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Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis

Inès R.H. Ben-Nejma, Aneta J. Keliris, Jasmijn Daans, View ORCID ProfilePeter Ponsaerts, Marleen Verhoye, View ORCID ProfileAnnemie Van der Linden, View ORCID ProfileGeorgios A. Keliris
doi: https://doi.org/10.1101/723981
Inès R.H. Ben-Nejma
1Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp Belgium
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  • For correspondence: Ines.Ben-Nejma@uantwerpen.be georgios.keliris@uantwerpen.be
Aneta J. Keliris
1Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp Belgium
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Jasmijn Daans
2Experimental Cell transplantation Group, Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp Belgium
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Peter Ponsaerts
2Experimental Cell transplantation Group, Laboratory of Experimental Hematology, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp Belgium
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  • ORCID record for Peter Ponsaerts
Marleen Verhoye
1Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp Belgium
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Annemie Van der Linden
1Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp Belgium
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  • ORCID record for Annemie Van der Linden
Georgios A. Keliris
1Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp Belgium
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  • ORCID record for Georgios A. Keliris
  • For correspondence: Ines.Ben-Nejma@uantwerpen.be georgios.keliris@uantwerpen.be
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ABSTRACT

Background Alzheimer’s disease (AD) is the most common form of dementia in the elderly population. Currently, no effective cure is available for AD. According to the amyloid hypothesis, the accumulation and deposition of the amyloid-beta (Aβ) peptides plays a key role in AD pathology. Soluble Aβ (sAβ) oligomers were shown to be synaptotoxic and involved in pathological hypersynchronisation of brain resting-state networks in different transgenic developmental-onset mouse models of amyloidosis. However, the impact of protein overexpression during brain postnatal development may cause additional phenotypes unrelated to AD. To address this concern, we investigated sAβ effects on functional resting-state networks in transgenic mature-onset amyloidosis Tet-Off APP (TG) mice.

Methods TG mice and control littermates were raised on doxycycline (DOX) diet from 3d up to 3m of age to suppress transgenic Aβ production. Thereafter, longitudinal resting-state functional MRI was performed on a 9.4T MR-system starting from week 0 (3m old mice) up to 28w post DOX treatment. Ex vivo immunohistochemistry and ELISA analysis (additional mice cohort) was performed to address the development of amyloid pathology.

Results Functional Connectivity (FC) analysis demonstrated early abnormal hypersynchronisation in the TG mice compared to the controls at 8w post DOX treatment. This effect was observed particularly across regions of the default mode-like network, known to be affected in AD. Ex vivo analyses performed at this time point confirmed a 20-fold increase in total sAβ levels and the absence of Aβ plaques in the TG mice compared to the controls. On the contrary at week 28, TG mice showed an overall hypoconnectivity, coinciding with a widespread deposition of Aβ plaques in the brain.

Conclusions By preventing developmental influence of APP and/or sAβ during brain postnatal development, we demonstrated FC abnormalities driven by sAβ synaptotoxicity on resting state neuronal networks in mature-induced TG mice. Thus, the Tet-Off APP mouse model could be a powerful tool while used as a mature-onset model to shed light into amyloidosis mechanisms in AD. Therefore, this inducible APP expression model used in combination with early non-invasive in vivo rsfMRI readout for sAβ synaptotoxicity sets the stage for future Aβ targeting preventative treatment studies.

  • ABBREVIATIONS

    (s)Aβ
    (soluble) amyloid-beta
    AD
    Alzheimer’s disease
    ANTs
    Advanced Normalization Tools
    APP
    amyloid precursor protein
    BOLD
    blood oxygen level-dependent
    CamKIIα
    calmodulin-dependent protein kinase type II alpha chain
    Ctrl
    control
    DEA
    diethylamine
    DMN
    default mode (like) network
    DOX
    doxycycline
    EEG
    electroencephalography
    ELISA
    enzyme-linked immunosorbent assay
    EPI
    echo planar imaging
    fAD
    familial form of AD
    FC
    functional connectivity
    GE
    gradient echo
    ICA
    independent component analysis
    NFTs
    neurofibrillary tangles
    PBS
    Phosphate-buffered saline
    PCR
    polymerase chain reaction
    ROI
    region of interest
    rsfMRI
    resting state functional magnetic resonance imaging
    sAD
    sporadic form of AD
    tetO
    tetracycline-responsive
    TG
    Tet-Off APP
    tTA
    tetracycline-Transactivator
    VOI
    volume of interest
    WT
    wild type
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted August 03, 2019.
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    Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis
    Inès R.H. Ben-Nejma, Aneta J. Keliris, Jasmijn Daans, Peter Ponsaerts, Marleen Verhoye, Annemie Van der Linden, Georgios A. Keliris
    bioRxiv 723981; doi: https://doi.org/10.1101/723981
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    Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis
    Inès R.H. Ben-Nejma, Aneta J. Keliris, Jasmijn Daans, Peter Ponsaerts, Marleen Verhoye, Annemie Van der Linden, Georgios A. Keliris
    bioRxiv 723981; doi: https://doi.org/10.1101/723981

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