Amyloid-beta neuroprotection mediated by a targeted antioxidant.
Amyloid-beta (Aβ)-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 Aβ, plays a significant role in effecting cellular pathogenesis. Here we employ particularly toxic forms of Aβ 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 Aβ-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 Aβ's effects on gene expression in neurons, as well as the ability of CAT-SKL to modify such Aβ-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.
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, 48201.
Courtney R
CR
Giordano
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, 48201.
Laura J
LJ
Terlecky
1] Department of Oncology, Wayne State University School of Medicine, Detroit, MI, 48201 [2] Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, 48201.
Aliccia
A
Bollig-Fischer
Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, CA, N6A 5C1.
Paul A
PA
Walton
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, 48201.
Stanley R
SR
Terlecky
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D015870:Gene Expression / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species