Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3.
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 (Fe(2+)/H(2)O(2)), 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/Fe(2+)/H(2)O(2) showed significantly increased GSK-3 activity compared with control cultures or cultures treated with cuprizone, or Fe(2+)/H(2)O(2) 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.
Lovell
Mark A
MA
Sanders-Brown Center on Aging and Alzheimer's Disease Research Center, 101 Sanders-Brown Bldg, University of Kentucky, Lexington, KY 40536-0230, USA. malove2@uky.edu
Xiong
Shuling
S
Xie
Chengsong
C
Davies
Peter
P
Markesbery
William R
WR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology*; D002614:Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology; D003300:Copper / Q000037:antagonists & inhibitors / Q000378:metabolism; D003471:Cuprizone / Q000008:administration & dosage / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D007150:Immunohistochemistry; D007501:Iron / Q000037:antagonists & inhibitors / Q000378:metabolism; D045022:Lactate Dehydrogenases / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D016875:tau Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D016875:tau Proteins; D003471:Cuprizone; D003300:Copper; D007501:Iron; D045022:Lactate Dehydrogenases; D038362:Glycogen Synthase Kinase 3