TAU Thr231 phosphorylation as a potential Alzheimer's disease biomarker
Autor(a) principal: | |
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Data de Publicação: | 2017 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10773/22056 |
Resumo: | Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques (senile plaques) and intracellular neurofibrillary tangles formed by hyperphosphorylated TAU protein. TAU protein when hyperphosphorylated loses the ability to bind to microtubules and can be released into peripheral fluids. This process leads to neuronal degradation and neuronal death. Phosphorylation at threonine 231 has been shown to be specific for AD and to precede assembly of paired helical filaments in the human brain. In order to understand more about this residue we analysed SH-SY5Y cells undifferentiated and in differentiated cells induced by retinoic acid (RA). Treatment with RA increased expression of TAU phosphorylated at Thr231 (TAUpThr231) as determined by Western blot analysis. We further explored TAU phosphorylation by immunocytochemistry and noticed that in undifferentiated SH-SY5Y cells, TAUpThr231 was located mainly in the nucleus. In contrast, TAU and TAUpThr231 was redistributed to the neurites and in the soma of SH-SY5Y cells, which were induced to differentiate by retinoic acid (RA). In order to evaluate the potential of TAUpThr231 as a biomarker, we measured TAUpThr231 in CSF by a sandwich enzyme immunoassay and observed that the ratio of TAUpThr231/TAU levels discriminated significantly the AD group for the non-AD group. These findings indicate that TAUpThr231/t-TAU ratio levels may be a valuable marker for the clinical diagnosis of AD, irrespective of age and gender. |
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TAU Thr231 phosphorylation as a potential Alzheimer's disease biomarkerDoença de AlzheimerFosforilaçãoMarcadores bioquímicosDiferenciação celularAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques (senile plaques) and intracellular neurofibrillary tangles formed by hyperphosphorylated TAU protein. TAU protein when hyperphosphorylated loses the ability to bind to microtubules and can be released into peripheral fluids. This process leads to neuronal degradation and neuronal death. Phosphorylation at threonine 231 has been shown to be specific for AD and to precede assembly of paired helical filaments in the human brain. In order to understand more about this residue we analysed SH-SY5Y cells undifferentiated and in differentiated cells induced by retinoic acid (RA). Treatment with RA increased expression of TAU phosphorylated at Thr231 (TAUpThr231) as determined by Western blot analysis. We further explored TAU phosphorylation by immunocytochemistry and noticed that in undifferentiated SH-SY5Y cells, TAUpThr231 was located mainly in the nucleus. In contrast, TAU and TAUpThr231 was redistributed to the neurites and in the soma of SH-SY5Y cells, which were induced to differentiate by retinoic acid (RA). In order to evaluate the potential of TAUpThr231 as a biomarker, we measured TAUpThr231 in CSF by a sandwich enzyme immunoassay and observed that the ratio of TAUpThr231/TAU levels discriminated significantly the AD group for the non-AD group. These findings indicate that TAUpThr231/t-TAU ratio levels may be a valuable marker for the clinical diagnosis of AD, irrespective of age and gender.A doença de Alzheimer (AD) é uma doença neurodegenerativa progressiva caracterizada pela presença de placas de amilóide extracelulares (placas senis) e tranças neurofibrilhares intracelulares formadas pela proteína TAU hiperfosforilada. A proteína TAU quando hiperfosforilada perde a capacidade de se ligar a microtúbulos e pode ser libertada para fluidos periféricos. Este processo leva à degradação neuronal e à morte neuronal. A fosforilação na treonina 231 tem-se demonstrado ser específica para a AD e preceder a formação de filamentos helicoidais emparelhados no cérebro humano. Para melhor perceber a função deste resíduo e a contribuição para a localização da TAU, analisámos células SH-SY5Y indiferenciadas e células diferenciadas, pela adição de ácido retinoico (RA). O tratamento com RA aumentou a expressão de TAU fosforilada na Thr231 (TAUpThr231) conforme determinado por Western blot. Explorámos ainda a fosforilação da TAU por imunocitoquímica e percebemos que em células SH-SY5Y indiferenciadas, a phosphoTAU231 estava localizada