Modulation of PHF-like tau phosphorylation in cultured neurones and transfected cells.
Two cellular systems have been used to investigate the modulation of tau hyperphosphorylation. In the first system, the effects of the excitatory amino acid glutamate, the microtubule destabilising agent colchicine, and beta 25-35-amyloid peptide on tau phosphorylation were studied in rat cortical neurones in primary culture. Using immunocytochemistry and western blot analysis, we demonstrated that tau in these cultures is normally highly phosphorylated, but a proportion becomes rapidly dephosphorylated following treatment of the cultures with glutamate or colchicine. These changes in tau phosphorylation occurred prior to cell death. In the second system, the ability of p42 MAP and p44 MAP kinases, glycogen synthase kinases 3 alpha and 3 beta (GSK-3 alpha and GSK-3 beta) to phosphorylate tau in transfected COS cells was investigated. Both GSK-3 alpha and GSK-3 beta phosphorylated tau to produce a PHF-like state of phosphorylation but the MAP kinases failed to induce such a transformation in tau. These results suggest that aberrant regulation of GSK-3 alpha/beta may be a pathogenic mechanism in Alzheimer's disease.
Anderton
B H
BH
Department of Neuroscience, Institute of Psychiatry, London, United Kingdom.
Brion
J P
JP
Couck
A M
AM
Davis
D R
DR
Gallo
J M
JM
Hanger
D P
DP
Ladhani
K
K
Latimer
D A
DA
Lewis
C
C
Lovestone
S
S
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D005609:Free Radicals; D007150:Immunohistochemistry; D009454:Neurofibrils / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D038461:Proline-Directed Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D014162:Transfection; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D005609:Free Radicals; D016875:tau Proteins; D038461:Proline-Directed Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases