title: Effects of the superoxide dismutase/catalase mimetic EUK-207 in a mouse model of Alzheimer's disease: protection against and interruption of progression of amyloid and tau pathology and cognitive decline.
abstract: Alzheimer's disease (AD) is characterized by progressive cognitive deficits, accumulation of amyloid-β (Aβ) and intracellular neurofibrillary tangles, and neuronal death. Additionally, mitochondrial dysfunction and free radical damage are hallmarks of AD brain. Here we set out to define the role of oxidative stress in AD pathogenesis and progression by chronically treating 3xTg-AD mice with the superoxide dismutase (SOD)/catalase mimetic, EUK-207. Treatment started at 4 months before onset of pathology and cognitive deficits, and continued until 9 months, when the AD phenotype was established. Cognitive performance was assessed using fear conditioning, and brain oxidative stress, Aβ, and tau pathology were analyzed. At 9 months, 3xTg-AD mice exhibited a decline in performance in both contextual and cued fear conditioning, as compared to wild-type mice. EUK-207-treated 3xTg-AD mice did not display any deficit in fear conditioning and exhibited reduced Aβ, tau, and phosphorylated tau accumulation in amygdala and hippocampus, as well as brain levels of Aβ42, oxidized nucleic acids, and lipid peroxidation. The effects of a 3-month treatment after pathology onset at 9 months on cognitive performance, brain oxidative stress, Aβ, and tau pathology were also evaluated. EUK-207-treated 3xTg-AD mice did not display any deficit in fear conditioning and were protected against increases in brain levels of oxidized nucleic acids and lipid peroxidation; they also had reduced Aβ, tau, and hyperphosphorylated tau accumulation in amygdala and hippocampus. Our results confirm a critical role for oxidative stress in AD pathogenesis and progression and suggest the potential usefulness of EUK-207 in AD treatment.
authors.affiliation: Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Clausen
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Xu
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Bi
authors.forename: Michel
authors.initials: M
authors.lastname: Baudry
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009942:Organometallic Compounds / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C476761:EUK 207; D009942:Organometallic Compounds; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D002374:Catalase; D013482:Superoxide Dismutase