Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's disease
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Tipo de documento: | Dissertação |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10773/25073 |
Resumo: | Alzheimer’s disease (AD) and Type 2 Diabetes Mellitus (T2DM) are respectively characterized as a neurodegenerative disorder and a peripheral metabolic. Evidence strongly suggests an association between these two diseases, where T2DM is starting to be considered as a risk factor for AD. Both diseases share many pathophysiological features, including insulin resistance, amyloid type aggregation and oxidative stress. The anti-diabetic drug metformin was shown to affect APP metabolism and Aβ generation, through AMPK-dependent mechanism. There are however conflicting reports, where metformin is considered to provide neuroprotection or conversely increase the risk of AD; the clinical significance of metformin action on AD pathology remains to be clarified. This work aims to contribute towards clarifying the molecular mechanism underlying the effects of metformin on AD patients. Using patient-derived human dermal fibroblast cultures as an experimental model, metformin was shown to supress APP cleavage resulting in intracellular protein accumulation. Moreover, the drug decreased MAPT and β-Actin gene expression levels. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder most commonly affecting children and teens. It was fist associated to dementia in 2011, where adults diagnosed with dementia revealed an increased prevalence of prior childhood ADHD symptoms. The present study is pioneer regarding the molecular association between both diseases, investigating whether adult ADHD may precede AD long before its clinical onset. |
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Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's diseaseDementiaAlzheimer’s DiseaseType 2 Diabetes MellitusMetforminAttention-deficit/hyperactivity disorderAPP (Alzheimer’s precursor protein)TauAlzheimer’s disease (AD) and Type 2 Diabetes Mellitus (T2DM) are respectively characterized as a neurodegenerative disorder and a peripheral metabolic. Evidence strongly suggests an association between these two diseases, where T2DM is starting to be considered as a risk factor for AD. Both diseases share many pathophysiological features, including insulin resistance, amyloid type aggregation and oxidative stress. The anti-diabetic drug metformin was shown to affect APP metabolism and Aβ generation, through AMPK-dependent mechanism. There are however conflicting reports, where metformin is considered to provide neuroprotection or conversely increase the risk of AD; the clinical significance of metformin action on AD pathology remains to be clarified. This work aims to contribute towards clarifying the molecular mechanism underlying the effects of metformin on AD patients. Using patient-derived human dermal fibroblast cultures as an experimental model, metformin was shown to supress APP cleavage resulting in intracellular protein accumulation. Moreover, the drug decreased MAPT and β-Actin gene expression levels. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder most commonly affecting children and teens. It was fist associated to dementia in 2011, where adults diagnosed with dementia revealed an increased prevalence of prior childhood ADHD symptoms. The present study is pioneer regarding the molecular association between both diseases, investigating whether adult ADHD may precede AD long before its clinical onset.A Doença de Alzheimer (AD) e a Diabetes Melitos Tipo 2 (T2DM) são caracterizadas como uma doença neurodegenerativa e uma patologia metabólica periférica, respetivamente. Diversas evidências sugerem uma associação entre as duas doenças e a T2DM começa a ser considerada como um fator de risco para a AD. Ambas partilham diversas características patofisiológicas, incluindo resistência à insulina, agregação de amiloide e stress oxidativo. O fármaco antidiabético metformina foi demonstrado afetar o metabolismo da APP e a produção de Aβ, através de um mecanismo dependente de AMPK. Devido a artigos conflituosos onde a metformina é considerada como um agente neuroprotetor ou que aumente o risco de AD, o significado clínico da ação da metformina na patologia da AD continua por ser esclarecido. Este trabalho tem como objetivo contribuir para clarificar o mecanismo molecular subjacente aos efeitos da metformina nos pacientes com AD. Com recurso a culturas fibroblastos da derme derivados de pacientes como modelo experimental, metformina revelou suprimir a clivagem da APP levando e a acumulação intracelular da proteína. O fármaco também diminuiu os níveis de expressão dos genes MAPT e β-Actina. Síndrome de Défice de Atenção e Hiperatividade (ADHD) é uma perturbação do desenvolvimento neuronal que afeta maioritariamente crianças. Foi pela primeira vez associado à demência em 2011, onde adultos diagnosticados com demência revelaram uma elevada prevalência de sintomas de ADHD enquanto crianças. Este estudo é pioneiro no que respeita a associação molecular entre as duas doenças, com o objetivo de investigar se a presença de sintomas de ADHD na fase adulta antecedam a AD antes do seu aparecimento clínico.2020-12-11T00:00:00Z2018-12-06T00:00:00Z2018-12-06info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10773/25073TID:202235467engMorgado, Bárbara Marcosinfo: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:RCAAP2024-02-22T11:48:55Zoai:ria.ua.pt:10773/25073Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T02:58:31.302459Repositório 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 |
Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's disease |
title |
Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's disease |
spellingShingle |
Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's disease Morgado, Bárbara Marcos Dementia Alzheimer’s Disease Type 2 Diabetes Mellitus Metformin Attention-deficit/hyperactivity disorder APP (Alzheimer’s precursor protein) Tau |
title_short |
Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's disease |
title_full |
Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's disease |
title_fullStr |
Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's disease |
title_full_unstemmed |
Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's disease |
title_sort |
Fibroblasts as a cellular model to evaluate risk factors associated with Alzheimer's disease |
author |
Morgado, Bárbara Marcos |
author_facet |
Morgado, Bárbara Marcos |
author_role |
author |
dc.contributor.author.fl_str_mv |
Morgado, Bárbara Marcos |
dc.subject.por.fl_str_mv |
Dementia Alzheimer’s Disease Type 2 Diabetes Mellitus Metformin Attention-deficit/hyperactivity disorder APP (Alzheimer’s precursor protein) Tau |
topic |
Dementia Alzheimer’s Disease Type 2 Diabetes Mellitus Metformin Attention-deficit/hyperactivity disorder APP (Alzheimer’s precursor protein) Tau |
description |
Alzheimer’s disease (AD) and Type 2 Diabetes Mellitus (T2DM) are respectively characterized as a neurodegenerative disorder and a peripheral metabolic. Evidence strongly suggests an association between these two diseases, where T2DM is starting to be considered as a risk factor for AD. Both diseases share many pathophysiological features, including insulin resistance, amyloid type aggregation and oxidative stress. The anti-diabetic drug metformin was shown to affect APP metabolism and Aβ generation, through AMPK-dependent mechanism. There are however conflicting reports, where metformin is considered to provide neuroprotection or conversely increase the risk of AD; the clinical significance of metformin action on AD pathology remains to be clarified. This work aims to contribute towards clarifying the molecular mechanism underlying the effects of metformin on AD patients. Using patient-derived human dermal fibroblast cultures as an experimental model, metformin was shown to supress APP cleavage resulting in intracellular protein accumulation. Moreover, the drug decreased MAPT and β-Actin gene expression levels. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder most commonly affecting children and teens. It was fist associated to dementia in 2011, where adults diagnosed with dementia revealed an increased prevalence of prior childhood ADHD symptoms. The present study is pioneer regarding the molecular association between both diseases, investigating whether adult ADHD may precede AD long before its clinical onset. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-12-06T00:00:00Z 2018-12-06 2020-12-11T00:00:00Z |
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/10773/25073 TID:202235467 |
url |
http://hdl.handle.net/10773/25073 |
identifier_str_mv |
TID:202235467 |
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: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) |
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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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1799137639585021952 |