Friday, January 25, 2013

Desferrioxamine

     Desferrioxamine

    Autopsy samples from AD patients reveal elevated levels of iron, particularly in the neurons of the basal ganglia Iron is relevant to neurodegenerative pathogenesis in the brains of AD patients, as evidenced by their disrupted brain-iron distribution. Since we had discovered that the APP 5'UTR is a modified ironresponsive element, we decided to test whether iron chelation by Df can suppress translation conferred to a luciferase reporter by APP mRNA 5'UTR sequences. In the first step, a Luciferase-reporter construct, MS121, was prepared by inserting a PCR-generated APP-mRNA 5'UTR fragment.

    Neuroblastoma cells (SY5Y) were transfected with this APP-5'UTR-specific construct and cells were then exposed to Df (5uM), before preparation aof cell lysates and use of a luciferase assay to determine levels of reporter gene activity. As a negative control, neuroblastoma cells were transfected with a parental pGL-3 reporter plasmid. The results showed that the APP 5'UTR was clearly a target for the action of Df to suppress APP-5'UTR translational regulation.

     Desferrioxine was shown to be beneficial for Alzheimer's patients in one study. However, the use of this iron chelator is currently restricted to the treatment of patients with sickle cell disease, thalassemias, arid to counteract iron poisoning. We reasoned that Df would be a strong positive control to screen for new compounds, including anticholinesterase derivatives (phenserine), which might suppress APP mRNA translation without chelating intracellular iron.

No comments: