Journal
NEUROBIOLOGY OF AGING
Volume 29, Issue 9, Pages 1348-1358Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2007.03.012
Keywords
glycogen synthase kinase-3 beta; protein phosphatase 2A; I-2(PP-2A)
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The activity of protein phosphatase-2A (PP-2A) is significantly suppressed in the brain of Alzheimer's disease (AD) patients, but the mechanism is not understood. Here, we found an in vivo association of glycogen synthase kinase 30 (GSK-3 beta) with inhibitor-2 of PP-2A (I-2(PP-2A)). The activation of GSK-3 resulted in accumulation of I-2(PP-IA) with concomitant suppression of PP-2A activity and increases of tau phosphorylation in HEK293, N2a and PC12 cells, while inhibition of GSK-3 caused decreases of I-2(PP-2A) with increased PP-2A activity and decreased tau phosphorylation. A positive correlation between GSK-3 beta and I-2(PP-2A) (R = 0.9158) and a negative correlation between GSK3 beta and PP-2A (R = -0.9166) were detected. GSK-3 activation did not affect I-2(PP-2A) mRNA level, while it increased the mRNA level of a heterogeneous ribonucleoprotein A18 (hnRNP A18). The activation of GSK-3 increased the expression and the activity of proteasome system. It suggests that activation of GSK-3 inhibits PP-2A through up-regulation of I-2(PP-2A) with hnRNP A18-involved mechanism. (c) 2007 Elsevier Inc. All rights reserved.
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