{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:51:54Z","timestamp":1760403114612,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,11]],"date-time":"2021-04-11T00:00:00Z","timestamp":1618099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"This work was supported by the Italian \u201cMinistero della Salute\u201d with the \u201cProgetto Ordinario di Ricerca Finalizzata (RF-2013-02355682)\u201d","award":["RF-2013-02355682"],"award-info":[{"award-number":["RF-2013-02355682"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Salmon calcitonin is a good model for studying amyloid behavior and neurotoxicity. Its slow aggregation rate allows the purification of low molecular weight prefibrillar oligomers, which are the most toxic species. It has been proposed that these species may cause amyloid pore formation in neuronal membranes through contact with negatively charged sialic acid residues of the ganglioside GM1. In particular, it has been proposed that an electrostatic interaction may be responsible for the initial contact between prefibrillar oligomers and GM1 contained in lipid rafts. Based on this evidence, the aim of our work was to investigate whether the neurotoxic action induced by calcitonin prefibrillar oligomers could be counteracted by treatment with neuraminidase, an enzyme that removes sialic acid residues from gangliosides. Therefore, we studied cell viability in HT22 cell lines and evaluated the effects on synaptic transmission and long-term potentiation by in vitro extracellular recordings in mouse hippocampal slices. Our results showed that treatment with neuraminidase alters the surface charges of lipid rafts, preventing interaction between the calcitonin prefibrillar oligomers and GM1, and suggesting that the enzyme, depending on the concentration used, may have a partial or total protective action in terms of cell survival and modulation of synaptic transmission.<\/jats:p>","DOI":"10.3390\/ijms22083947","type":"journal-article","created":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T03:04:06Z","timestamp":1618196646000},"page":"3947","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Role of Electrostatic Interactions in Calcitonin Prefibrillar Oligomer-Induced Amyloid Neurotoxicity and Protective Effect of Neuraminidase"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2102-5034","authenticated-orcid":false,"given":"Ida","family":"Cariati","sequence":"first","affiliation":[{"name":"Medical-Surgical Biotechnologies and Translational Medicine (Phd), Department of Clinical Sciences and Translational Medicine, \u201cTor Vergata\u201d University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7174-0714","authenticated-orcid":false,"given":"Roberto","family":"Bonanni","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, \u201cTor Vergata\u201d University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Marini","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, \u201cTor Vergata\u201d University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Maria","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, \u201cTor Vergata\u201d University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatrice","family":"Zarrilli","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, \u201cTor Vergata\u201d University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4779-2212","authenticated-orcid":false,"given":"Virginia","family":"Tancredi","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, \u201cTor Vergata\u201d University of Rome, Via Montpellier 1, 00133 Rome, Italy"},{"name":"Centre of Space Bio-Medicine, \u201cTor Vergata\u201d University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Frank","sequence":"additional","affiliation":[{"name":"UniCamillus-Saint Camillus International University of Health Sciences, Via di Sant\u2019Alessandro 8, 00131 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2105-0395","authenticated-orcid":false,"given":"Giovanna","family":"D\u2019Arcangelo","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, \u201cTor Vergata\u201d University of Rome, Via Montpellier 1, 00133 Rome, Italy"},{"name":"Centre of Space Bio-Medicine, \u201cTor Vergata\u201d University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0749-2824","authenticated-orcid":false,"given":"Marco","family":"Diociaiuti","sequence":"additional","affiliation":[{"name":"Centro Nazionale Malattie Rare, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrn1007","article-title":"Unfolding the role of protein misfolding in neurodegenerative diseases","volume":"4","author":"Soto","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1038\/s41593-018-0235-9","article-title":"Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases","volume":"21","author":"Soto","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1038\/nm1066","article-title":"Protein aggregation and neurodegenerative disease","volume":"10","author":"Ross","year":"2004","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1016\/j.bbadis.2014.06.006","article-title":"Native metastable prefibrillar oligomers are the most neurotoxic species among amyloid aggregates","volume":"1842","author":"Diociaiuti","year":"2014","journal-title":"Biochim. Biophys. Acta BBA Mol. Basis Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.bbadis.2010.01.007","article-title":"Lipid raft disruption protects mature neurons against amyloid oligomer toxicity","volume":"1802","author":"Contrusciere","year":"2010","journal-title":"Biochim. Biophys. Acta BBA Mol. Basis Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9277","DOI":"10.3390\/ijms12129277","article-title":"The Slowly Aggregating Salmon Calcitonin: A Useful Tool for the Study of the Amyloid Oligomers Structure and Activity","volume":"12","author":"Diociaiuti","year":"2011","journal-title":"Int. J. Mol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1111\/j.1471-4159.2007.04809.x","article-title":"Soluble oligomers from a non-disease related protein mimic A\u03b2-induced tau hyperphosphorylation and neurodegeneration","volume":"103","author":"Vieira","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9115","DOI":"10.1038\/s41598-020-66033-6","article-title":"Amyloid Aggregation of Insulin: An Interaction Study of Green Tea Constituents","volume":"10","author":"Gancar","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1111\/j.1742-4658.2010.07569.x","article-title":"Amyloid oligomers: Diffuse oligomer-based transmission of yeast prions","volume":"277","author":"Taguchi","year":"2010","journal-title":"FEBS J."