Amyloid-beta neuroprotection mediated by a targeted antioxidant

作者：Giordano Courtney R; Terlecky Laura J; Bollig Fischer Aliccia; Walton Paul A; Terlecky Stanley R^*

来源：Scientific Reports, 2014, 4(1): 4983.

DOI：10.1038/srep04983

Amyloid-beta (A beta)-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 beta, plays a significant role in effecting cellular pathogenesis. Here we employ particularly toxic forms of A beta 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 beta-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 beta's effects on gene expression in neurons, as well as the ability of CAT-SKL to modify such Ab-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.

• 出版日期2014-5-15