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Amyloid plaque deposition accelerates tau propagation via activation of microglia in a humanized APP mouse model

Kevin A. Clayton, Jean Christophe Delpech, Shawn Herron, Naotoshi Iwahara, Takashi Saito, Takaomi C. Saido, Seiko Ikezu, View ORCID ProfileTsuneya Ikezu
doi: https://doi.org/10.1101/2020.09.22.308015
Kevin A. Clayton
1Departments of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
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Jean Christophe Delpech
1Departments of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
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Shawn Herron
1Departments of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
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Naotoshi Iwahara
1Departments of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
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Takashi Saito
2Department of Neurocognitive Science, Nagoya City University, Nagoya, Aichi, Japan
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Takaomi C. Saido
3Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako, Saitama, Japan
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Seiko Ikezu
1Departments of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
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Tsuneya Ikezu
1Departments of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA
4Department of Neurology, Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA, 02118, USA
5Center for Systems Neuroscience, Boston University, Boston, MA, 02215, USA
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  • ORCID record for Tsuneya Ikezu
  • For correspondence: tikezu@bu.edu
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Abstract

Microglia have an emerging role in development of tau pathology after amyloid plaque deposition in Alzheimer’s disease, although it has not been definitively shown. We hypothesize that plaque-associated activated microglia accelerate tau propagation via enhanced phagocytosis and secretion of tau. Here we show that the injection of adeno-associated virus expressing P301L tau mutant into the medial entorhinal cortex (MEC) in humanized APPNL-G-F knock-in mice induces exacerbated tau propagation in the dentate gyrus compared to wild type mice. Depletion of microglia dramatically reduces accumulation of phosphorylated tau (pTau) in the dentate gyrus as well as an extracellular vesicle (EV) marker, Tumor susceptibility gene 101, co-localized in microglia. Mac2+ activated microglia secrete significantly more EVs compared to Mac2− microglia in APPNL-G-F mice in vivo when injected with lentivirus expressing EV reporter gene mEmerald-CD9, suggesting enhanced EV secretion by microglial activation. Our findings indicate that amyloid plaque-mediated acceleration of tau propagation is dependent on activated microglia, which show enhanced EV secretion in vivo.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    AAV
    adeno-associated virus
    Aβ
    amyloid-β peptide
    AD
    Alzheimer’s disease
    APOE
    Apolipoprotein E
    CA1
    Cornus Ammonis 1
    Clec7A
    C-type lectin domain family 7 member A
    CSF1R
    Colony stimulating factor 1 receptor
    DG
    Dentate Gyrus
    EVs
    Extracellular vesicles
    GCL
    granule cell layer
    GFAP
    Glial fibrillary acidic protein
    HEK293
    Human embryonic kidney cells
    mE-CD9
    mEmerald-CD9 conjugate
    MGnD
    Disease-associated neurodegenerative microglia
    MEC
    Medial Entorhinal Cortex
    mi9RT
    tandem miR-9 target sequence
    NFTs
    neurofibrillary tangles
    OML
    outer molecular layer
    PFA
    paraformaldehyde
    pTau
    phosphorylated-Tau
    TA
    Temporoammonic
    TREM2
    Triggering Receptor Expressed on Myeloid Cells 2
    Tsg101
    Tumor susceptibility gene 101
    WT
    wild type
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    Posted September 22, 2020.
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    Amyloid plaque deposition accelerates tau propagation via activation of microglia in a humanized APP mouse model
    Kevin A. Clayton, Jean Christophe Delpech, Shawn Herron, Naotoshi Iwahara, Takashi Saito, Takaomi C. Saido, Seiko Ikezu, Tsuneya Ikezu
    bioRxiv 2020.09.22.308015; doi: https://doi.org/10.1101/2020.09.22.308015
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    Amyloid plaque deposition accelerates tau propagation via activation of microglia in a humanized APP mouse model
    Kevin A. Clayton, Jean Christophe Delpech, Shawn Herron, Naotoshi Iwahara, Takashi Saito, Takaomi C. Saido, Seiko Ikezu, Tsuneya Ikezu
    bioRxiv 2020.09.22.308015; doi: https://doi.org/10.1101/2020.09.22.308015

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