Affiliations: [a] Sanders-Brown Center on Aging and Alzheimer's Disease Research Center, 101 Sanders-Brown Bldg, University of Kentucky, Lexington, KY 40536-0230, USA | [b] Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA | [c] Departments of Pathology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA | [d] Departments of Pathology and Neurology, University of Kentucky, Lexington, KY 40536-0230, USA
Correspondence:
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Corresponding author: Mark A. Lovell, 135 Sanders-Brown Bldg., 800 S. Limestone St., Lexington, KY 40536, USA. Tel.: +1 859 257 1412 x 251; Fax: +1 859 323 2866; E-mail: [email protected].
Abstract: Neurofibrillary tangles (NFT) containing paired helical filaments (PHF) composed of abnormally phosphorylated tau are one of the hallmark lesions of the Alzheimer's disease (AD) brain. Although phosphorylation of tau is thought to precede the formation of PHF, the kinases/phosphatases involved remain poorly understood. Here we report that treatment of primary rat cortical neuron cultures with cuprizone, a copper chelator, in combination with oxidative stress (Fe2+/H2O2), significantly increased aberrant tau phosphorylation identified by TG3 immunochemistry. To determine the potential contribution of glycogen synthase kinase-3 (GSK-3) to the phosphorylation of tau in this model, activity of GSK-3 was determined. Cultures treated with cuprizone/Fe2+/H2O2 showed significantly increased GSK-3 activity compared with control cultures or cultures treated with cuprizone, or Fe2+/H2O2 alone. Concomitant treatment of cultures with lithium, a GSK-3 inhibitor, significantly decreased GSK-3 activity and reduced TG3 staining. Together these data suggest a culture model of hyperphosphorylated tau that implicates increased GSK-3 activity.
