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    The MK2 cascade mediates transient alteration in mGluR-LTD and spatial learning in a murine model of Alzheimer's disease

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    Muller_et_al_Aging_Cell (1.401Mb)
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    Publication date
    2022-10
    Author
    Privitera, Lucia
    Hogg, Ellen L.
    Lopes, M.
    Domingos, L.B.
    Gaestel, M.
    Muller, Jurgen
    Wall, M.J.
    Corrêa, Sonia A.L.
    Keyword
    APP/PS1 mouse
    Arc/Arg3.1
    Hippocampus
    mGluR5 signalling
    p38 MAPK signalling
    Synaptic plasticity
    Rights
    © 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
    Peer-Reviewed
    Yes
    Open Access status
    openAccess
    
    Metadata
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    Abstract
    A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APPswe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling.
    URI
    http://hdl.handle.net/10454/19174
    Version
    Published version
    Citation
    Privitera L, Hogg EL, Lopes M et al (2022) The MK2 cascade mediates transient alteration in mGluR-LTD and spatial learning in a murine model of Alzheimer's disease. Aging Cell. 21(10): e13717.
    Link to publisher’s version
    https://doi.org/10.1111/acel.13717
    Type
    Article
    Collections
    Life Sciences Publications

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