Extracellular regulation of Tau aggregation and amyloid crossinteractions in Alzheimer’s Disease

Detalhes bibliográficos
Autor(a) principal: Freitas , Daniela Plasencia de
Data de Publicação: 2022
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/56505
Resumo: Tese de mestrado, Biologia Molecular e Genética, 2022, Universidade de Lisboa, Faculdade de Ciências
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spelling Extracellular regulation of Tau aggregation and amyloid crossinteractions in Alzheimer’s Diseaseinterações Aβ42-tausinergismo Aβ42-tauagregações sem heparinachaperões extracelularesTeses de mestrado - 2022Departamento de Biologia VegetalTese de mestrado, Biologia Molecular e Genética, 2022, Universidade de Lisboa, Faculdade de CiênciasAlzheimer’s disease (AD) is a progressive neurodegenerative disease, which constitutes the main cause of senile dementia and a major healthcare challenge for this century. From a molecular and cellular perspective, the appearance of proteinaceous aggregates in the brain mainly formed by the amyloid-β peptide (Aβ) in extracellular plaques, and later by tau in intracellular neurofibrillary tangles, constitute prototypical disease hallmarks that also include neuroinflammation, oxidative damage and neuronal injury. Even though Aβ oligomerization and aggregation seems to be a necessary initial step for pathology development, it is now understood that tau drives disease progression and that both proteins engage in synergistic interactions. Moreover, even though Aβ and tau primarily aggregate in distinct brain localizations, tau and its oligomers are released from degenerating neurons. Spreading of misfolded tau conformers to other brain regions proceeds in a pattern that correlates with the evolving brain damage and progressive dysfunction during AD progression. This highlights the relevance of the extracellular milieu as an environment where crucial molecular events in AD might be occurring, and raises the possibility that interactions between misfolded tau and Aβ involving cross-seeding might be relevant to understand AD development. Such interactions are likely occurring during prodromal and early AD, and their molecular understanding is thus critical to establish effective therapies that may halt subsequent aggregation and disease progression. Indeed, most trials for treatments against AD have targeted late-stage Aβ fibrillar aggregates, without much success, and this calls for novel approaches. Thus, there is a pressing need for exploring the potential of endogenous biological mechanisms that counteract tau aggregation in the brain. Indeed, recent findings from the host laboratory uncovered that S100B, a Ca2+-binding protein highly abundant in the brain that acts as a pro-inflammatory alarmin in late-stages of AD, is also acting as a protective chaperone inhibiting tau and Aβ42 aggregation, seeding and toxicity, at early-stage AD. The main aim of this project was to investigate in vitro the aggregation of tau and its cross-interactions with Aβ, and to establish how the S100B chaperone regulates such mixed aggregation system. As models for tau aggregation, we resorted to two tau constructs derived from the full-length tau protein: the tau AD core (TADC, tau 306-378) and the tau K18 peptide (tauK18, tau 244-372) which form fibrils similar to those in AD patients. We employed a recently reported protocol to induce cofactor-free aggregation of tau, which obviates the use of heparin that is known to induce fibril polymorphs unrelated to the pathology. We used this procedure to investigate in vitro the cofactor-free tau-K18 aggregation kinetics, which has not yet been described in the literature. Under conditions in which monomeric Aβ42 is combined with any of these tau peptides, opposite effects were observed: while Aβ42 aggregation was inhibited by either TADC or K18, Aβ42 monomers accelerated TADC aggregation in a concentration-dependent manner, generating toxic species. These results highlight the complexity of the cross-interactions between these amyloidogenic peptides similar to what may occur in the diseased human brain. S100B was also able to inhibit TADC aggregation and toxicity; however, a dual-behavior was observed as at low molar ratios an apparent accelerating effect was evidenced, which nonetheless did not fully correlate with higher toxicity-species. Additionally, we used two amyloid-sensitive fluorophores, X-34 and ThT to test if these compounds might distinguish between different types of aggregates. Overall, these results evidence the complex interplay between tau and Aβ pathologies, emphasizing the need for more research to elucidate their interactions and consequences over proteotoxicity spreading and deposition in the brain during AD progression.Gomes, Cláudio M.Repositório da Universidade de LisboaFreitas , Daniela Plasencia de202220222025-10-28T00:00:00Z2022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/56505enginfo:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:04:09Zoai:repositorio.ul.pt:10451/56505Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:07:03.139818Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Extracellular regulation of Tau aggregation and amyloid crossinteractions in Alzheimer’s Disease
title Extracellular regulation of Tau aggregation and amyloid crossinteractions in Alzheimer’s Disease
spellingShingle Extracellular regulation of Tau aggregation and amyloid crossinteractions in Alzheimer’s Disease
Freitas , Daniela Plasencia de
interações Aβ42-tau
sinergismo Aβ42-tau
agregações sem heparina
chaperões extracelulares
Teses de mestrado - 2022
Departamento de Biologia Vegetal
title_short Extracellular regulation of Tau aggregation and amyloid crossinteractions in Alzheimer’s Disease
title_full Extracellular regulation of Tau aggregation and amyloid crossinteractions in Alzheimer’s Disease
title_fullStr Extracellular regulation of Tau aggregation and amyloid crossinteractions in Alzheimer’s Disease
title_full_unstemmed Extracellular regulation of Tau aggregation and amyloid crossinteractions in Alzheimer’s Disease
title_sort Extracellular regulation of Tau aggregation and amyloid crossinteractions in Alzheimer’s Disease
author Freitas , Daniela Plasencia de
author_facet Freitas , Daniela Plasencia de
author_role author
dc.contributor.none.fl_str_mv Gomes, Cláudio M.
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Freitas , Daniela Plasencia de
dc.subject.por.fl_str_mv interações Aβ42-tau
sinergismo Aβ42-tau
agregações sem heparina
chaperões extracelulares
Teses de mestrado - 2022
Departamento de Biologia Vegetal
topic interações Aβ42-tau
sinergismo Aβ42-tau
agregações sem heparina
chaperões extracelulares
Teses de mestrado - 2022
Departamento de Biologia Vegetal
description Tese de mestrado, Biologia Molecular e Genética, 2022, Universidade de Lisboa, Faculdade de Ciências
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022-01-01T00:00:00Z
2025-10-28T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/56505
url http://hdl.handle.net/10451/56505
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/embargoedAccess
eu_rights_str_mv embargoedAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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