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Neuronal dynamics and miRNA signaling differ between SH-SY5Y APPSwe and PSEN1 Mutant iPSC-Derived AD models upon modulation with miR-124 Mimic and Inhibitor

2021Artigo científico Acesso aberto
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dc.contributor.authorGarcia, Gonçalo
dc.contributor.authorPinto, Sara
dc.contributor.authorCunha, Mar
dc.contributor.authorFernandes, Adelaide
dc.contributor.authorKoistinaho, Jari
dc.contributor.authorBrites, Dora
dc.date.accessioned2021-10-12T13:24:11Z
dc.date.available2021-10-12T13:24:11Z
dc.date.issued2021
dc.description© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).pt_PT
dc.description.abstractNeuronal miRNA dysregulation may have a role in the pathophysiology of Alzheimer’s disease (AD). miRNA(miR)-124 is largely abundant and a critical player in many neuronal functions. However, the lack of models reliably recapitulating AD pathophysiology hampers our understanding of miR-124’s role in the disease. Using the classical human SH-SY5Y-APP695 Swedish neuroblastoma cells (SH-SWE) and the PSEN1 mutant iPSC-derived neurons (iNEU-PSEN), we observed a sustained upregulation of miR-124/miR-125b/miR-21, but only miR-124 was consistently shuttled into their exosomes. The miR-124 mimic reduced APP gene expression in both AD models. While miR-124 mimic in SH-SWE neurons led to neurite outgrowth, mitochondria activation and small Aβ oligomer reduction, in iNEU-PSEN cells it diminished Tau phosphorylation, whereas miR-124 inhibitor decreased dendritic spine density. In exosomes, cellular transfection with the mimic predominantly downregulated miR-125b/miR-21/miR-146a/miR-155. The miR-124 inhibitor upregulated miR-146a in the two experimental cell models, while it led to distinct miRNA signatures in cells and exosomes. In sum, though miR-124 function may be dependent on the neuronal AD model, data indicate that keeping miR-124 level strictly controlled is crucial for proper neuronal function. Moreover, the iNEU-PSEN cellular model stands out as a useful tool for AD mechanistic studies and perhaps for the development of personalized therapeutic strategies.pt_PT
dc.description.sponsorshipThis work is part of an EU Joint Program—Neurodegenerative Disease Research (JPND) project—supported by Fundação para a Ciência e a Tecnologia (FCT) (JPco-fuND/0003/2015 and PTDC/MED-NEU/31395/2017 to Dora Brites, UID/DTP/04138/2019 and UIDB/UIDP/04138/2020 to iMed.ULisboa, and PhD fellowship SFRH/BD/128738/2017 to Gonçalo Garcia).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCells. 2021 Sep 14;10(9):2424pt_PT
dc.identifier.doi10.3390/cells10092424pt_PT
dc.identifier.eissn2073-4409
dc.identifier.urihttp://hdl.handle.net/10451/49862
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relation.publisherversionhttps://www.mdpi.com/journal/cellspt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAlzheimer’s diseasept_PT
dc.subjectCell experimental modelspt_PT
dc.subjectiPSC-derived neuronspt_PT
dc.subjectInflammatory-associated miRNAspt_PT
dc.subjectmiR-124-3p modulationpt_PT
dc.subjectNeuronal dysfunctionpt_PT
dc.subjectNeuropathological hallmarks of ADpt_PT
dc.subjectParacrine signalingpt_PT
dc.subjectSecretomept_PT
dc.subjectSmall extracellular vesicles (exosomes)pt_PT
dc.titleNeuronal dynamics and miRNA signaling differ between SH-SY5Y APPSwe and PSEN1 Mutant iPSC-Derived AD models upon modulation with miR-124 Mimic and Inhibitorpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/152623/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/154706/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/157836/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/66729/PT
oaire.citation.issue9pt_PT
oaire.citation.titleCellspt_PT
oaire.citation.volume10pt_PT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
person.familyNameGarcia
person.familyNameCastro da Costa Pinto
person.familyNameCunha
person.familyNameFernandes
person.familyNameBrites
person.givenNameGonçalo
person.givenNameSara Filipa
person.givenNameMar
person.givenNameAdelaide
person.givenNameDora
person.identifier695914
person.identifierM-8293-2013
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person.identifier.ciencia-id921C-9B98-2867
person.identifier.orcid0000-0001-5526-5362
person.identifier.orcid0000-0002-9785-8956
person.identifier.orcid0000-0001-9999-5885
person.identifier.orcid0000-0002-2782-9519
person.identifier.orcid0000-0002-3024-9777
person.identifier.scopus-author-id57190496766
person.identifier.scopus-author-id7004026610
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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