title: Pramlintide Antagonizes Beta Amyloid (Aβ)- and Human Amylin-Induced Depression of Hippocampal Long-Term Potentiation.
abstract: 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 Aβ1-42and 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 Aβ1-42and 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.
authors.affiliation: Faculty of Engineering, Tokyo University of Science, Yamaguchi, Sanyo-onoda, Yamaguchi, Japan.|Department of Medicine (Neurology), University of Alberta, Edmonton, AB, T6G 2S2, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Kimura
authors.affiliation: Department of Medicine (Neurology), University of Alberta, Edmonton, AB, T6G 2S2, Canada.|Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
authors.forename: D
authors.initials: D
authors.lastname: MacTavish
authors.affiliation: Department of Medicine (Neurology), University of Alberta, Edmonton, AB, T6G 2S2, Canada.|Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2S2, Canada.|Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Medicine (Neurology), University of Alberta, Edmonton, AB, T6G 2S2, Canada.|Department of Biochemistry, University of Alberta, Edmonton, AB, T6G 2S2, Canada.|Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2S2, Canada.|Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Westaway
authors.affiliation: Department of Medicine (Neurology), University of Alberta, Edmonton, AB, T6G 2S2, Canada. jack.jhamandas@ualberta.ca.|Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2S2, Canada. jack.jhamandas@ualberta.ca.
authors.forename: Jack H
authors.initials: JH
authors.lastname: Jhamandas
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity
chemical_list: D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C105254:pramlintide
keywords: Alzheimer’s disease; Amylin receptor; Amyloid; Diabetes; Hippocampus; LTP; Synaptic plasticity