Study of iron and copper metabolism in Alzheimer\2019s disease

Tese de mestrado, Biologia (Biologia Molecular humana), 2009, Universidade de Lisboa, Faculdade de CiênciasAlzheimer's disease (AD) is the most frequent neurodegenerative disorder worldwide, remarkably characterized by memory impairment. The distinction between normal aging and AD is a relevant step to combat this disease efficiently; thus, the identification of biomarkers and genetic factors underlying AD pathology is extremely important. Oxidative injury in the brain, mediated by the imbalance of redox-active metals, iron (Fe) and copper (Cu), has been recognized to contribute to the pathology of AD. In this context, we further investigated this hypothesis by: (I) comparing serum biochemical markers of Fe/Cu metabolism in a sample of 73 AD patients and 60 healthy controls; (II) testing, in the same sample, a set of Fe/Cu metabolism-related genes and APOE for association with AD. Significant differences were found between female AD patients and controls for serum Fe concentration (71.02 ± 22.34 µg/dL and 86.38 ± 20.80 µg/dL, respectively, p=0.001) and transferrin saturation (22.29 ± 7.89 % and 26.21 ± 6.24 %, respectively, p=0.007). A significant association with AD was found for TF transferrin gene (p=0.0082) and for the first time for SLC40A1 ferroportin (Fpn) gene (p=0.0355). APOEε4 was also significantly associated with AD (p=0.0004), in agreement with previous studies. We hypothesize that the lower serum Fe concentration observed in AD patients can be due to impaired Fe excretion from cells, since Fpn is the only known Fe exporter in mammalian cells. The intracellular accumulation of Fe, particularly in the brain, where Fpn is also expressed, would lead to a rise in oxidative damage, contributing to the AD physiopathology. Further research is demanded in a greater sample to confirm the results obtained in this pilot study. Noteworthy, an integrative approach was followed to deal with heterogeneity in this complex disorder, and new directions were raised related to the study of the involvement of Fe metabolism in AD.Resumo alargado em português disponível no document