Downregulation of 14-3-3 Proteins in Alzheimer's Disease

Mol Neurobiol. 2020 Jan;57(1):32-40. doi: 10.1007/s12035-019-01754-y. Epub 2019 Sep 5.


One of the most abundant proteins expressed in the brain, 14-3-3 comprises about 1% of the brain's total soluble proteins. The 14-3-3 isoforms bind to specific phosphoserine- and phosphothreonine-containing motifs found on a variety of signaling proteins (kinases and transcription factors, among others) to regulate a wide array of cellular processes including cell cycling, apoptosis, and autophagy. Previously, we described the expression of different 14-3-3 isoforms in the rat frontal cortex and reported their downregulation in a rodent model of neurodegeneration. To further investigate possible roles of 14-3-3 proteins in neurodegeneration, the present study examined different 14-3-3 isoforms in the frontal cortex of postmortem Alzheimer's disease (AD) patients and control subjects. Among the different 14-3-3 isoforms in the human frontal cortex, the relative abundance of expression is in the following order: 14-3-3-eta > tau > sigma > gamma > epsilon > zeta/delta > beta/alpha. These relative abundance levels of different 14-3-3 isoforms in human frontal cortex closely resemble those in rat frontal cortex, suggesting a conserved expression pattern of different 14-3-3 isoforms in mammalian species. In the AD samples, there was a significant decrease in total 14-3-3 levels and the 14-3-3-eta and 14-3-3-gamma isoforms, while no significant difference in the expression level of other 14-3-3 isoforms between AD and control brains was detected. Together, these results demonstrate an abundance of several 14-3-3 isoforms in the frontal cortex and that a downregulation of total 14-3-3 protein levels and specific 14-3-3 isoforms is associated with neurodegeneration. Given the known function of 14-3-3 proteins as inhibitors of apoptosis, the present results suggest that 14-3-3 proteins may play an important role in neurodegeneration and deserve further investigations into AD and other neurodegenerative disorders.

Keywords: 14-3-3 proteins; Alzheimer’s disease; Apoptosis; Frontal cortex; Neurodegeneration.

MeSH terms

  • 14-3-3 Proteins / metabolism*
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Brain / metabolism*
  • Down-Regulation / physiology
  • Female
  • Frontal Lobe / metabolism
  • Humans
  • Male
  • Middle Aged
  • Protein Isoforms / metabolism
  • tau Proteins / metabolism*


  • 14-3-3 Proteins
  • Protein Isoforms
  • tau Proteins