Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells.
A hallmark of several neurodegenerative disorders, including Alzheimer's disease and tauopathies, is the hyperphosphorylation of the microtubule-associated protein tau. Tau phosphorylation by proline-directed and non-proline-directed protein kinases has been tested using antibodies PHF1 and 12E8, respectively. The effect of the lipid peroxidation product acrolein on these modes of phosphorylation has been assayed. We have found that acrolein, a peroxidation product from arachidonic acid, increases the phosphorylation of tau at the site recognized by PHF-1 both in human neuroblastoma cells and in primary cultures of mouse embryo cortical neurons. Whereas the basal phosphorylation of tau protein at the PHF1 site seems to be largely mediated by glycogen synthase kinase-3 (which is also activated in response to Abeta peptide), the acrolein-induced tau hyperphosphorylation at the same site is also due to p38 stress-activated kinase. These results support the view that oxidative stress and subsequent formation of lipid peroxidation products may contribute to tau protein phosphorylation in Alzheimer's disease and tauopathies.
Gómez-Ramos
Alberto
A
Centro de Biología Molecular, (CSIC/UAM), Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.
Díaz-Nido
Javier
J
Smith
Mark A
MA
Perry
George
G
Avila
Jesús
J
D000171:Acrolein / Q000633:toxicity*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000502:physiology*; D008094:Lithium / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D016875:tau Proteins; D016718:Arachidonic Acid; D000171:Acrolein; D008094:Lithium; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580