• Open Access

Mutant presenilin-1 deregulated peripheral immunity exacerbates Alzheimer-like pathology

Authors

  • Yuyan Zhu,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL, USA
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    • These authors contributed equally to this work.

  • Demian Obregon,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL, USA
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    • These authors contributed equally to this work.

  • Huayan Hou,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL, USA
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    • These authors contributed equally to this work.

  • Brian Giunta,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL, USA
    2. Neuroimmunology Laboratory, Department of Psychiatry & Behavioral Medicine; College of Medicine, University of South Florida, Tampa, FL, USA
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  • Jared Ehrhart,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL, USA
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  • Frank Fernandez,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL, USA
    2. Neuroimmunology Laboratory, Department of Psychiatry & Behavioral Medicine; College of Medicine, University of South Florida, Tampa, FL, USA
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  • Takashi Mori,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL, USA
    2. Departments of Medical Science and Pathology, Saitama Medical Center/Saitama Medical University, Kawagoe, Japan
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  • William Nikolic,

    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL, USA
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  • Yangbing Zhao,

    1. Departments of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • Dave Morgan,

    1. Alzheimer Research Laboratory, Department of Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, Tampa, FL, USA
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  • Terrence Town,

    1. Departments of Neurosurgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    2. Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
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  • Jun Tan

    Corresponding author
    1. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL, USA
    2. Neuroimmunology Laboratory, Department of Psychiatry & Behavioral Medicine; College of Medicine, University of South Florida, Tampa, FL, USA
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Correspondence to: Dr. Jun TAN, Neuroimmunology Laboratory,
Department of Psychiatry & Behavioral Medicine,
College of Medicine, University of South Florida,
3515 E Fletcher Ave. Tampa, FL 33613, USA.
Tel.: 813-0974-9326
Fax: 813-0974-3223
E-mail: jtan@hsc.usf.edu

Abstract

Mutations in the presenilin-1 (PS1) gene are independent causes of familial Alzheimer's disease (AD). AD patients have dysregulated immunity, and PS1 mutant mice exhibit abnormal systemic immune responses. To test whether immune function abnormality caused by a mutant human PS1 gene (mhPS1) could modify AD-like pathology, we reconstituted immune systems of AD model mice carrying a mutant human amyloid precursor protein gene (mhAPP; Tg2576 mice) or both mhAPP and mhPS1 genes (PSAPP mice) with allo-geneic bone marrow cells. Here, we report a marked reduction in amyloid-β (Aβ) levels, β-amyloid plaques and brain inflammatory responses in PSAPP mice following strain-matched wild-type PS1 bone marrow reconstitution. These effects occurred with immune switching from pro-inflammatory T helper (Th) 1 to anti-inflammatory Th2 immune responses in the periphery and in the brain, which likely instructed microglia to phagocytose and clear Aβ in an ex vivo assay. Conversely, Tg2576 mice displayed accelerated AD-like pathology when reconstituted with mhPS1 bone marrow. These data show that haematopoietic cells bearing the mhPS1 transgene exacerbate AD-like pathology, suggesting a novel therapeutic strategy for AD based on targeting PS1 in peripheral immune cells.

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