Publicação
Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models
| Resumo: | Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and chronic inflammation, with no treatments able to halt disease progression. Several pro- and antiinflammatory microRNAs (miRNAs), such as miRNA(miR)-124-3p, have been found dysregulated in AD. Previously, our laboratory identified elevated levels of miR-124-3p in SH-SY5Y neuroblastoma cells with the Swedish mutation (APP695) and in PSEN1 mutant neurons. Interestingly, when upregulated, miR-124 improved AD-associated features, causing a reduction in APP expression, Tau phosphorylation and amyloid species. Moreover, soluble and exosomal miR-124 were able to protect microglia activation by interferon-gamma stimulation. To explore the NLRP3-autophagy axis in the context of AD, we assessed relevant markers in the hippocampus and prefrontal cortices of 6- and 9-month-old female and male 5xFAD mice. Additionally, glial activation and synaptic markers were assessed to identify the best conditions for testing our therapeutic approach. We then assessed the effectiveness of the retro-orbital delivery of miR-124-transfected neural exosomes (miR-124-EXOs) in wild-type mice. Lastly, 5xFAD mice were treated with mock/miR-124- transfected EXOs, and cognitive performance was evaluated using behavioral tests. 5xFAD mice at 9- months of age displayed the greatest alterations in messenger RNA (mRNA) levels of Nlrp3/Il1b/Becn1. mRNA levels of Trem2/P2yr12/Cx3cr1/Gfap/Il6/Asc were most significantly increased in female mice. Conversely, Dlg4/Syp mRNA levels were decreased. Western blots of TREM2/S100B supported the activation of glial cells in females and downregulated levels of PSD95 in the hippocampus indicated synaptic loss. Retro-orbital delivery of miR-124-EXOS successfully increased the expression of miR124 up to 14 days post injection. Delivery of mock/miR-124-transfected EXOs to 9-month-old female 5xFAD mice was able to prevent cognitive decline. This study contributes to the understanding of the NLRP3-autophagy axis and inflammatory phenotype of 5xFAD mice. Moreover, it highlights miR-124- EXOs delivery via retro-orbital route as a promising approach to slow AD progression and cognitive loss. |
|---|---|
| Autores principais: | Lourenço, Maria Queirós Varandas |
| Assunto: | Doença de Alzheimer Neuroinflamação Modelo de murganho 5xFAD Exossomas enriquecidos com miR-124 Administração por via retro-orbital Teses de mestrado - 2024 |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| _version_ | 1865920782363787264 |
|---|---|
| author | Lourenço, Maria Queirós Varandas |
| author_facet | Lourenço, Maria Queirós Varandas Lourenço, Maria Queirós Varandas |
| author_role | author |
| contributor_name_str_mv | Brites, Dora Maria Tuna de Oliveira, 1951- Carvalho, Margarida Henriques da Gama, 1972- Repositório Científico de Acesso Aberto da ULisboa |
| country_str | PT |
| creators_json_str | [{\"Person.name\":\"Lourenço, Maria Queirós Varandas\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Brites, Dora Maria Tuna de Oliveira, 1951- Carvalho, Margarida Henriques da Gama, 1972- Repositório Científico de Acesso Aberto da ULisboa |
| datacite.creators.creator.creatorName.fl_str_mv | Lourenço, Maria Queirós Varandas |
| datacite.date.Accepted.fl_str_mv | 2024-01-01T00:00:00Z |
| datacite.date.available.fl_str_mv | 2027-10-20T00:00:00Z |
| datacite.date.embargoed.fl_str_mv | 2027-10-20T00:00:00Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_f1cf |
| datacite.subjects.subject.fl_str_mv | Doença de Alzheimer Neuroinflamação Modelo de murganho 5xFAD Exossomas enriquecidos com miR-124 Administração por via retro-orbital Teses de mestrado - 2024 |
| datacite.titles.title.fl_str_mv | Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models |
| dc.contributor.none.fl_str_mv | Brites, Dora Maria Tuna de Oliveira, 1951- Carvalho, Margarida Henriques da Gama, 1972- Repositório Científico de Acesso Aberto da ULisboa |
| dc.creator.none.fl_str_mv | Lourenço, Maria Queirós Varandas |
| dc.date.Accepted.fl_str_mv | 2024-01-01T00:00:00Z |
