Autoreactive-Aβ antibodies promote APP β-secretase processing

Authors

  • Juan Deng,

    1. Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry and Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
    2. Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China
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    • These authors contributed to this work equally.

  • Huayan Hou,

    1. Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry and Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
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    • These authors contributed to this work equally.

  • Brian Giunta,

    1. Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry and Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
    2. Neuroimmunology Laboratory, Department of Psychiatry and Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
    3. James A. Haley Veterans’ Hospital, Tampa, Florida, USA
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  • Takashi Mori,

    1. Departments of Biomedical Sciences and Pathology, Saitama Medical Center and Saitama Medical University, Kawagoe, Saitama, Japan
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  • Yan-Jiang Wang,

    1. Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China
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  • Frank Fernandez,

    1. Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry and Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
    2. Neuroimmunology Laboratory, Department of Psychiatry and Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
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  • Sascha Weggen,

    1. Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany
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  • Wataru Araki,

    1. Department of Demyelinating Disease and Aging, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
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  • Demian Obregon,

    1. Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry and Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
    2. James A. Haley Veterans’ Hospital, Tampa, Florida, USA
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  • Jun Tan

    1. Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry and Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
    2. James A. Haley Veterans’ Hospital, Tampa, Florida, USA
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Address correspondence and reprint requests to Jun Tan, Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry and Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA. E-mail: jtan@health.usf.edu.

Abstract

J. Neurochem. (2012) 120, 732–740.

Abstract

Several prior investigations of Alzheimer’s disease (AD) patients have indicated naturally occurring autoantibodies against amyloid-β (Aβ) species are produced. Although many studies have focused on the relative concentrations or binding affinities of autoantibodies against Aβ-related proteins in AD and aging, data regarding their functional properties are limited. It is generally believed that these antibodies act to aid in clearance of Aβ. However, as antibodies which bind to Aβ also typically bind to the parent amyloid precursor protein (APP), we reasoned that certain Aβ-targeting autoantibodies may bind to APP thereby altering its conformation and processing. Here we show for the first time, that naturally occurring Aβ-reactive autoantibodies isolated from AD patients, but not from healthy controls, promote β-secretase activity in cultured cells. Furthermore, using monoclonal antibodies to various regions of Aβ, we found that antibodies generated against the N-terminal region, especially Aβ1-17, dose dependently promoted amyloidogenic processing of APP viaβ-secretase activation. Thus, this property of certain autoantibodies in driving Aβ generation could be of etiological importance in the development of sporadic forms of AD. Furthermore, future passive or active anti-Aβ immunotherapies must consider potential off-target effects resulting from antibodies targeting the N-terminus of Aβ, as co-binding to the corresponding region of APP may actually enhance Aβ generation.

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