Kimura R, MacTavish D, Yang J, Westaway D, Jhamandas Jack H
Faculty of Engineering, Tokyo University of Science, Yamaguchi, Sanyo-onoda, Yamaguchi, Japan.
Department of Medicine (Neurology), University of Alberta, Edmonton, AB, T6G 2S2, Canada.
Mol Neurobiol. 2017 Jan;54(1):748-754. doi: 10.1007/s12035-016-9684-x. Epub 2016 Jan 15.
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 Aβ 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. Aβ (50 nM) and human amylin (50 nM), but not Aβ (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 Aβ 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.
淀粉样β肽（Aβ）的积累是阿尔茨海默病（AD）的一个病理标志。我们之前已经证明，Aβ和人胰淀素的电生理及神经毒性作用是通过胰淀素受体来表达的。最近，有报道称胰淀素的合成类似物普兰林肽可改善转基因AD小鼠模型的认知功能。在本研究中，我们检测了普兰林肽对Aβ和人胰淀素诱发的海马体Schaeffer侧支-CA1突触长时程增强（LTP）抑制的影响。在小鼠海马脑片中，记录CA1区辐射层对Schaeffer侧支传入纤维电刺激的场兴奋性突触后电位（fEPSP），并通过3次θ波爆发刺激（TBS）方案诱导LTP。Aβ（50 nM）和人胰淀素（50 nM）可抑制LTP，但Aβ（50 nM）则不能。预先应用普兰林肽（250 nM）可阻断Aβ和人胰淀素诱导的LTP降低，而不影响基线传递或LTP。我们还检测了普兰林肽对过度表达淀粉样前体蛋白的转基因小鼠（TgCRND8）LTP的影响。与观察到强烈LTP的野生型对照不同，10至12月龄的TgCRND8小鼠表现出LTP减弱。在TgCRND8小鼠中，应用普兰林肽可增强基础LTP。我们的数据表明，普兰林肽作为一种功能性胰淀素受体拮抗剂，可逆转Aβ和人胰淀素对LTP的影响，还可增加脑内淀粉样蛋白水平升高的转基因小鼠的LTP。因此，胰淀素受体拮抗剂可能是治疗AD的潜在有用治疗药物。
