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    Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents

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    Authors
    Qi, Yingjie
    Klyubin, Igor
    Harney, Sarah C
    Hu, NengWei
    Cullen, William K
    Grant, Marianne K
    Steffen, Julia
    Wilson, Edward N
    Do Carmo, Sonia
    Remy, Stefan
    Fuhrmann, Martin
    Ashe, Karen H
    Cuello, A C
    Rowan, Michael J
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    Issue Date
    2014-12-24
    Keywords
    ALZHEIMER'S DISEASE
    NEUROLOGY
    
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    Citation
    Acta Neuropathologica Communications. 2014 Dec 24;2(1):175
    URI
    http://dx.doi.org/10.1186/s40478-014-0175-x
    http://hdl.handle.net/10147/575160
    Abstract
    Abstract Long before synaptic loss occurs in Alzheimer’s disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Aß in a very complete model of Alzheimer’s disease amyloidosis, the McGill-R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2–3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor-mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Aß antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the γ-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Aß selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer’s disease amyloidosis.
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