Author(s):
C. Crespo, Ângela 
; Marques, Liliana ; Marcelino, Erica ; Maruta, Carolina ; Costa, Sónia ; Timóteo, Ângela ; Vilares, Arminda ; Silva, Bruno ; Simões Couto, Frederico ; Faustino, Paula ; Correia, Ana Paula ; Verdelho, Ana ; Porto, Graça ; Guerreiro, Manuela ; Herrero, Ana ; Costa, Cristina ; de Mendonça, Alexandre ; Costa, Luciana ; Martins, Madalena
Date: 2012
Persistent ID: http://hdl.handle.net/10400.18/1323
Origin: Repositório Científico do Instituto Nacional de Saúde
Subject(s): Determinantes Imunológicos em Doenças Crónicas
Description
This work was supported by Fundação Astrazeneca through the “Programa de Apoio à Investigação” . Presented at the “International Conference in Alzheimer’s Disease 2009 The distinction between normal aging and Alzheimer's disease (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 as 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 117 AD patients and 91 healthy controls; (II) testing in the same sample a set of Fe/Cu metabolism-related genes and APOE for association with AD. Genetic analysis was performed through high density SNP genotyping of the candidate genes CP, CYBRD1, HAMP, HFE, IREB1, IREB2, SLC11A2, SLC40A1, TF, TFR2, FB19, CALR, and APOE. Biochemical analysis was assessed for: serum Fe, transferrin, transferrin saturation and serum ferritin levels. The most significant difference was found between AD patients and controls for serum Fe concentration (76.63 ± 26.36 μg/dL and 86.67 ± 25.18 μg/dL, respectively, P=0.003), although other significant differences were also found for transferrin and ferritin levels (P=0.016 and P=0.033, respectively). Significant associations with AD were found for two SNPs in TF (P=0.0147 and P=0.0415), one SNP in TFR2 (P=0.0055) and for the first time in IREB1 (P=0.0258) and SLC40A1 (P=0.0210) genes. In addition to the significant independent effects, evidence for interaction between IREB1 and TFR2, CP, IREB2 and SLC40A1 markers was also found. The overall results suggest the involvement of these iron metabolism genes in Alzheimer etiology. APOE was also significantly associated with AD (P=0.0007), 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 codified by SLC40A1 is the only known Fe exporter in mammalian cells. Also, the TFR2 polymorphism found to be associated with AD is located at the putative promoter region of the TfR2_beta isoform which seems to be involved in SLC40A1 transcriptional regulation. On the other hand, IREB1 codifies a cytosolic protein which binds to iron-responsive elements (IREs) found in RNA from several iron metabolism-related proteins as ferritin, TfR, Fpn itself and importantly GEECD, Tomar, Portugal, Jun2012 APP. 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 Fe metabolism involvement in AD.