},{"key":"ref_10","first-page":"2541","article-title":"Solution conditions can promote formation of either amyloid protofilaments or mature fibrils from the HypF N-terminal domain","volume":"10","author":"Chiti","year":"2008","journal-title":"Protein Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1529\/biophysj.105.079475","article-title":"Calcitonin Forms Oligomeric Pore-Like Structures in Lipid Membranes","volume":"91","author":"Diociaiuti","year":"2006","journal-title":"Biophys. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-41462-0","article-title":"Calcitonin native prefibrillar oligomers but not monomers induce membrane damage that triggers NMDA-mediated Ca2+-influx, LTP impairment and neurotoxicity","volume":"9","author":"Belfiore","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1073\/pnas.92.6.1989","article-title":"Amyloid peptides are toxic via a common oxidative mechanism","volume":"92","author":"Schubert","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1046\/j.1471-4159.1997.69062285.x","article-title":"Cytotoxic Amyloid Peptides Inhibit Cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT) Reduction by Enhancing MTT Formazan Exocytosis","volume":"69","author":"Liu","year":"1997","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.brainresbull.2010.02.013","article-title":"Lipid rafts: Keys to neurodegeneration","volume":"82","author":"Schengrund","year":"2010","journal-title":"Brain Res. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/s12035-013-8614-4","article-title":"Lipid Rafts in Neurodegeneration and Neuroprotection","volume":"50","author":"Sonnino","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"906964","DOI":"10.4061\/2011\/906964","article-title":"Amyloid Oligomer Neurotoxicity, Calcium Dysregulation, and Lipid Rafts","volume":"2011","author":"Paradisi","year":"2011","journal-title":"Int. J. Alzheimer\u2019s Dis."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chiricozzi, E., Lunghi, G., Di Biase, E., Fazzari, M., Sonnino, S., and Mauri, L. (2020). GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030868"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1021\/jz4024354","article-title":"Amyloid aggregation: Role of biological membranes and the aggregate\u2013membrane system","volume":"5","author":"Bucciantini","year":"2014","journal-title":"J. Phys. Chem. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106272","DOI":"10.1016\/j.bpc.2019.106272","article-title":"GM1 Ganglioside role in the interaction of Alpha-synuclein with lipid membranes: Morphology and structure","volume":"255","author":"Perissinotto","year":"2019","journal-title":"Biophys. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s10719-015-9579-5","article-title":"GM1 ganglioside and Alzheimer\u2019s disease","volume":"32","author":"Yanagisawa","year":"2015","journal-title":"Glycoconj. J."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Diociaiuti, M., Bombelli, C., Zanetti-Polzi, L., Belfiore, M., Fioravanti, R., Macchia, G., and Giordani, C. (2019). The Interaction between Amyloid Prefibrillar Oligomers of Salmon Calcitonin and a Lipid-Raft Model: Molecular Mechanisms Leading to Membrane Damage, Ca2+-Influx and Neurotoxicity. Biomolecules, 10.","DOI":"10.3390\/biom10010058"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.neuron.2014.02.027","article-title":"Soluble A\u03b2 Oligomers Are Rapidly Sequestered from Brain ISF In Vivo and Bind GM1 Ganglioside on Cellular Membranes","volume":"82","author":"Hong","year":"2014","journal-title":"Neuron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.bbr.2008.02.016","article-title":"Soluble oligomers of the amyloid \u03b2-protein impair synaptic plasticity and behavior","volume":"192","author":"Selkoe","year":"2008","journal-title":"Behav. Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/nn1372","article-title":"Natural oligomers of the amyloid-\u03b2 protein specifically disrupt cognitive function","volume":"8","author":"Cleary","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1126\/science.285.5435.1870","article-title":"Long-Term Potentiation\u2014A Decade of Progress?","volume":"285","author":"Malenka","year":"1999","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1007\/s12035-015-9136-z","article-title":"GM1 Ganglioside: Past Studies and Future Potential","volume":"53","author":"Aureli","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0006-8993(96)01468-0","article-title":"Sialic acid residues indirectly modulate the binding properties of AMPA-type glutamate receptors","volume":"753","author":"Hoffman","year":"1997","journal-title":"Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0006-8993(85)90847-9","article-title":"The role of monosialoganglioside GM1 in the synaptic plasticity: In vitro study on rat hippocampal slices","volume":"345","author":"Wieraszko","year":"1985","journal-title":"Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"42027","DOI":"10.1074\/jbc.M102834200","article-title":"Reduction in cholesterol and sialic acid content protects cells from the toxic effects of \u03b2-amyloid peptides","volume":"276","author":"Wang","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1096\/fj.11-189381","article-title":"Toxic effects of amyloid fibrils on cell membranes: The importance of ganglioside GM1","volume":"26","author":"Bucciantini","year":"2011","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.bpj.2018.02.003","article-title":"Toxic HypF-N Oligomers Selectively Bind the Plasma Membrane to Impair Cell Adhesion Capability","volume":"114","author":"Keshavan","year":"2018","journal-title":"Biophys. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nature23658","article-title":"Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors","volume":"549","author":"Penn","year":"2017","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1177\/026119290203002S36","article-title":"Directive 86\/609\/EEC on the Protection of Animals Used for Experimental and Other Scientific Purposes","volume":"30","author":"Louhimies","year":"2002","journal-title":"Altern. Lab. Anim."},{"key":"ref_35","first-page":"330","article-title":"Effects of short-term aerobic exercise in a mouse model of Niemann-Pick type C disease on synaptic and muscle plasticity","volume":"55","author":"Palmieri","year":"2019","journal-title":"Ann. Ist. Super. 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