Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology: In Focus

R. Liu, X. W. Zhou, H. Tanila, C. Bjorkdahl, J. Z. Wang, Z. Z. Guan, Y. Cao, J. Å Gustafsson, B. Winblad, J. J. Pei

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

Down-regulation of protein phosphatase 2A (PP2A) is thought to play a critical role in tau hyperphosphorylation in Alzheimer's disease (AD). In vitro phosphorylation of PP2A catalytic subunit at Y307 efficiently inactivates PP2A. A specific antibody against phosphorylated (p) PP2A (Y307) (PP2Ac-Yp307) was used to investigate possible PP2A down-regulation by known pathophysiological changes associated with AD, such as Aβ accumulation and oestrogen deficiency. Immunohistochemistry and immunofluorescence confocal microscopy showed an aberrant accumulation of PP2Ac-Yp307 in neurons that bear pretangles or tangles in the susceptible brain regions, such as the entorhinal cortical cortex and the hippocampus. Experimentally, increased PP2Ac-Yp307 was observed in mouse N2a neuroblastoma cells that stably express the human amyloid precursor protein with Swedish mutation (APPswe) compared with wild-type, and in the brains of transgenic APPswe/ presenilin (PS1, A246E) mice, which corresponded to the increased tau phosphorylation. Treating N2a cells with Aβ25-35 mimicked the changes of PP2Ac-Yp307 and tau phosphorylation in N2a APPswe cells. Knockout of oestrogen receptor (ER) α or ERβ gave similar changes of PP2Ac-Yp307 level and tau phosphorylation in the mouse brain. Taken together, these findings suggest that increased PP2A phosphorylation (Y307) can be mediated by Aβ deposition or oestrogen deficiency in the AD brain, and consequently compromise dephosphorylation of abnormally hyperphosphorylated tau, and lead to neurofibrillary tangle formation.

Original languageEnglish (US)
Pages (from-to)241-257
Number of pages17
JournalJournal of Cellular and Molecular Medicine
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2008

Keywords

  • Alzheimer's disease
  • Oestrogen receptor
  • PP2A phosphorylation (Y307)
  • Tau phosphorylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

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