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Presynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβ

2020Journal article Open access
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dc.contributor.authorMarttinen, Mikael
dc.contributor.authorFerreira, Catarina B.
dc.contributor.authorPaldanius, Kaisa M. A.
dc.contributor.authorTakalo, Mari
dc.contributor.authorNatunen, Teemu
dc.contributor.authorMäkinen, Petra
dc.contributor.authorLeppänen, Luukas
dc.contributor.authorLeinonen, Ville
dc.contributor.authorTanigaki, Kenji
dc.contributor.authorKang, Gina
dc.contributor.authorHiroi, Noboru
dc.contributor.authorSoininen, Hilkka
dc.contributor.authorRilla, Kirsi
dc.contributor.authorHaapasalo, Annakaisa
dc.contributor.authorHiltunen, Mikko
dc.date.accessioned2021-04-07T11:28:06Z
dc.date.available2021-04-07T11:28:06Z
dc.date.issued2020
dc.description© 2020 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 (http://creativecommons.org/licenses/by/4.0/).pt_PT
dc.description.abstractAlzheimer's disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ. The in vitro and in vivo studies both revealed that the downregulation of SEPTIN5 reduced the levels of APP C-terminal fragments (APP CTFs) and Aβ in neuronal cells and in the cortex of Septin5 knockout mice. Mechanistic elucidation revealed that the downregulation of SEPTIN5 increased the degradation of APP CTFs, without affecting the secretory pathway-related trafficking or the endocytosis of APP. Furthermore, we found that the APP CTFs were degraded, to a large extent, via the autophagosomal pathway and that the downregulation of SEPTIN5 enhanced autophagosomal activity in neuronal cells as indicated by altered levels of key autophagosomal markers. Collectively, our data suggest that the downregulation of SEPTIN5 increases the autophagy-mediated degradation of APP CTFs, leading to reduced levels of Aβ in neuronal cells.pt_PT
dc.description.sponsorshipThis research was supported by the Academy of Finland (grant numbers 307866 and 315459), the Sigrid Jusélius Foundation, the Strategic Neuroscience Funding of the University of Eastern Finland, and the National Institute of Mental Health of the National Institutes of Health (grant numbers R01MH099660, R01DC015776, R21HD053114, and U54HD090260). Catarina B. Ferreira is a PhD Fellow (NeurULisboa - Integrated Neurosciences PhD program, supported by an individual grant from Fundação para a Ciência e Tecnologia (FCT), (PD/BD/128390/2017, SFRH/PD/BD/114441/2016, PD/BD/128091/2016). Work was also supported by Santa Casa da Misericórdia de Lisboa (MB37-2017) and SynaNet (LISBOA-01-0145-FEDER-0073919), under the grant agreement no. 692340, and the project was co-financed by FEDER, POR Lisboa 2020, Programa Operacional Regional de Lisboa, from PORTUGAL 2020 and by Fundação para a Ciência e a Tecnologia.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCells. 2020 Nov 15;9(11):2482pt_PT
dc.identifier.doi10.3390/cells9112482pt_PT
dc.identifier.eissn2073-4409
dc.identifier.urihttp://hdl.handle.net/10451/47271
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationSFRH/PD/BD/114441/2016pt_PT
dc.relationThe role of septins on synaptic function and on amyloid precursor protein processing
dc.relationLISBOA-01-0145-FEDER-0073919pt_PT
dc.relationModulation of BDNF effects by adenosine: a new strategy for schizophrenia treatment - Adenosinergic signaling as a new pharmacological target for schizophrenia treatment
dc.relationNeurologic and Psychiatric Disorders: from synapses to networks
dc.relation.publisherversionhttps://www.mdpi.com/journal/cellspt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAβpt_PT
dc.subjectAlzheimer’s diseasept_PT
dc.subjectAPP C-terminal fragmentspt_PT
dc.subjectAutophagypt_PT
dc.subjectSEPTIN5pt_PT
dc.titlePresynaptic vesicle protein SEPTIN5 regulates the degradation of APP C-Terminal fragments and the levels of Aβpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleThe role of septins on synaptic function and on amyloid precursor protein processing
oaire.awardTitleModulation of BDNF effects by adenosine: a new strategy for schizophrenia treatment - Adenosinergic signaling as a new pharmacological target for schizophrenia treatment
oaire.awardTitleNeurologic and Psychiatric Disorders: from synapses to networks
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F128390%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F128091%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/692340/EU
oaire.citation.issue11pt_PT
oaire.citation.titleCellspt_PT
oaire.citation.volume9pt_PT
oaire.fundingStreamOE
oaire.fundingStreamH2020
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication9aa55628-12af-4efa-a02a-e7265c11794b
relation.isProjectOfPublicationb0d32d85-a98a-42a1-be51-7ceca8459454
relation.isProjectOfPublicationa8d0a09b-e946-45d0-ac79-0b6e4fff9e49
relation.isProjectOfPublication.latestForDiscoverya8d0a09b-e946-45d0-ac79-0b6e4fff9e49

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