Beta Amyloid-Induced Depression of Hippocampal Long-Term Potentiation Is Mediated through the Amylin Receptor

Department of Medicine, Hyogo College of Medicine, Nishinomiya, 663-8501, Hyogo, Japan, and Department of Medicine (Neurology) and Centre for Neuroscience, and Department of Biochemistry, Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2012; 32(48):17401-6. DOI: 10.1523/JNEUROSCI.3028-12.2012
Source: PubMed


Alzheimer's disease (AD) is characterized by accumulation of amyloid-β peptide (Aβ) in the brain regions that subserve memory and cognition. The amylin receptor is a potential target receptor for expression of the deleterious actions of soluble oligomeric Aβ species. We investigated whether the amylin receptor antagonist, AC253, neutralizes the depressant effects of Aβ(1-42) and human amylin on hippocampal long-term potentiation (LTP). Furthermore, we examined whether depressed levels of LTP observed in transgenic mice, which overexpress amyloid precursor protein (TgCRND8), could be restored with AC253. In mouse hippocampal brain slices, field EPSPs were recorded from the stratum radiatum layer of the CA1 area (cornu ammonis 1 region of the hippocampus) in response to electrical stimulation of Schaeffer collateral afferents. LTP was induced by 3-theta burst stimulation protocols. Aβ(1-42) (50 nm) and human amylin (50 nm), but not Aβ(42-1) (50 nm), depressed LTP evoked using both stimulation protocols. Preapplication of AC253 (250 nm) blocked Aβ- and human amylin-induced reduction of LTP without affecting baseline transmission or LTP on its own. In contrast to wild-type controls, where robust LTP is observed, 6- to 12-month-old TgCRND8 mice show blunted LTP that is significantly enhanced by application of AC253. Our data demonstrate that the effects of Aβ(1-42) and human amylin on LTP are expressed via the amylin receptor, and moreover, blockade of this receptor increases LTP in transgenic mice that show increased brain amyloid burden. Amylin receptor antagonists could serve as potentially useful therapeutic agents in AD.

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Available from: Ryoichi Kimura, Oct 16, 2014
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    • "Most of the in vivo and in vitro models of AD are based on alteration of amyloid precursor protein metabolism and accumulation of Aβ (Larson et al., 1999; Moechars et al., 1999; Chapman et al., 2001; Rowan et al., 2003). Soluble Aβ oligomers were repeatedly shown to induce long-term potentiation (LTP) impairment in both the dentate gyrus and the CA1 region of the hippocampus (Wang et al., 2002; Kimura et al., 2012). The possible mechanisms of this effect may include abnormal [Ca 2þ ] elevation, AMPA receptors phosphorylation and trafficking corruption and GSK-3 kinase activation (Hsieh et al., 2006; D'Amelio et al., 2011; Hu et al., 2015). "
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    ABSTRACT: We have explored the potential neuroprotective effect of local lentiviraly-mediated overexpression of nerve growth factor (NGF) on in vivo long-term potentiation (LTP) in the rat hippocampus under pathological conditions. The suspension of lentiviral particles was prepared using a genetic construct containing the human NGF gene under the control of a neuron-specific CaMKII promoter. Two weeks after the viral injection NGF concentration in the hippocampus doubled. In vivo recordings of total electrical activity in the dentate gyrus were performed. While the increased expression of NGF did not affect the amplitude of evoked postsynaptic potentials recorded after a high-frequency stimulation of the perforant path, it prevented the LTP decline induced by the i.c.v. administration of 50nM beta-amyloid (25-35) 1h prior to tetanization. Our results demonstrate that increased endogenous NGF concentration can rescue hippocampal neuronal function from beta-amyloid peptide induced impairment. Copyright © 2015. Published by Elsevier B.V.
    Brain research 08/2015; DOI:10.1016/j.brainres.2015.07.051 · 2.84 Impact Factor
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    • "Interestingly, previous studies have shown that Aβ modulates activity of a suite of ionic conductances, mostly potassium channels through amylin receptor, which resulting in aberrant neuronal excitability5051. In addition, another independent study showed that Aβ -induced depression of hippocampal long-term potentiation is associated with the amylin receptor52. These findings suggest that alternation of neuronal excitability might contribute to Aβ-induced LTP impairment. "
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    ABSTRACT: Neurodegeneration and synaptic dysfunction observed in Alzheimer's disease (AD) have been associated with progressive decrease in neuronal activity. Here, we investigated the effects of Notoginsenoside R1 (NTR1), a major saponin isolated from Panax notoginseng, on neuronal excitability and assessed the beneficial effects of NTR1 on synaptic and memory deficits under the Aβ-enriched conditions in vivo and in vitro. We assessed the effects of NTR1 on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular and intracellular recording techniques. We found that NTR1 increased the membrane excitability of CA1 pyramidal neurons in hippocampal slices by lowering the spike threshold possibly through a mechanism involving in the inhibition of voltage-gated K(+) currents. In addition, NTR1 reversed Aβ1-42 oligomers-induced impairments in long term potentiation (LTP). Reducing spontaneous firing activity with 10 nM tetrodotoxin (TTX) abolished the protective effect of NTR1 against Aβ-induced LTP impairment. Finally, oral administration of NTR1 improved the learning performance of the APP/PS1 mouse model of AD. Our work reveals a novel mechanism involving in modulation of cell strength, which contributes to the protective effects of NTR1 against Aβ neurotoxicity.
    Scientific Reports 09/2014; 4:6352. DOI:10.1038/srep06352 · 5.58 Impact Factor
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    • "Aβ, in a manner identical to human amylin, can directly activate AMY3 to raise cyclic adenosine monophosphate (cAMP), increase intracellular calcium, and PKA and MAPK phosphorylation (Fu et al., 2012). Furthermore, AC253 acting via AMY3 receptors, can re-establish the long-term potentiation (LTP) in hippocampus of AD mice (TgCRND8) (Kimura et al., 2012). Thus, many of the effects of Aβ, at a cellular level, appear to be expressed via the amylin receptor and such observations support the presence of a direct interaction between oligomer Aβ and amylin receptors. "
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    ABSTRACT: Amylin (islet amyloid polypeptide) and amyloid-beta (Aβ) protein, which are deposited within pancreatic islets of diabetics and brains of Alzheimer's patients respectively, share many biophysical and physiological properties. Emerging evidence indicates that the amylin receptor is a putative target receptor for the actions of human amylin and Aβ in the brain. The amylin receptor consists of the calcitonin receptor dimerized with a receptor activity-modifying protein and is widely distributed within central nervous system. Both amylin and Aβ directly activate this G protein-coupled receptor and trigger multiple common intracellular signal transduction pathways that can culminate in apoptotic cell death. Moreover, amylin receptor antagonists can block both the biological and neurotoxic effects of human amylin and Aβ. Amylin receptors thus appear to be involved in the pathophysiology of Alzheimer's disease and diabetes, and could serve as a molecular link between the two conditions that are associated epidemiologically.
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