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Dual Effect of Beta-Amyloid on α7 and α4β2 Nicotinic Receptors Controlling the Release of Glutamate, Aspartate and GABA in Rat Hippocampus

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      Abstract

      BackgroundWe previously showed that beta-amyloid (Aβ), a peptide considered as relevant to Alzheimer's Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer's Disease pathology, evaluating the effect of Aβ (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, α4β2 and α7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA.Methodology/FindingsWe used a dual approach: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Aβ considered (10 µM in vivo and 100 nM in vitro). In vivo administration of 100 nM Aβ (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Aβ and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (α7 and α4β2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Aβ concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Aβ concentrations (1 nM and 100 pM) selectively acted on α7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA.Conclusions/SignificanceThe results reinforce the concept that Aβ has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used.

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      Most cited references 58

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        A beta oligomers - a decade of discovery.

        Converging lines of evidence suggest that progressive accumulation of the amyloid beta-protein (A beta) plays a central role in the genesis of Alzheimer's disease, but it was long assumed that A beta had to be assembled into extracellular amyloid fibrils to exert its cytotoxic effects. Over the past decade, data have emerged from the use of synthetic A beta peptides, cell culture models, beta-amyloid precursor protein transgenic mice and human brain to suggest that pre-fibrillar, diffusible assemblies of A beta are also deleterious. Although the precise molecular identity of these soluble toxins remains unsettled, accumulating evidence suggests that soluble forms of A beta are indeed the proximate effectors of synapse loss and neuronal injury. Here we review recent progress in understanding the role of soluble oligomers in Alzheimer's disease.
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          Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.

          A purified protein derived from the twisted beta-pleated sheet fibrils in cerebrovascular amyloidosis associated with Alzheimer's disease has been isolated by Sephadex G-100 column chromatography with 5 M guanidine-HC1 in 1 N acetic acid and by high performance liquid chromatography. Amino acid sequence analysis and a computer search reveals this protein to have no homology with any protein sequenced thus far. This protein may be derived from a unique serum precursor which may provide a diagnostic test for Alzheimer's disease and a means to understand its pathogenesis.
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            Author and article information

            Affiliations
            [1 ]Department of Drug Sciences, Centre of Excellence in Applied Biology, University of Pavia, Pavia, Italy
            [2 ]Section of Pharmacology and Toxicology, Department of Experimental Medicine, University of Genoa, Genoa, Italy
            [3 ]Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
            Biological Research Center of the Hungarian Academy of Sciences, Hungary
            Author notes

            Conceived and designed the experiments: EM SG SP SZ MG MM. Performed the experiments: EM SP CL FB SZ GO AS AC. Analyzed the data: EM SP SG CL SZ MG MM. Contributed reagents/materials/analysis tools: SG MM. Wrote the paper: EM SP SG SZ MG MM.

            Contributors
            Role: Editor
            Journal
            PLoS One
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            1932-6203
            2012
            11 January 2012
            : 7
            : 1
            3256170
            22253754
            PONE-D-11-14035
            10.1371/journal.pone.0029661
            (Editor)
            Mura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 13
            Categories
            Research Article
            Biology
            Biochemistry
            Neurochemistry
            Neurochemicals
            Neuroscience
            Neurochemistry
            Neurochemicals
            Medicine
            Neurology
            Dementia

            Uncategorized

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