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

R Liu1, X-W Zhou, H Tanila

  • 1Karolinska Institutet, KI-Alzheimer Disease Research Center (KI-ADRC), Novum, Huddinge, Sweden.

Journal of Cellular and Molecular Medicine
|January 23, 2008
PubMed

Insights

Protein phosphatase 2A (PP2A) inactivation via Y307 phosphorylation is linked to Alzheimer's disease (AD). Amyloid-beta (Abeta) and estrogen deficiency increase this inactivation, promoting tau hyperphosphorylation and neurofibrillary tangle formation in AD.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pathology

Background:

  • Protein phosphatase 2A (PP2A) down-regulation is implicated in Alzheimer's disease (AD) tau hyperphosphorylation.
  • Phosphorylation of PP2A at Y307 inactivates the enzyme.

Purpose of the Study:

  • To investigate the role of amyloid-beta (Abeta) accumulation and estrogen deficiency in PP2A down-regulation in AD.
  • To examine the correlation between PP2A inactivation and tau hyperphosphorylation in AD pathogenesis.

Main Methods:

  • Immunohistochemistry and immunofluorescence confocal microscopy to detect phosphorylated PP2A (Y307) (PP2Ac-Yp307).
  • Utilized cell culture models (N2a neuroblastoma cells) expressing mutated amyloid precursor protein (APPswe).
  • Employed transgenic mouse models (APPswe/PS1 A246E) and estrogen receptor knockout mice.

Main Results:

  • Aberrant accumulation of PP2Ac-Yp307 observed in neurons with tau pathology in AD-vulnerable brain regions.
  • Increased PP2Ac-Yp307 and tau phosphorylation in APPswe cells and APPswe/PS1 mice.
  • Abeta25-35 treatment and estrogen receptor knockout mimicked these changes, indicating Abeta and estrogen deficiency mediate PP2A inactivation.

Conclusions:

  • Increased PP2A phosphorylation at Y307 is mediated by Abeta deposition or estrogen deficiency in the AD brain.
  • PP2A inactivation compromises tau dephosphorylation, leading to neurofibrillary tangle formation.
  • These findings highlight a critical pathway in AD neurodegeneration.

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