Disruption of the Choroid Plexus Circadian Rhythm’s in Alzheimer’s Disease
Autor(a) principal: | |
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Data de Publicação: | 2019 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.6/10165 |
Resumo: | Alzheimer´s disease (AD) is a neurodegenerative disorder, characterized by amyloid beta (Abeta) and tau protein deposition in the brain parenchyma and blood vessels. Abeta accumulation in areas of the brain controlling circadian rhythms can delay or shift activity rhythms. The circadian rhythm is coordinated by the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The choroid plexus (CP), a recent characterized extra-SCN circadian oscillator, is also known to exhibit morphological changes in AD which are exacerbated by the presence of Abeta deposits in CP epithelial cells. Melatonin is a hormone secreted by the pineal gland and there’s some evidence that, in AD patients, the circulating levels of this hormone are diminished. Under normal circumstances, melatonin acts as a neuroprotector against AD, but how this protection occurs is still to be fully comprehended. It also acts as a Zeitgeber, synchronizing the rhythms of the circadian genes, regulating the body’s circadian clocks. In this study we addressed the question whether Abeta contributes to CP’s circadian clock disruption and if melatonin modulates circadian clock genes expression therein. Using an AD mouse model (APP/PS1), we investigated changes in the expression of CP clock genes at different time points, in female and male animals, aged 6 and 12 months old. In addition, in vitro studies using Z310 cell line treated with Abeta and melatonin were used to examine if melatonin modulated Bmal1 circadian expression. We demonstrated that only Bmal1 circadian expression is altered in AD mice model 12 months old. Contrarily, Cry2 and Per2 expression were not affected in the APP/PS1 model. In addition, we found that melatonin modulated several parameters in the circadian expression of Bmal1. These results indicate that Abeta deposition on the CP disrupted the rhythmic circadian expression of Bmal1 and that melatonin modulates CP clock gene circadian rhythms in the presence of Abeta. |
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Disruption of the Choroid Plexus Circadian Rhythm’s in Alzheimer’s DiseaseAmiloide BetaDoença de AlzheimerMelatoninaRitmo CircadianoDomínio/Área Científica::Ciências Médicas::Ciências BiomédicasAlzheimer´s disease (AD) is a neurodegenerative disorder, characterized by amyloid beta (Abeta) and tau protein deposition in the brain parenchyma and blood vessels. Abeta accumulation in areas of the brain controlling circadian rhythms can delay or shift activity rhythms. The circadian rhythm is coordinated by the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The choroid plexus (CP), a recent characterized extra-SCN circadian oscillator, is also known to exhibit morphological changes in AD which are exacerbated by the presence of Abeta deposits in CP epithelial cells. Melatonin is a hormone secreted by the pineal gland and there’s some evidence that, in AD patients, the circulating levels of this hormone are diminished. Under normal circumstances, melatonin acts as a neuroprotector against AD, but how this protection occurs is still to be fully comprehended. It also acts as a Zeitgeber, synchronizing the rhythms of the circadian genes, regulating the body’s circadian clocks. In this study we addressed the question whether Abeta contributes to CP’s circadian clock disruption and if melatonin modulates circadian clock genes expression therein. Using an AD mouse model (APP/PS1), we investigated changes in the expression of CP clock genes at different time points, in female and male animals, aged 6 and 12 months old. In addition, in vitro studies using Z310 cell line treated with Abeta and melatonin were used to examine if melatonin modulated Bmal1 circadian expression. We demonstrated that only Bmal1 circadian expression is altered in AD mice model 12 months old. Contrarily, Cry2 and Per2 expression were not affected in the APP/PS1 model. In addition, we found that melatonin modulated several parameters in the circadian expression of Bmal1. These results indicate that Abeta deposition on the CP disrupted the rhythmic circadian expression of Bmal1 and that melatonin modulates CP clock gene circadian rhythms in the presence of Abeta.A doença de Alzheimer (AD) é uma doença neurodegenerativa caracterizada pela deposição do péptido beta-amilóide (Abeta) e proteína Tau no parênquima e vasos sanguíneos do cérebro. A acumulação destes, quando ocorre em áreas do cérebro responsáveis pelo controlo de ritmos circadianos, pode conduzir a alterações nos ritmos de atividade. O ritmo circadiano é coordenado por um marcador de atividade circadiana central que está localizado no núcleo supraquiasmático (SCN) do hipotálamo. No plexo coroide (CP), um oscilador extra-SCN recentemente caraterizado como tal, também se verificam alterações morfológicas na AD que são representadas pela acumulação de Abeta nas suas células epiteliais . A melatonina é uma hormona secretada pela glândula pineal, cujos níveis se encontram diminuídos na AD. Em condições normais, a melatonina tem uma função neuroprotetora na AD, e mesmo quando a doença já está instalada, esta ação continua presente, embora ainda se desconheça parcialmente os mecanismos responsáveis por esta neuroproteção. A melatonina funciona também como “Zeitgeber”, sincronizando os ritmos de expressão dos diferentes genes relógio, regulando desta forma os diversos relógios circadianos distribuídos pelo organismo. Neste estudo, foi