Amyloid-beta neuroprotection mediated by a targeted antioxidant

Abstract

Amyloid-beta (A 2)-induced neurotoxicity is a major contributor to the pathologies associated with Alzheimer's disease (AD). The formation of reactive oxygen species (ROS), an early response induced by the peptide and oligomeric derivatives of A 2, plays a significant role in effecting cellular pathogenesis. Here we employ particularly toxic forms of A 2 with cultured primary cortical/hippocampal neurons to elicit ROS and drive cellular dysfunction. To prevent and even reverse such effects, we utilized a cell-penetrating, peroxisome-targeted, protein biologic - called CAT-SKL. We show the recombinant enzyme enters neurons, reverses A 2-induced oxidative stress, and increases cell viability. Dramatic restorative effects on damaged neuronal processes were also observed. In addition, we used DNA microarrays to determine A 2's effects on gene expression in neurons, as well as the ability of CAT-SKL to modify such A 2-induced expression profiles. Our results suggest that CAT-SKL, a targeted antioxidant, may represent a new therapeutic approach for treatment of disorders, like Alzheimer's disease, that are driven through oxidative stress. Preclinical testing is ongoing.