Bimodal modulation of tau protein phosphorylation and conformation by extracellular Zn2+ in human-tau transfected cells.
Abnormal homeostasis of heavy metals is a well-documented physiopathological mechanism in Alzheimer's disease. An exacerbation of these abnormalities is best illustrated in the amyloid plaques in Alzheimer's disease brain tissue, in which zinc reaches the enormous concentration of 1000 microM. Zinc in the plaques is thought to originate from impaired glutamatergic neurons distributed in the associative cortex and limbic structures of normal brain. Although the characteristics of zinc binding to Abeta and its role in promotion of Abeta aggregation have been intensively studied, the contribution of zinc to the development of tau pathology remains elusive. To further document the effect of zinc we have investigated the modifications of tau phosphorylation, conformation and association to microtubules induced by zinc in clonal cell lines expressing a human tau isoform. A bimodal dose dependent effect of zinc was observed. At 100 microM zinc induced a tau dephosphorylation on the PHF-1 epitope, and at higher zinc concentrations induced the appearance of the abnormal tau conformational epitope MC1 and reduced the electrophoretic mobility of tau, known to be associated to increased tau phosphorylation. High zinc concentrations also increased glycogen synthase kinase-3beta (GSK-3beta) phosphorylation on tyrosine 216, a phosphorylation associated with increased activity of this tau kinase. Live imaging of tau-EGFP expressing cells demonstrated that high zinc concentrations induced a release of tau from microtubules. These results suggest that zinc plays a significant role in the development of tau pathology associated to Alzheimer's disease.
Boom
Alain
A
Laboratory of Histology, Neuroanatomy and Neuropathology, Faculty of Medicine, Université Libre de Bruxelles, 808, route de Lennik, CP-620, B-1070 Brussels, Belgium. aboom@ulb.ac.be
Authelet
Michèle
M
Dedecker
Robert
R
Frédérick
Christelle
C
Van Heurck
Roxane
R
Daubie
Valery
V
Leroy
Karelle
K
Pochet
Roland
R
Brion
Jean-Pierre
JP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000939:Epitopes; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006706:Homeostasis; D006801:Humans; D007211:Indoles / Q000378:metabolism; D008301:Maleimides / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019287:Zinc Sulfate / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007211:Indoles; D008301:Maleimides; C085349:PHF-1 monoclonal antibody; D011993:Recombinant Fusion Proteins; C417521:SB 216763; D016875:tau Proteins; D019287:Zinc Sulfate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3