utilizado um modelo de murganhos da AD (APP/PS1), de ambos os sexos e com idades de 6 e 12 meses, para determinar alterações na expressão dos genes relógio no CP, em diferentes momentos ao longo do tempo. Para os estudos in vitro foi utilizada a linha celular Z310 tratada com Abeta e melatonina de modo a avaliar se a melatonina tinha um efeito modulador na ritmicidade do Bmal1. Demonstramos que apenas o Bmal1 sofreu alterações na expressão circadiana e que esta ocorre em modelos APP/PS1 com 12 meses de idade. Contrariamente, a expressão do Per2 e Cry2 não é afetada no modelo APP/PS1. Também foi observado que a melatonina tem a capacidade de modular diversos parâmetros na ritmicidade do Bmal1. Estes resultados sugerem uma desregulação do ritmo circadiano da expressão do Bmal1 num modelo da AD, bem como um efeito modulador da melatonina na expressão dos genes relógio do CPPaixão, Telma Alexandra QuintelaSantos, Cecília Reis Alves dosuBibliorumFurtado, André Filipe Lino2020-06-23T00:30:15Z2019-07-112019-06-242019-07-11T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10400.6/10165TID:202364631enginfo: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:RCAAP2023-12-15T09:51:35Zoai:ubibliorum.ubi.pt:10400.6/10165Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T00:50:11.678425Repositório 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 |
Disruption of the Choroid Plexus Circadian Rhythm’s in Alzheimer’s Disease |
title |
Disruption of the Choroid Plexus Circadian Rhythm’s in Alzheimer’s Disease |
spellingShingle |
Disruption of the Choroid Plexus Circadian Rhythm’s in Alzheimer’s Disease Furtado, André Filipe Lino Amiloide Beta Doença de Alzheimer Melatonina Ritmo Circadiano Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas |
title_short |
Disruption of the Choroid Plexus Circadian Rhythm’s in Alzheimer’s Disease |
title_full |
Disruption of the Choroid Plexus Circadian Rhythm’s in Alzheimer’s Disease |
title_fullStr |
Disruption of the Choroid Plexus Circadian Rhythm’s in Alzheimer’s Disease |
title_full_unstemmed |
Disruption of the Choroid Plexus Circadian Rhythm’s in Alzheimer’s Disease |
title_sort |
Disruption of the Choroid Plexus Circadian Rhythm’s in Alzheimer’s Disease |
author |
Furtado, André Filipe Lino |
author_facet |
Furtado, André Filipe Lino |
author_role |
author |
dc.contributor.none.fl_str_mv |
Paixão, Telma Alexandra Quintela Santos, Cecília Reis Alves dos uBibliorum |
dc.contributor.author.fl_str_mv |
Furtado, André Filipe Lino |
dc.subject.por.fl_str_mv |
Amiloide Beta Doença de Alzheimer Melatonina Ritmo Circadiano Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas |
topic |
Amiloide Beta Doença de Alzheimer Melatonina Ritmo Circadiano Domínio/Área Científica::Ciências Médicas::Ciências Biomédicas |
description |
Alzheimer´s disease (AD) is a neurodegenerative disorder, characterized by amyloid beta (Abeta) and tau protein deposition in the brain parenchyma and blood vessels. Abeta accumulation in areas of the brain controlling circadian rhythms can delay or shift activity rhythms. The circadian rhythm is coordinated by the master circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The choroid plexus (CP), a recent characterized extra-SCN circadian oscillator, is also known to exhibit morphological changes in AD which are exacerbated by the presence of Abeta deposits in CP epithelial cells. Melatonin is a hormone secreted by the pineal gland and there’s some evidence that, in AD patients, the circulating levels of this hormone are diminished. Under normal circumstances, melatonin acts as a neuroprotector against AD, but how this protection occurs is still to be fully comprehended. It also acts as a Zeitgeber, synchronizing the rhythms of the circadian genes, regulating the body’s circadian clocks. In this study we addressed the question whether Abeta contributes to CP’s circadian clock disruption and if melatonin modulates circadian clock genes expression therein. Using an AD mouse model (APP/PS1), we investigated changes in the expression of CP clock genes at different time points, in female and male animals, aged 6 and 12 months old. In addition, in vitro studies using Z310 cell line treated with Abeta and melatonin were used to examine if melatonin modulated Bmal1 circadian expression. We demonstrated that only Bmal1 circadian expression is altered in AD mice model 12 months old. Contrarily, Cry2 and Per2 expression were not affected in the APP/PS1 model. In addition, we found that melatonin modulated several parameters in the circadian expression of Bmal1. These results indicate that Abeta deposition on the CP disrupted the rhythmic circadian expression of Bmal1 and that melatonin modulates CP clock gene circadian rhythms in the presence of Abeta. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-07-11 2019-06-24 2019-07-11T00:00:00Z 2020-06-23T00:30:15Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
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masterThesis |
status_str |
publishedVersion |
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http://hdl.handle.net/10400.6/10165 TID:202364631 |
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http://hdl.handle.net/10400.6/10165 |
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TID:202364631 |
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eng |
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eng |
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info:eu-repo/semantics/openAccess |
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openAccess |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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