| dc.date.available.fl_str_mv | 2027-10-20T00:00:00Z |
| dc.date.embargoed.fl_str_mv | 2027-10-20T00:00:00Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10400.5/96474 |
| dc.language.none.fl_str_mv | eng |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_f1cf |
| dc.subject.none.fl_str_mv | Doença de Alzheimer Neuroinflamação Modelo de murganho 5xFAD Exossomas enriquecidos com miR-124 Administração por via retro-orbital Teses de mestrado - 2024 |
| dc.title.fl_str_mv | Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_bdcc |
| description | Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and chronic inflammation, with no treatments able to halt disease progression. Several pro- and antiinflammatory microRNAs (miRNAs), such as miRNA(miR)-124-3p, have been found dysregulated in AD. Previously, our laboratory identified elevated levels of miR-124-3p in SH-SY5Y neuroblastoma cells with the Swedish mutation (APP695) and in PSEN1 mutant neurons. Interestingly, when upregulated, miR-124 improved AD-associated features, causing a reduction in APP expression, Tau phosphorylation and amyloid species. Moreover, soluble and exosomal miR-124 were able to protect microglia activation by interferon-gamma stimulation. To explore the NLRP3-autophagy axis in the context of AD, we assessed relevant markers in the hippocampus and prefrontal cortices of 6- and 9-month-old female and male 5xFAD mice. Additionally, glial activation and synaptic markers were assessed to identify the best conditions for testing our therapeutic approach. We then assessed the effectiveness of the retro-orbital delivery of miR-124-transfected neural exosomes (miR-124-EXOs) in wild-type mice. Lastly, 5xFAD mice were treated with mock/miR-124- transfected EXOs, and cognitive performance was evaluated using behavioral tests. 5xFAD mice at 9- months of age displayed the greatest alterations in messenger RNA (mRNA) levels of Nlrp3/Il1b/Becn1. mRNA levels of Trem2/P2yr12/Cx3cr1/Gfap/Il6/Asc were most significantly increased in female mice. Conversely, Dlg4/Syp mRNA levels were decreased. Western blots of TREM2/S100B supported the activation of glial cells in females and downregulated levels of PSD95 in the hippocampus indicated synaptic loss. Retro-orbital delivery of miR-124-EXOS successfully increased the expression of miR124 up to 14 days post injection. Delivery of mock/miR-124-transfected EXOs to 9-month-old female 5xFAD mice was able to prevent cognitive decline. This study contributes to the understanding of the NLRP3-autophagy axis and inflammatory phenotype of 5xFAD mice. Moreover, it highlights miR-124- EXOs delivery via retro-orbital route as a promising approach to slow AD progression and cognitive loss. |
| dirty | 0 |
| eu_rights_str_mv | embargoedAccess |
| format | masterThesis |
| fulltext.url.fl_str_mv | https://repositorio.ulisboa.pt/bitstreams/4510d677-1e1c-40fe-bcc0-82b6319ceddf/download |
| id | ul_2f64a7f8c8fc0d0802c8e75d4b34afef |
| identifier.url.fl_str_mv | http://hdl.handle.net/10400.5/96474 |
| instacron_str | ul |
| institution | Universidade de Lisboa |
| instname_str | Universidade de Lisboa |
| language | eng |
| network_acronym_str | ul |
| network_name_str | Repositório da Universidade de Lisboa |
| oai_identifier_str | oai:repositorio.ulisboa.pt:10400.5/96474 |
| organization_str_mv | urn:organizationAcronym:ul |
| person_str_mv | Lourenço, Maria Queirós Varandas |
| publishDate | 2024 |
| reponame_str | Repositório da Universidade de Lisboa |
| repository_id_str | urn:repositoryAcronym:ul |
| service_str_mv | urn:repositoryAcronym:ul |
