期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 30, 期 1, 页码 183-208出版社
IOS PRESS
DOI: 10.3233/JAD-2012-111298
关键词
Aging; Alzheimer's disease; amyloid-beta; antioxidants; fear conditioning; free radicals; learning; oxidative stress; superoxide dismutase/catalase mimetics; tau
资金
- Alzheimer's Association [IIG07-60194]
Alzheimer's disease (AD) is characterized by progressive cognitive deficits, accumulation of amyloid-beta (A beta) 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, A beta, 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 A beta, tau, and phosphorylated tau accumulation in amygdala and hippocampus, as well as brain levels of A beta(42), 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, A beta, 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 A beta, 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.
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