Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease
(A) TC-2153 failed to increase tyrosine phosphorylation of STEP substrates in STEP KO cortical neurons. WT and STEP KO cultures were treated with TC-2153 (0.1 and 1 µM), vehicle (0.1% DMSO), or sodium orthovanadate (Na3VO4, 1 mM) for 1 h. Phosphorylation of GluN2B Y1472, Pyk2 Y402, and ERK1/2 Y204/187 was normalized to total protein level and then to GAPDH as loading control (*p<0.05, **p<0.01 one-way ANOVA with post hoc Bonferroni test, compared with veh-treated controls, n = 4). (B–G) TC-2153 increased the phosphorylation of ERK1/2 Y204/187 and Pyk2 Y402 in frontal cortex and hippocampus, but not in cerebellum, spleen, kidney, or pancreas, all tissues that do not have STEP. Mice were injected i.p. with TC-2153 (10 mg/kg; n = 4) or vehicle (n = 4) and were sacrificed 3 h later. Changes are expressed as the mean ± s.e.m. of pERK1/2 and pPyk2 normalized to total protein level and then to GAPDH (*p<0.05, **p<0.01; two-way ANOVA follow by Tukey's H.S.D. test).