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The calcium-binding protein S100B as a novel chaperone preventing Tau aggregation in Alzheimer’s disease

2025-04-16Tese de doutoramento Acesso embargado
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datacite.subject.fosCiências Médicas::Ciências da Saúdept_PT
dc.contributor.advisorGomes, Cláudio Emanuel Moreira
dc.contributor.authorMoreira, Guilherme G.
dc.date.accessioned2025-06-06T16:57:23Z
dc.date.embargo2028-05
dc.date.issued2025-04-16
dc.date.submitted2025-02-04
dc.description.abstractAlzheimer's disease (AD), the foremost cause of dementia, is characterized by persistent neuroinflammation and amyloid- and tau protein aggregation. Notably, S100 proteins are upregulated in neurodegenerative conditions, including AD, where they localize in proximity to amyloid plaques and neurons with tau-containing neurofibrillary tangles (NFTs). This dissertation examines the role of S100B in modulating tau aggregation during the early stages of AD. Our findings reveal that S100B colocalizes with microtubule-bound tau and interacts dynamically with tau in a calcium-dependent manner, specifically targeting aggregation-prone segments within the repeat region. As a holdase-type chaperone, S100B inhibits tau aggregation at substoichiometric concentrations by suppressing secondary nucleation pathways, as confirmed through seeding assays and direct observation of S100B's interaction with tau oligomers and fibrils. Furthermore, S100B, consistent with its extracellular chaperone function, effectively inhibits proteopathic tau seeding. In exploring tau liquid-liquid phase separation (LLPS), identified as an early event in tau aggregation, we demonstrate that S100B inhibits tau condensation in a calcium-dependent manner, shifting the phase boundary to higher PEG concentrations. S100B integrates into tau droplets, stabilizing tau and reducing the formation of toxic aggregates, preserving the liquid-like properties of tau droplets. Additionally, S100B’s capacity to buffer Zn²⁺, mitigates Zn²⁺-induced tau LLPS. In subsequent investigations, we assessed the inhibitory effects of various S100 proteins on K18 aggregation. S100B and S100A1 were identified as the most potent inhibitors, while other S100 proteins demonstrated varying inhibition levels. Kinetic analyses revealed distinct preferences: S100B and S100A1 predominantly inhibited secondary aggregation pathways, while S100A9 targeted primary pathways. NMR studies mapped tau-binding regions for S100A1 across tau’s repeat domain, whereas S100A9 interacted with the PHF6 segment and the C-terminal region. S100A1 reduced the seeding activity of pre-formed K18 fibrils in tau-RD biosensor cells, whereas S100A9 was ineffective. These findings underscore the neuroprotective role of S100 proteins, particularly S100B, in tauopathies.pt_PT
dc.description.sponsorshipPT/FB/BL-2014-343pt_PT
dc.description.sponsorshipPPBI-POCI-01-0145-FEDER-022122pt_PT
dc.identifier.tid101764073pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.5/101426
dc.language.isoengpt_PT
dc.relationBiosystems and Integrative Sciences Institute
dc.subjectAlzheimer's diseasept_PT
dc.subjectProtein aggregationpt_PT
dc.subjectTaupt_PT
dc.subjectS100B proteinpt_PT
dc.subjectMolecular chaperonept_PT
dc.subjectDoença de Alzheimerpt_PT
dc.subjectAgregação proteicapt_PT
dc.subjectProteína S100Bpt_PT
dc.subjectChaperona molecularpt_PT
dc.titleThe calcium-binding protein S100B as a novel chaperone preventing Tau aggregation in Alzheimer’s diseasept_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardNumber2020.06443.BD
oaire.awardNumberPTDC/NEU-NMC/2138/2014
oaire.awardNumberUIDB/04046/2020
oaire.awardTitleBiosystems and Integrative Sciences Institute
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//2020.06443.BD/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FNEU-NMC%2F2138%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04046%2F2020/PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameDa Silva Veríssimo Moreira
person.givenNameGuilherme Gil
person.identifierB-6154-2018
person.identifier.ciencia-idAC17-77D0-DAA2
person.identifier.orcid0000-0003-4791-5403
person.identifier.scopus-author-id57212030809
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
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
rcaap.rightsembargoedAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isAuthorOfPublicationdcbdb152-9c39-4254-8c31-f3134af9ba91
relation.isAuthorOfPublication.latestForDiscoverydcbdb152-9c39-4254-8c31-f3134af9ba91
relation.isProjectOfPublication43e644de-12a6-4167-8127-2f60c8921976
relation.isProjectOfPublication32f2fc47-1b31-43ab-9520-3c74809ff486
relation.isProjectOfPublicationcd397b4c-17e6-40cc-8cdd-1dd1c0da5113
relation.isProjectOfPublication.latestForDiscovery32f2fc47-1b31-43ab-9520-3c74809ff486
thesis.degree.nameTese de doutoramento, Bioquímica (Bioquímica Estrutural), Universidade de Lisboa, Faculdade de Ciências, 2025pt_PT

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