Genetic variants associated to CSF biomarkers in Alzheimer’s disease
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2014
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A doença de Alzheimer (DA) é uma doença neurológica devastadora de início precoce que afeta mais de 30 milhões de indivíduos mundialmente. A doença caracteriza-se por disrupção da função neuronal e subsequente declínio gradual na cognição, mudanças no comportamento e personalidade, bem como disfunção na execução das atividades de vida diária, conduzindo por fim à morte.
Durante as últimas décadas, os biomarcadores do líquido cefalorraquidiano (LCR) têm sido intensivamente investigados na área da DA, principalmente para aplicação na prática clínica. A proteína amiloide-beta (Aβ1-42), tau total (T-tau) e tau fosforilada (P-tau) são biomarcadores estabelecidos na doença. Nos indivíduos com DA, a concentração de Aβ1-42 no LCR está diminuída e associada com a apreensão desta proteína nas placas senis, enquanto T-tau e P-tau estão aumentadas, traduzindo a extensão do dano neuronal.
Para melhor entender os mecanismos biológicos subjacentes à regulação dos biomarcadores da DA e a sua relação com a doença examinamos a correlação entre polimorfismos associados com biomarcadores de DA e/ou risco para DA e polimorfismos associados com os biomarcadores Aβ1-42, T-tau e P-tau no LCR.
O principal objetivo do presente estudo foi, portanto, replicar e validar top findings de variantes genéticas associadas aos biomarcadores do LCR na DA. Deste modo, congregou-se uma população de 675 amostras (600 amostras de indivíduos com DA e 75 de controlos saudáveis) tendo sido estas obtidas de 10 centros do consórcio europeu e testadas para 67 polimorfismos.
Os nossos resultados evidenciaram cinco genes, APOE, LOC100129500, PVRL2, SNAR-I e TOMM40, com papel primordial na regulação dos níveis dos biomarcadores do LCR e, possivelmente, implicados na patogénese da doença.
Alzheimer’s disease (AD) is a devastating neurological disorder of the elderly, affecting up to 30 million individuals worldwide. It is associated with disruption of neuronal function and subsequent gradual decline in cognition, behavior and personality changes, as well as impairments in the performance of activities of daily living, ultimately leading to death. During the last decades cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the field of AD, to be mainly applied in clinical practice. Amyloid-beta (Aβ1-42), total tau (T-tau), and phosphorylated tau (P-tau) are established biomarkers for AD. In patients, the concentration of CSF Aβ1-42 is decreased and associated to the sequestration of Aβ1-42 in amyloid plaques in the brain, while T-tau and P-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the correlation between selected SNPs (previously associated to AD biomarkers and/or AD risk) and AD markers Aβ1-42, T-tau and P-tau in CSF. The main goal of this study was therefore to replicate and validate the top findings of genetic variants associated to AD CSF biomarkers. A cohort of 675 samples (600 AD patients and 75 healthy controls) collected within the European consortium centres was tested for 67 SNPs. Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I and TOMM40, as main players in the regulation of CSF biomarkers levels, and as such possibility implicated in AD pathogenesis.
Alzheimer’s disease (AD) is a devastating neurological disorder of the elderly, affecting up to 30 million individuals worldwide. It is associated with disruption of neuronal function and subsequent gradual decline in cognition, behavior and personality changes, as well as impairments in the performance of activities of daily living, ultimately leading to death. During the last decades cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the field of AD, to be mainly applied in clinical practice. Amyloid-beta (Aβ1-42), total tau (T-tau), and phosphorylated tau (P-tau) are established biomarkers for AD. In patients, the concentration of CSF Aβ1-42 is decreased and associated to the sequestration of Aβ1-42 in amyloid plaques in the brain, while T-tau and P-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the correlation between selected SNPs (previously associated to AD biomarkers and/or AD risk) and AD markers Aβ1-42, T-tau and P-tau in CSF. The main goal of this study was therefore to replicate and validate the top findings of genetic variants associated to AD CSF biomarkers. A cohort of 675 samples (600 AD patients and 75 healthy controls) collected within the European consortium centres was tested for 67 SNPs. Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I and TOMM40, as main players in the regulation of CSF biomarkers levels, and as such possibility implicated in AD pathogenesis.
Descrição
Dissertação de Mestrado em Biotecnologia para as Ciências da Saúde
Palavras-chave
Doença de Alzheimer , Biomarcadores