Pin1 affects Tau phosphorylation in response to Abeta oligomers.
We show that in hippocampal cultured neurons, dephosphorylation of peptidyl-prolyl cis-trans isomerase Pin1 on Ser16 is occurring during the early stages of exposure to Abeta (1-42) oligomers. This occurrence, resulting in Pin1 activation, is paralleled by Tau(Thr231) dephosphorylation, probably due to Pin1-mediated Tau isomerisation. Indeed, in the presence of the specific Pin1 inhibitor juglone, Abeta-induced Tau(Thr231)dephosphorylation is prevented. The involvement of protein phosphatase 2A (PP2A) in dephosphorylation of isomerised Tau is shown by the co-treatment of neurons with Abeta (1-42) and okadaic acid, a PP2A inhibitor, leading to Tau(Thr231) hyperphosphorylation. We also report the modulation, via Pin1, of Ser199, Ser396, Ser400 and Ser404 phosphorylation state in response to Abeta treatment. Taken together, these data suggest for the first time that an early Pin1 response might be transiently evoked by Abeta 1-42 oligomers, preventing Tau hyperphosphorylation. This evidence highlights the role of Pin1 as Tau phosphorylation modulator during Alzheimer onset.
Bulbarelli
Alessandra
A
Department of Experimental Medicine University of Milano-Bicocca, via Cadore 48, 20052 Monza (MI), Italy. alessandra.bulbarelli@unimib.it
Lonati
Elena
E
Cazzaniga
Emanuela
E
Gregori
Maria
M
Masserini
Massimo
M
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005562:Formazans; D006624:Hippocampus / Q000166:cytology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018625:Microscopy, Atomic Force / Q000379:methods; D009285:Naphthoquinones / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D020005:Propanols / Q000494:pharmacology; D051381:Rats; D013778:Tetrazolium Salts; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D003561:Cytarabine; D004791:Enzyme Inhibitors; D005562:Formazans; D007166:Immunosuppressive Agents; D009285:Naphthoquinones; D019319:Okadaic Acid; D010446:Peptide Fragments; D020005:Propanols; D013778:Tetrazolium Salts; D016875:tau Proteins; C414604:PDZD2 protein, rat; C075222:amyloid beta-protein (1-42); C079782:MTT formazan; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated; C005134:juglone