Dissecting cross-talk between microglia and motoneurons in ALS: signaling events and soluble factors
Autor(a) principal: | |
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Data de Publicação: | 2013 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10362/10925 |
Resumo: | Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina |
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7160 |
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Dissecting cross-talk between microglia and motoneurons in ALS: signaling events and soluble factorsInflammatory mediatorsMicroglia modulatory effects of motoneuron degenerationMicroglia-motoneuron communicationNeuroinflammationSOD1 accumulationDissertação para obtenção do Grau de Mestre em Genética Molecular e BiomedicinaConvergence of pathways in motoneuron (MN) injury include microglia in the initiation and progression of Amyotrophic Lateral Sclerosis (ALS). Neuroinflammation is a pathological hallmark of ALS and microglia may acquire neurotoxic or neuroprotective properties in response to misfolded superoxide dismutase-1 (SOD1) or other molecules produced by the injured MN. We assessed: (i) the role of microglia in preventing/restoring MN dysfunction using a mixed culture of NSC-34 MN-like cells (mutated in G93A) and of N9 microglia cells, added at 0 or 2 days-invitro(M0, M2) and cultured till 4 and 7 days-in-vitro; (ii) neurodegenerative network in organotypic cultures from lumbar segments of spinal cord (SC) obtained from the ALS mice model TgSOD1-G93A at 7 day-old and aged for 10 days-in-vitro, as well as the response to lipopolysaccharide (LPS, 1μg/mL) immunostimulation. Western blot assays for SOD1, high-mobility-group-box-protein-1 (HMGB1) and toll-like receptor-4 (TLR-4), and fluorimetric/colorimetric assays for ATP, glutamate and nitric oxide (NO), were used. Microglia (M0/M2) decreased the accumulation of human/mouse mutated SOD1 (P<0.01). In addition, elevation of glutamate efflux (P<0.01), and reduction of extracellular ATP (P<0.01), MMP-2(P<0.05) and MMP-9 (P<0.01) was observed by M2 at 7 days-in-vitro. Reduction of NO (P<0.05) and MMP-2 (P<0.01) was obtained with M0. HMGB1 increased by M0 and decreased by M2, suggesting HMGB1 release from the cell. Accumulation of SOD1 was verified in SC organotypic cultures, but no changes in ATP or NO were obtained, although a slight decrease in ATP by LPS was verified. Downregulation of TLR-4 by LPS may indicate the exhaustion of the inflammatory response mechanisms in the aged SC culture. Together, these results suggest that microglia by inhibiting MMP activation and HMGB1 cytoplasmic translocation in the ALS model are key in modulating MN degeneration and should be considered as therapeutic targets in ALS.supported by FEDER (COMPETE Programme) and by National funds (Fundação para a Ciência e a Tecnologia – FCT, Portugal) with the projects PTDC/SAU-FAR/118787/2010 to D.B. and PEst-OE/SAU/UI4013/2011 and 2012 to iMed.ULFaculdade de Ciências e TecnologiaBrites, DoraVaz, AnaRUNBarbosa, Marta Isabel da Silva Rodrigues2014-01-02T17:17:35Z20132013-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10362/10925enginfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T03:45:01Zoai:run.unl.pt:10362/10925Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:19:51.504682Repositório 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 |
Dissecting cross-talk between microglia and motoneurons in ALS: signaling events and soluble factors |
title |
Dissecting cross-talk between microglia and motoneurons in ALS: signaling events and soluble factors |
spellingShingle |
Dissecting cross-talk between microglia and motoneurons in ALS: signaling events and soluble factors Barbosa, Marta Isabel da Silva Rodrigues Inflammatory mediators Microglia modulatory effects of motoneuron degeneration Microglia-motoneuron communication Neuroinflammation SOD1 accumulation |
title_short |
Dissecting cross-talk between microglia and motoneurons in ALS: signaling events and soluble factors |
title_full |
Dissecting cross-talk between microglia and motoneurons in ALS: signaling events and soluble factors |
title_fullStr |
Dissecting cross-talk between microglia and motoneurons in ALS: signaling events and soluble factors |
title_full_unstemmed |
Dissecting cross-talk between microglia and motoneurons in ALS: signaling events and soluble factors |
title_sort |
Dissecting cross-talk between microglia and motoneurons in ALS: signaling events and soluble factors |
author |
Barbosa, Marta Isabel da Silva Rodrigues |
author_facet |
Barbosa, Marta Isabel da Silva Rodrigues |
author_role |
author |
dc.contributor.none.fl_str_mv |
Brites, Dora Vaz, Ana RUN |
dc.contributor.author.fl_str_mv |
Barbosa, Marta Isabel da Silva Rodrigues |
dc.subject.por.fl_str_mv |
Inflammatory mediators Microglia modulatory effects of motoneuron degeneration Microglia-motoneuron communication Neuroinflammation SOD1 accumulation |
topic |
Inflammatory mediators Microglia modulatory effects of motoneuron degeneration Microglia-motoneuron communication Neuroinflammation SOD1 accumulation |
description |
Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina |
publishDate |
2013 |
dc.date.none.fl_str_mv |
2013 2013-01-01T00:00:00Z 2014-01-02T17:17:35Z |
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/10362/10925 |
url |
http://hdl.handle.net/10362/10925 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Faculdade de Ciências e Tecnologia |
publisher.none.fl_str_mv |
Faculdade de Ciências e Tecnologia |
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 |
|
_version_ |
1799137841448484864 |