| spelling | engpt_PTAlzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and chronic inflammation, with no treatments able to halt disease progression. Several pro- and antiinflammatory microRNAs (miRNAs), such as miRNA(miR)-124-3p, have been found dysregulated in AD. Previously, our laboratory identified elevated levels of miR-124-3p in SH-SY5Y neuroblastoma cells with the Swedish mutation (APP695) and in PSEN1 mutant neurons. Interestingly, when upregulated, miR-124 improved AD-associated features, causing a reduction in APP expression, Tau phosphorylation and amyloid species. Moreover, soluble and exosomal miR-124 were able to protect microglia activation by interferon-gamma stimulation. To explore the NLRP3-autophagy axis in the context of AD, we assessed relevant markers in the hippocampus and prefrontal cortices of 6- and 9-month-old female and male 5xFAD mice. Additionally, glial activation and synaptic markers were assessed to identify the best conditions for testing our therapeutic approach. We then assessed the effectiveness of the retro-orbital delivery of miR-124-transfected neural exosomes (miR-124-EXOs) in wild-type mice. Lastly, 5xFAD mice were treated with mock/miR-124- transfected EXOs, and cognitive performance was evaluated using behavioral tests. 5xFAD mice at 9- months of age displayed the greatest alterations in messenger RNA (mRNA) levels of Nlrp3/Il1b/Becn1. mRNA levels of Trem2/P2yr12/Cx3cr1/Gfap/Il6/Asc were most significantly increased in female mice. Conversely, Dlg4/Syp mRNA levels were decreased. Western blots of TREM2/S100B supported the activation of glial cells in females and downregulated levels of PSD95 in the hippocampus indicated synaptic loss. Retro-orbital delivery of miR-124-EXOS successfully increased the expression of miR124 up to 14 days post injection. Delivery of mock/miR-124-transfected EXOs to 9-month-old female 5xFAD mice was able to prevent cognitive decline. This study contributes to the understanding of the NLRP3-autophagy axis and inflammatory phenotype of 5xFAD mice. Moreover, it highlights miR-124- EXOs delivery via retro-orbital route as a promising approach to slow AD progression and cognitive loss.application/pdfpt_PTTesting miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research modelsLourenço, Maria Queirós VarandasBrites, Dora Maria Tuna de Oliveira, 1951-Carvalho, Margarida Henriques da Gama, 1972-HostingInstitutionOrganizationalRepositório Científico de Acesso Aberto da ULisboae-mailmailto:repositorio@reitoria.ulisboa.ptrepositorio@reitoria.ulisboa.ptURNurn:tid:203880196202420242027-10-20T00:00:00Z2024-01-01T00:00:00ZHandlehttp://hdl.handle.net/10400.5/96474http://purl.org/coar/access_right/c_f1cfembargoed accessDoença de AlzheimerNeuroinflamaçãoModelo de murganho 5xFADExossomas enriquecidos com miR-124Administração por via retro-orbitalTeses de mestrado - 20243434468 bytesliteraturehttp://purl.org/coar/resource_type/c_bdccmaster thesishttp://purl.org/coar/access_right/c_f1cfapplication/pdffulltexthttps://repositorio.ulisboa.pt/bitstreams/4510d677-1e1c-40fe-bcc0-82b6319ceddf/download |
| spellingShingle | Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models Lourenço, Maria Queirós Varandas Doença de Alzheimer Neuroinflamação Modelo de murganho 5xFAD Exossomas enriquecidos com miR-124 Administração por via retro-orbital Teses de mestrado - 2024 Lourenço, Maria Queirós Varandas Doença de Alzheimer Neuroinflamação Modelo de murganho 5xFAD Exossomas enriquecidos com miR-124 Administração por via retro-orbital Teses de mestrado - 2024 |
| status | SINGLETON |
| subject.fl_str_mv | Doença de Alzheimer Neuroinflamação Modelo de murganho 5xFAD Exossomas enriquecidos com miR-124 Administração por via retro-orbital Teses de mestrado - 2024 |
| title | Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models |
| title_full | Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models |
| title_fullStr | Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models |
| title_full_unstemmed | Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models |
| title_short | Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models |
| title_sort | Testing miRNA-engineered exosomes as regulators of inflammation in Alzheimer’s disease research models |
| topic | Doença de Alzheimer Neuroinflamação Modelo de murganho 5xFAD Exossomas enriquecidos com miR-124 Administração por via retro-orbital Teses de mestrado - 2024 |
| topic_facet | Doença de Alzheimer Neuroinflamação Modelo de murganho 5xFAD Exossomas enriquecidos com miR-124 Administração por via retro-orbital Teses de mestrado - 2024 |
| url | http://hdl.handle.net/10400.5/96474 |
| visible | 1 |