Role of glial cells as contributors to the onset and propagation of als disease

Bibliographic Details
Main Author: Cunha, Carolina
Publication Date: 2017
Language: eng
Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Download full: http://hdl.handle.net/10451/32317
Summary: Tese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2017
id RCAP_a9ede8198c3bcb6e4cd0a8deb13e4162
oai_identifier_str oai:repositorio.ulisboa.pt:10451/32317
network_acronym_str RCAP
network_name_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository_id_str https://opendoar.ac.uk/repository/7160
spelling Role of glial cells as contributors to the onset and propagation of als diseaseTeses de doutoramento - 2017Domínio/Área Científica::Ciências Médicas::Medicina BásicaTese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2017Amyotrophic lateral sclerosis (ALS) is a motor neuron (MN) disease comprehending critical neuroinflammatory pathways, where microglia and astrocytes play a crucial role. ALS onset events are largely unknown and identification of disease steps during progression and dissemination, including the possible role of exosomes, are not clarified. Several models were used to improve data validity and deepen knowledge in ALS. We identified innovative targets to regulate microglia M1 polarization, including NLRP3-inflammasome, HMGB1 alarmin and MFG-E8/lactadherin, and demonstrated the sorting of microglial microRNA(miR) 155/miR-146a into exosomes. We showed that ALS NSC-34 MNs and their exosomes are enriched in miR-124, which are captured and drive early N9-microglia M1 polarization, with later development of M1/M2 subpopulations containing increased miR-124/miR-146a/miR-155. Moving from in vitro models to the spinal cord of the SOD1G93A ALS mouse model, we observed that depressed intercellular communication and increased miR-155 were early disease events preceding the inflammatory status of the symptomatic stage. Upregulated CX3CL1-CX3CR1, connexin-43/pannexin-1 and miR-124/miR-125b/miR-146a/miR-21 emerged as candidate targets for pathological neuroinflammation. Reduced MN number, together with aberrant/reactive astrocytes showing deficient glutamate transporters and GFAP, additionally characterized such state. Differently deregulated profiles of microglia isolated from the spinal cord of 7-day old SOD1G93A mice, after short- and long-term cultures, highlighted that cells present transient phenotypes accordingly to ALS environmental progression-stimuli and ultimately acquire a less responsive phenotype to stimulation. Astrocytes isolated from these mice promoted diverse inflammatory polarized subtypes in wild-type and ALS microglia, thus accounting to microglia heterogeneous populations, while strengthened deregulated microglia-astrocyte cross-talk as part of ALS neurodegenerative mechanisms. Our studies in ALS models reveal early promising biomarkers and novel targets to control excessive neuroinflammation and spread, including exosomal microRNAs. Due to multiple microglia phenotypes induced by MNs and their exosomes, and by reactive astrocytes, in the ALS disease, differentiated and combined therapeutic approaches may be recommended.Santa Casa da Misericórdia de Lisboa, programa de Investigação Científica em Esclerose Lateral Amiotrófica, projeto ELA-2015-002, The EU Joint Programme-Neurodegenerative Disease Research (JPND), projeto JPCOFUND/003/2015Brites, Dora, 1951-Botelho, Ana Rita Mendonça VazRepositório da Universidade de LisboaCunha, Carolina2020-12-13T01:30:12Z201720172017-01-01T00:00:00Zdoctoral thesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10451/32317TID:101460821enginfo:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-03-17T13:49:46Zoai:repositorio.ulisboa.pt:10451/32317Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T02:55:23.464090Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Role of glial cells as contributors to the onset and propagation of als disease
title Role of glial cells as contributors to the onset and propagation of als disease
spellingShingle Role of glial cells as contributors to the onset and propagation of als disease
Cunha, Carolina
Teses de doutoramento - 2017
Domínio/Área Científica::Ciências Médicas::Medicina Básica
title_short Role of glial cells as contributors to the onset and propagation of als disease
title_full Role of glial cells as contributors to the onset and propagation of als disease
title_fullStr Role of glial cells as contributors to the onset and propagation of als disease
title_full_unstemmed Role of glial cells as contributors to the onset and propagation of als disease
title_sort Role of glial cells as contributors to the onset and propagation of als disease
author Cunha, Carolina
author_facet Cunha, Carolina
author_role author
dc.contributor.none.fl_str_mv Brites, Dora, 1951-
Botelho, Ana Rita Mendonça Vaz
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Cunha, Carolina
dc.subject.por.fl_str_mv Teses de doutoramento - 2017
Domínio/Área Científica::Ciências Médicas::Medicina Básica
topic Teses de doutoramento - 2017
Domínio/Área Científica::Ciências Médicas::Medicina Básica
description Tese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2017
publishDate 2017
dc.date.none.fl_str_mv 2017
2017
2017-01-01T00:00:00Z
2020-12-13T01:30:12Z
dc.type.driver.fl_str_mv doctoral thesis
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/32317
TID:101460821
url http://hdl.handle.net/10451/32317
identifier_str_mv TID:101460821
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.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
_version_ 1833601533461135360

Similar Items