ehrlich MD

    1. Department of Neurology, Mount Sinai School of Medicine, New York, NY
    2. Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY
    3. Department of Pediatrics, Mount Sinai School of Medicine, New York, NY
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Abstract

Objective

Recent evidence suggests that high molecular weight soluble oligomeric Aβ (oAβ) assemblies (also known as Aβ-derived diffusible ligands, or ADDLs) may represent a primary neurotoxic basis for cognitive failure in Alzheimer disease (AD). To date, most in vivo studies of oAβ/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid of human subjects with AD or from the conditioned media of Aβ-secreting cells into experimental animals. We sought to study the bioactivities of endogenously formed oAβ/ADDLs generated in situ from the physiological processing of human amyloid precursor protein (APP) and presenitin1 (PS1) transgenes.

Methods

We produced and histologically characterized single transgenic mice overexpressing APPE693Q or APPE693Q X PS1ΔE9 bigenic mice. APPE693Q mice were studied in the Morris water maze (MWM) task at 6 and 12 months of age. Following the second MWM evaluation, mice were sacrificed, and brains were assayed for Aβtotal, Aβ40, Aβ42, and oAβ/ADDLs by enzyme-linked immunosorbent assay (ELISA) and were also histologically examined. Based on results from the oAβ/ADDL ELISA, we assigned individual APPE693Q mice to either an undetectable oAβ/ADDLs group or a readily detectable oAβ/ADDLs group. A days to criterion (DTC) analysis was used to determine delays in acquisition of the MWM task.

Results

Both single transgenic and bigenic mice developed intraneuronal accumulation of APP/Aβ, although only APPE693Q X PS1Δ9 bigenic mice developed amyloid plaques. The APPE693Q mice did not develop amyloid plaques at any age studied, up to 30 months. APPE693Q mice were tested for spatial learning and memory, and only 12-month-old APPE693Q mice with readily detectable oAβ/ADDLs displayed a significant delay in acquisition of the MWM task when compared to nontransgenic littermates.

Interpretation

These data suggest that cerebral oAβ/ADDL assemblies generated in brain in situ from human APP transgenes may be associated with cognitive impairment. We propose that a DTC analysis may be a sensitive method for assessing the cognitive impact in mice of endogenously generated oligomeric human Aβ assemblies. ANN NEUROL 2010

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