| Summary: | The leading hypothesis for Alzheimer's Disease (AD) has traditionally focused on the aggregation of Amyloid-β into amyloid plaques. However, research has yet to definitively prove the role of the amyloid peptide in the pathology of the disease. Given that all therapeutics targeting amyloid plaques have failed in clinical trials, with one exception, there is a need to explore alternative approaches to treatment of this disease. Therefore, we examined other factors that are altered during AD pathogenesis. Many AD patients have dysregulation of metal ions, such as copper and zinc, in addition to accumulation of Amyloid-β. The interaction between Amyloid-β and copper can result in the production of reactive oxygen species (ROS). ROS can cause damage to neurons and surrounding tissues resulting in degradation of the brain. Therefore, our work focuses on disrupting the interaction between Amyloid-β and copper via chelation therapy to prevent ROS formation and, in turn, reduce neurotoxicity. In this study, copper chelation with beta alanine reduced the amount of ROS produced in the brains of C. elegans expressing pan-neuronal Amyloid-β, amino acids 1-42. In response to chelation, the expression of the antioxidant gene, gst-4, was also reduced. Importantly, there was also a positive correlation between copper chelation and increased lifespan in the Amyloid-β expressing C. elegans. Consistent with our previous in vitro work, Amyloid-β expression in vivo was not altered following treatment. Taken together, these results suggest that copper chelation has the potential to serve as an AD therapeutic resulting in increased longevity.
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