An okadaic acid-induced model of tauopathy and cognitive deficiency.
Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes cognitive and behavioral deterioration in the elderly. Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of AD that has been shown to correlate positively with the severity of dementia in the neocortex of AD patients. In an attempt to characterize an in vivo AD tauopathy model, okadaic acid (OA), a protein phosphatase inhibitor, was microinfused into the right lateral dorsal hippocampus area of ovariectomized adult rat. Cognitive deficiency was seen in OA-treated rats without a change in motor function. Both silver staining and immunohistochemistry staining revealed that OA treatment induces NFTs-like conformational changes in both the cortex and hippocampus. Phosphorylated tau as well as cyclin-dependent kinase 5 (cdk5) and its coactivator, p25, were significantly increased in these regions of the brain. Oxidative stress was also increased with OA treatment as measured by protein carbonylation and lipid peroxidation. These data suggest that the unilateral microinfusion of OA into the dorsal hippocampus causes cognitive deficiency, NFTs-like pathological changes, and oxidative stress as seen in AD pathology via tau hyperphosphorylation caused by inhibition of protein phosphatases.
Zhang
Zhang
Z
Deptment of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Simpkins
James W
JW
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D018782:Maze Learning / Q000187:drug effects; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D019319:Okadaic Acid / Q000008:administration & dosage / Q000633:toxicity*; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology
D004791:Enzyme Inhibitors; D019319:Okadaic Acid
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