P4‐317: Alzheimer's Patients Exhibit Defective Serum Ceruloplasmin Associated with Defective Copper Binding

Abstract

b-amyloid (Ab)-rich regions of the brain is a distinct feature of Alzheimer's disease (AD). Compelling evidence shows a strong correlation between accumulation of aggregated neurotoxic b-amyloid peptides and oxidative stress in the brains of patients afflicted with AD. One hypothesis for this correlation involves the direct and harmful interaction of aggregated Ab peptides with cellular proteins responsible for maintaining normal, cellular levels of reactive oxygen species (ROS). Objective: To identify specific, destructive interactions of Ab peptides with cellular antioxidant enzymes and to inhibit these harmful protein-amyloid interactions. Methods: Using cell-free and cellular assays, in addition to fluorescence microscopy, we demonstrate that exposure of human neuroblastoma cells to cytotoxic preparations of aggregated Ab peptides results in significant intracellular co-localization of Ab with catalase-an antioxidant enzyme responsible for catalyzing the degradation of the ROS, hydrogen peroxide (H 2 O 2 )-and that these catalase-Ab interactions contribute to an observed increase in cellular levels of H 2 O 2 . Furthermore, we evaluate the effects of generating protein-resistive surface coatings on aggregated Ab peptides in cells by using two oligo(ethylene glycol) derivatives of 6-methylbenzothiazole aniline (BTA-EG 4 and BTA-EG 6 ) as synthetic molecular probes that exhibit the following characteristics: 1)capability of generating protein-resistive surface coatings on aggregated Ab peptides (to inhibit catalase-amyloid interactions in cells), 2)lack of toxicity, 3)cell permeability, 4)capability of localizing to the same subcellular compartments of cells as Ab, 5)intrinsic fluorescence properties (to visualize the intracellular localization of the molecules), and 6)chemical stability in oxidative environments. We show that these small molecule inhibitors of catalase-amyloid interactions protects the hydrogen peroxide-degrading activity of catalase in an Ab-rich environment, leading to reduction of the co-localization of catalase and Ab in cells, inhibition of Ab-induced increase in cellular levels of H 2 O 2 (Figure 1), and neutralization of the toxicity of Ab peptides. Conclusion: These studies provide evidence for the important role of catalase-amyloid interactions in Ab-induced oxidative stress and propose a novel molecular strategy to inhibit such harmful interactions in AD.Background: Although there were implications on the way stress events affect memory and cognition, not many studies have been performed. The majority of these studies measured hippocampal volume in patients with PTSD (Post Traumatic Stress Disorder). Hippocampus which plays a vital role in memory formation was found to be of reduced volume in people who suffered PTSD compared to control subjects Many similarities are observed between PTSD and Alzheimer's Disease, such as (a) Hippocampus is the most vulnerable brain structure (b) The first symptom is memory problems, (c) Increased levels of glucocorticoids (GCs) are observed in both c...