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Phosphoprotein phosphatase 2A: a novel druggable target for Alzheimer's disease

Michael Voronkov1, Steven P Braithwaite, Jeffry B Stock

  • 1Signum Biosciences, Monmouth Junction, NJ 08852, USA.

Future Medicinal Chemistry
|June 8, 2011
PubMed

Insights

Enhancing phosphoprotein phosphatase 2A (PP2A) activity offers a promising therapeutic strategy for Alzheimer's disease by targeting tau hyperphosphorylation and neurofibrillary tangle formation.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • Tau hyperphosphorylation contributes to Alzheimer's disease (AD) pathogenesis via neurofibrillary tangle formation.
  • Kinase inhibitors targeting tau phosphorylation have shown limited success in AD drug development.
  • Phosphoprotein phosphatase 2A (PP2A) is the primary phosphatase for phospho-tau.

Purpose of the Study:

  • To review the evidence supporting PP2A activation as a viable therapeutic strategy for Alzheimer's disease.
  • To explore various chemotypes and mechanisms for enhancing PP2A activity against phospho-tau.

Main Methods:

  • Review of existing scientific literature on PP2A activators and their mechanisms.
  • Analysis of different chemical compounds (chemotypes) that modulate PP2A activity.
  • Examination of indirect mechanisms involving PP2A inhibitors and post-translational modifications.

Main Results:

  • Multiple chemotypes demonstrate the ability to enhance PP2A activity.
  • Compounds may act as direct allosteric activators or indirectly by modulating PP2A inhibitors.
  • Regulation of PP2A activity towards phospho-tau can be achieved through various pharmaceutical interventions.

Conclusions:

  • Enhancing PP2A activity is a pharmacologically achievable approach for next-generation Alzheimer's therapeutics.
  • PP2A represents a safe, selective, and effective target for pharmaceutical intervention in Alzheimer's disease treatment.

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