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FTY720 Attenuates Infection-Induced Enhancement of Aβ Accumulation in APP/PS1 Mice by Modulating Astrocytic Activation

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Abstract

It is well established that infection has a significant detrimental effect on patients with Alzheimer’s disease (AD), accelerating cognitive decline and, even in healthy ageing individuals, increasing amyloid-β (Aβ) accumulation in the brain. In animal models of AD infection can also cause damage, with evidence of increased neuroinflammation, amyloid pathology and deterioration of cognitive function. These changes are against a backdrop of an age- and AD-related increase in susceptibility to infection. Here we set out to determine whether FTY720, a molecule that binds sphingosine-1-phosphate (S1P) receptors and with known immunosuppressant effects mediating its therapeutic action in multiple sclerosis (MS), might modulate the impact of infection in a mouse model of AD. Transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice) and their littermates were/were not infected with Bordetella pertussis and were treated orally with FTY720 or vehicle beginning 3 days before infection. Infection increased astrocytic activation and enhanced blood brain barrier (BBB) permeability and these changes were attenuated in FTY720-treated B. pertussis-infected mice. Significantly, infection increased Aβ containing plaques and soluble Aβ and these infection-related changes were also attenuated in FTY720-treated B. pertussis-infected mice. The data suggest that this effect results from an FTY720-induced increase in Aβ phagocytosis by astrocytes. FTY720 did not impact on genotype-related changes in the absence of an infection indicating that its potential usefulness is restricted to reducing the impact of acute inflammatory stimuli in AD.

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Acknowledgments

This work was supported by grants from Science Foundation Ireland to KHGM (11/PI/1036) and MAL (11/PI/10154) and an Innovation Bursary (to KHGM and MAL from Trinity College Dublin).

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Authors and Affiliations

  1. Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland

    Róisín M. McManus, Orla M Finucane & Marina A. Lynch

  2. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland

    Róisín M. McManus, Mieszko M. Wilk & Kingston H. G. Mills

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  1. Róisín M. McManus
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  2. Orla M Finucane
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  3. Mieszko M. Wilk
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  4. Kingston H. G. Mills
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  5. Marina A. Lynch
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Correspondence to Marina A. Lynch.

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Conflict of Interest

Kingston Mills is a co-founder and shareholder in Opsona Therapeutics Ltd. and TriMod Therapeutics Ltd., university spin-out companies involved in the development of immunotherapeutics.

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McManus, R.M., Finucane, O.M., Wilk, M.M. et al. FTY720 Attenuates Infection-Induced Enhancement of Aβ Accumulation in APP/PS1 Mice by Modulating Astrocytic Activation. J Neuroimmune Pharmacol 12, 670–681 (2017). https://doi.org/10.1007/s11481-017-9753-6

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  • DOI: https://doi.org/10.1007/s11481-017-9753-6

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