Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 49, Issue 2, Pages 365-375Publisher
IOS PRESS
DOI: 10.3233/JAD-150497
Keywords
GSK-3 beta; methylation; phosphorylation; PP2A
Categories
Funding
- Nantong University and the New York State Office of People with Developmental Disabilities (OPWDD)
- U.S. Alzheimer's Association [IIRG-10-173154]
- National Natural Science Foundation of China [81030059, 81300978]
- Graduate research and innovation projects [YKC13050]
- Priority Academic Program Development of Jiangsu Higher Education institutions (PAPD)
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Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase-3 beta (GSK-3 beta) and protein phosphate 2A (PP2A) are crucial enzymes to regulate tau phosphorylation. GSK-3 beta activity is regulated by its inhibitory phosphorylation at Ser9. We previously reported the cross-talk between GSK-3 beta and PP2A signaling and showed that PP2A could dephosphorylate GSK-3 beta at Ser9. Here, we investigated the dephosphorylation of GSK-3 beta in brain extracts in the presence of phosphatase inhibitors and found that a PP2A-like phosphatase activity was required for dephosphorylation of GSK-3 beta at Ser9. PP2A interacted with GSK-3 beta and suppressed its Ser9 phosphorylation in vitro and in HEK-293FT cells. Activity of PP2A negatively correlated to the level of phosphorylated GSK-3 beta in kainic acid-induced excitotoxic mouse brain. Alteration of methylation of the catalytic subunit of PP2A (PP2Ac) at Leu309 did not affect GSK-3 beta phosphorylation. These findings suggest that Leu309 methylation is not required for PP2A to dephosphorylate GSK-3 beta at Ser9.
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