Hyperphosphorylation at serine 199/202 of tau factor in the gerbil hippocampus after transient forebrain ischemia

• DOI: 10.1016/j.bbrc.2006.06.096
• Publication Date: 2006-06-24T11:27:02Z
• Authors: Motohiro Morioka; Takayuki Kawano; Shigetoshi Yano; Yutaka Kai; Hiromasa Tsuiki; Yutaka Yoshinaga; Jun Matsumoto; Tatsumi Maeda; Jun-ichiro Hamada; Hideyuki Yamamoto; Kohji Fukunaga; Jun-ichi Kuratsu
• Keywords: Male; 0303 health sciences; Binding Sites; Apoptosis; Hippocampus; Brain Ischemia; 03 medical and health sciences; Reperfusion Injury; Serine; Animals; Phosphorylation; Gerbillinae; Protein Binding

We examined the phosphorylation state of tau factor in hippocampal delayed neuronal death (DND) after transient forebrain ischemia. A transient phosphorylation increase at serine 199/202 but not serine 396 of tau factor after transient ischemia was clearly observed. Intraventricular injections of olomoucine and U-0126 (CDK5 and MAP kinase inhibitors, respectively) inhibited hyperphosphorylation. In contrast, wortmannin (PI3 kinase inhibitor) increased phosphorylation at serine 199/202 and corresponded with an increase in GSK3 phosphorylation. Our findings suggest that CDK5, MAP kinase, and GSK3 phosphorylate these sites after ischemia. We prepared recombinant normal human tau (N-Tau40) with TAT-HA protein and dephosphorylated-form human Tau-40 (D-tau40) in which 199/202 serines were changed to alanine by site-directed mutagenesis. Intraventricularly injected D-tau40 protected somewhat against DND while N-Tau40 did not. These data suggest that hyperphosphorylation at serine 199/202 of tau factor is induced by MAP kinase, CDK5, and GSK3, and contributes to ischemic neuronal injury.