Browsing by Author "Couto, F"
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- Crosstalk between genetics, gene expression and biochemical markers supports systemic iron homeostasis dysregulation in alzheimer diseasePublication . Crespo, A; Silva, B; Ferreira, C; Marquesa, L; Marcelino, E; Maruta, C; Costa, S; Timóteo, A; Vilares, A; Couto, F; Faustino, P; Correia, AP; Verdelho, A; Porto, G; Guerreiro, M; Herrero Valverde, A; Costa, C; Mendonça, A; Costa, L; Martins, M
- Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patientsPublication . Guerreiro, C; Silva, B; Crespo, A; Marques, L; Costa, S; Timóteo, A; Marcelino, E; Maruta, C; Vilares, A; Matos, M; Couto, F; Faustino, P; Verdelho, A; Guerreiro, M; Herrero Valverde, A; Costa, C; Mendonça, A; Martins, M; Costa, LAlzheimer's disease (AD) is a neurodegenerative disorder of still unknown etiology and the leading cause of dementia worldwide. Besides its main neuropathological hallmarks, a dysfunctional homeostasis of transition metals has been reported to play a pivotal role in the pathogenesis of this disease. Dysregulation of iron (Fe) metabolism in AD has been suggested, particularly at the level of cellular iron efflux. Herein, we intended to further clarify the molecular mechanisms underlying Fe homeostasis in AD. In order to achieve this goal, the expression of specific Fe metabolism-related genes directly involved in Fe regulation and export was assessed in peripheral blood mononuclear cells (PBMCs) from 73AD patients and 74 controls by quantitative PCR. The results obtained showed a significant decrease in the expression of aconitase 1 (ACO1; P=0.007); ceruloplasmin (CP; P<0.001) and amyloid-beta precursor protein (APP; P=0.006) genes in AD patients compared with healthy volunteers. These observations point out to a significant downregulation in the expression of genes associated with ferroportin-mediated cellular Fe export in PBMCs from AD patients, when compared to controls. Taken together, these findings support previous studies suggesting impairment of Fe homeostasis in AD, which may lead to cellular Fe retention and oxidative stress, a typical feature of this disease.
- A disfunção dopaminérgica mesolímbica na psicose: uma revisão da literaturaPublication . Moura, P; Couto, F; Abreu, M; Vian, J; Moura, T; Frade, P; Levy, PIntrodução: Desde há algumas décadas que se pensa que uma hiperactividade dopaminérgica da via mesolímbica esteja implicada na génese dos sintomas positivos da esquizofrenia. Objectivos: Nesta revisão da literatura procurámos interligar as várias áreas do conhecimento actual, procurando fazer a ponte com a prática clínica. Métodos: Foi efectuada uma pesquisa sistemática da literatura em inglês, até Abril de 2014 através da PUBMED utilizando como termos MeSH (medical subject headings) “mesolimbic” e “psychosis”, tendo-se incluído revisões da literatura. Resultados e Conclusões: Foram encontrados 111 artigos, tendo-se excluído 56 por, após leitura do resumo, se concluir que não estavam relacionados com o tema. Dos restantes 55 foram seleccionados 14 artigos tendo sido mantidas as abreviaturas em inglês para facilitar a sua consulta posterior. São apresentadas evidências sobre o papel desempenhado por vários sistemas reguladores no desenvolvimento dos sintomas positivos associados não apenas a esta doença mas às várias perturbações em que ocorrem, assim como a possível relação entre esses vários factores. Entre os vários sistemas discutidos conta-se a influência do neurodesenvolvimento, da regulação pelos receptores nicotí- nicos da acetilcolina, a influência dos canais de potássio KCNQ, a regulação por péptidos neurotransmissores, pela adenosina e pela fosfodiesterase 10A, assim como avanços na compreensão da etiologia da esquizofrenia. Trata-se, portanto, de um enunciado do substrato neurobiológico dos sintomas positivos.
- Genetic and biochemical markers in patients with Alzheimer's disease support a concerted systemic iron homeostasis dysregulationPublication . Crespo, A; Silva, B; Marques, L; Marcelino, E; Maruta, C; Costa, S; Timóteo, A; Vilares, A; Couto, F; Faustino, P; Correia, AP; Verdelho, A; Porto, G; Guerreiro, M; Herrero Valverde, A; Costa, C; Mendonça, A; Costa, L; Martins, MAlzheimer's disease (AD) is the most common form of dementia in the elderly individuals, resulting from a complex interaction between environmental and genetic factors. Impaired brain iron homeostasis has been recognized as an important mechanism underlying the pathogenesis of this disease. Nevertheless, the knowledge gathered so far at the systemic level is clearly insufficient. Herein, we used an integrative approach to study iron metabolism in the periphery, at both genotypic and phenotypic levels, in a sample of 116 patients with AD and 89 healthy control subjects. To assess the potential impact of iron metabolism on the risk of developing AD, genetic analyses were performed along with the evaluation of the iron status profile in peripheral blood by biochemical and gene expression studies. The results obtained showed a significant decrease of serum iron, ferritin, and transferrin concentrations in patients compared with the control subjects. Also, a significant decrease of ferroportin (SLC40A1) and both transferrin receptors TFRC and TFR2 transcripts was found in peripheral blood mononuclear cells from patients. At the genetic level, significant associations with AD were found for single nucleotide polymorphisms in TF, TFR2, ACO1, and SLC40A1 genes. Apolipoprotein E gene, a well-known risk factor for AD, was also found significantly associated with the disease in this study. Taken together, we hypothesize that the alterations on systemic iron status observed in patients could reflect an iron homeostasis dysregulation, particularly in cellular iron efflux. The intracellular iron accumulation would lead to a rise in oxidative damage, contributing to AD pathophysiology.