Accumulation of amyloid-β peptide (Aβ) is a pathological hallmark of Alzheimer’s disease (AD). We have previously demonstrated that electrophysiological and neurotoxic effects of Aβ and human amylin are expressed via the amylin receptor. Recently, pramlintide, a synthetic analog of amylin, has been reported to improve cognitive function in transgenic AD mouse models. In this study, we examined the effects of pramlintide on Aβ1–42 and human amylin-evoked depression of long-term potentiation (LTP) at Schaeffer collateral-CA1 hippocampal synapses. In mouse hippocampal brain slices, field excitatory postsynaptic potentials (fEPSPs) were recorded from the stratum radiatum layer of the CA1 area in response to electrical stimulation of Schaeffer collateral afferents and LTP induced by 3-theta-burst stimulation (TBS) protocol. Aβ1–42 (50 nM) and human amylin (50 nM), but not Aβ42–1 (50 nM), depressed LTP. Pre-application of pramlintide (250 nM) blocked Aβ- and human amylin-induced reduction of LTP without affecting baseline transmission or LTP. We also examined the effects of pramlintide on LTP in transgenic mice (TgCRND8) that over-express amyloid precursor protein. In contrast to wild-type controls, where robust LTP was observed, 10- to 12-month-old TgCRND8 mice show blunted LTP. In TgCRND8 mice, basal LTP is enhanced by application of pramlintide. Our data indicate that pramlintide acts as a functional amylin receptor antagonist to reverse the effects of Aβ1–42 and human amylin on LTP and also increases LTP in transgenic mice that demonstrate increased ambient brain amyloid levels. Amylin receptor antagonists may thus serve as potentially useful therapeutic agents in treatment of AD.
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This research was supported by funding from the Canadian Institutes of Health Research (MOP 93601 to JHJ) and the Alberta Prion Research Institute (APRI 201400009 to DW). RK was a recipient of an Alberta Innovates—Health Solutions Visiting Scientist award.
Compliance with Ethical Standards
All experiments were carried out in compliance with the relevant laws and guidelines set by the Canadian Council for Animal Care and with the approval of the Human Research Ethics Board and Animal Care Use Committee (Health Sciences) at the University of Alberta.
Conflict of Interest
The authors declare that they have no competing interests.
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