Brain deregulation of endogenous (Fe, Cu, and Zn) as well and exogenous metals (Al) contributes to several neurodegenerative diseases. In that respect, Al is a well known neurotoxin that has been implicated as contributing factor of Alzheimer’s disease (AD). In a previous study (Drago et al., Rejuvenation Res. 2008; 11: 861-871), we found that, Al is significantly increased [at 14 months of age (m.o.a.)] in the cerebral cortex of female triple transgenic AD mice (3xTg-AD), an AD model overexpressing human mutant APP, PS1 and phosphorylated tau. In this study, we analyzed Al levels in the hippocampus of 3xTg-AD mice at 14 m.o.a. and found the metal increased when compared with age-matched wild-type (C57BL6/129SV, CTRL) mice. Suggesting the age dependency of the phenomenon, Al was not detected in the hippocampi of mice of both strains at 7 m.o.a.. Interestingly, hippocampal Al concentrations showed a significant positive correlation with the appearance of increased levels of human Aβ 1-40 and Aβ 1-42 present in the 3xTg-AD mice, thereby suggesting a functional link between changes in Al uptake and the development of the amyloid pathology. In order to assess the molecular basis of this age-dependent increase of hippocampal Al uptake, we evaluated, using microarray analysis, changes in expression levels of genes known to be involved in brain and cellular Al influx such as the transferrin receptor (TFR), the monocarboxylate transporters (MCTs), and the cystine-glutamate transporter (Xc-). When analyzing hippocampi of WT and 3xTg-AD mice at 3 and 12 m.o.a., we found a significant up-regulation of MCT1 and Xc- in 3 months old 3xTg-AD mice while this up-regulation was lost in AD mice at 12 m.o.a.. In contrast, TFR and MCT2 were up-regulated in young (3 m.o.a.) and old (12 m.o.a.) AD mice. Thus, we found that TRF and MCT2 mRNA levels increased with aging, matching the observed age-related increase in hippocampal Al. Overall, our findings suggest that Al homeostasis is linked to the progression of the amyloid pathology, likely through an altered expression of TFR and MCT2.
Increase of hippocampal aluminum is linked to the progression of amyloid pathology in a triple transgenic mouse model of Alzheimer's disease.
CIAVARDELLI, DOMENICO;
2011-01-01
Abstract
Brain deregulation of endogenous (Fe, Cu, and Zn) as well and exogenous metals (Al) contributes to several neurodegenerative diseases. In that respect, Al is a well known neurotoxin that has been implicated as contributing factor of Alzheimer’s disease (AD). In a previous study (Drago et al., Rejuvenation Res. 2008; 11: 861-871), we found that, Al is significantly increased [at 14 months of age (m.o.a.)] in the cerebral cortex of female triple transgenic AD mice (3xTg-AD), an AD model overexpressing human mutant APP, PS1 and phosphorylated tau. In this study, we analyzed Al levels in the hippocampus of 3xTg-AD mice at 14 m.o.a. and found the metal increased when compared with age-matched wild-type (C57BL6/129SV, CTRL) mice. Suggesting the age dependency of the phenomenon, Al was not detected in the hippocampi of mice of both strains at 7 m.o.a.. Interestingly, hippocampal Al concentrations showed a significant positive correlation with the appearance of increased levels of human Aβ 1-40 and Aβ 1-42 present in the 3xTg-AD mice, thereby suggesting a functional link between changes in Al uptake and the development of the amyloid pathology. In order to assess the molecular basis of this age-dependent increase of hippocampal Al uptake, we evaluated, using microarray analysis, changes in expression levels of genes known to be involved in brain and cellular Al influx such as the transferrin receptor (TFR), the monocarboxylate transporters (MCTs), and the cystine-glutamate transporter (Xc-). When analyzing hippocampi of WT and 3xTg-AD mice at 3 and 12 m.o.a., we found a significant up-regulation of MCT1 and Xc- in 3 months old 3xTg-AD mice while this up-regulation was lost in AD mice at 12 m.o.a.. In contrast, TFR and MCT2 were up-regulated in young (3 m.o.a.) and old (12 m.o.a.) AD mice. Thus, we found that TRF and MCT2 mRNA levels increased with aging, matching the observed age-related increase in hippocampal Al. Overall, our findings suggest that Al homeostasis is linked to the progression of the amyloid pathology, likely through an altered expression of TFR and MCT2.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