principalmente no núcleo. Em contraste, TAU e phosphoTAU231 foram redistribuídas para as dendrites e citosol das células SH-SY5Y diferenciadas pelo ácido retinoico (RA). Para avaliar o potencial deste resíduo como biomarcador; medimos TAUpThr231 em CSF por meio de um imunoensaio enzimático em sanduíche e observámos que a proporção de níveis de TAUpThr231 / TAU discriminou de forma significativa o grupo AD do grupo não-AD. Essas descobertas podem indicar que os níveis da relação TAUpThr231 / t-TAU podem ser um marcador valioso para o diagnóstico clínico de AD, independentemente da idade e do género.Universidade de Aveiro2017-12-132017-12-13T00:00:00Z2019-12-07T14:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10773/22056TID:201941279engSantos, Joana Rita Fanecainfo: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:RCAAP2024-02-22T11:43:20Zoai:ria.ua.pt:10773/22056Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T02:56:20.258887Repositório 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 |
TAU Thr231 phosphorylation as a potential Alzheimer's disease biomarker |
title |
TAU Thr231 phosphorylation as a potential Alzheimer's disease biomarker |
spellingShingle |
TAU Thr231 phosphorylation as a potential Alzheimer's disease biomarker Santos, Joana Rita Faneca Doença de Alzheimer Fosforilação Marcadores bioquímicos Diferenciação celular |
title_short |
TAU Thr231 phosphorylation as a potential Alzheimer's disease biomarker |
title_full |
TAU Thr231 phosphorylation as a potential Alzheimer's disease biomarker |
title_fullStr |
TAU Thr231 phosphorylation as a potential Alzheimer's disease biomarker |
title_full_unstemmed |
TAU Thr231 phosphorylation as a potential Alzheimer's disease biomarker |
title_sort |
TAU Thr231 phosphorylation as a potential Alzheimer's disease biomarker |
author |
Santos, Joana Rita Faneca |
author_facet |
Santos, Joana Rita Faneca |
author_role |
author |
dc.contributor.author.fl_str_mv |
Santos, Joana Rita Faneca |
dc.subject.por.fl_str_mv |
Doença de Alzheimer Fosforilação Marcadores bioquímicos Diferenciação celular |
topic |
Doença de Alzheimer Fosforilação Marcadores bioquímicos Diferenciação celular |
description |
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques (senile plaques) and intracellular neurofibrillary tangles formed by hyperphosphorylated TAU protein. TAU protein when hyperphosphorylated loses the ability to bind to microtubules and can be released into peripheral fluids. This process leads to neuronal degradation and neuronal death. Phosphorylation at threonine 231 has been shown to be specific for AD and to precede assembly of paired helical filaments in the human brain. In order to understand more about this residue we analysed SH-SY5Y cells undifferentiated and in differentiated cells induced by retinoic acid (RA). Treatment with RA increased expression of TAU phosphorylated at Thr231 (TAUpThr231) as determined by Western blot analysis. We further explored TAU phosphorylation by immunocytochemistry and noticed that in undifferentiated SH-SY5Y cells, TAUpThr231 was located mainly in the nucleus. In contrast, TAU and TAUpThr231 was redistributed to the neurites and in the soma of SH-SY5Y cells, which were induced to differentiate by retinoic acid (RA). In order to evaluate the potential of TAUpThr231 as a biomarker, we measured TAUpThr231 in CSF by a sandwich enzyme immunoassay and observed that the ratio of TAUpThr231/TAU levels discriminated significantly the AD group for the non-AD group. These findings indicate that TAUpThr231/t-TAU ratio levels may be a valuable marker for the clinical diagnosis of AD, irrespective of age and gender. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-12-13 2017-12-13T00:00:00Z 2019-12-07T14:00:00Z |
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/10773/22056 TID:201941279 |
url |
http://hdl.handle.net/10773/22056 |
identifier_str_mv |
TID:201941279 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
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info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade de Aveiro |
publisher.none.fl_str_mv |
Universidade de Aveiro |
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 |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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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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1799137617001840640 |