Downregulation of 14-3-3 Proteins in Alzheimer’s Disease
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.
Keywords14-3-3 proteins Alzheimer’s disease Frontal cortex Apoptosis Neurodegeneration
We thank the University of Kentucky Alzheimer’s Disease Center Tissue Bank, University of Maryland Brain and Tissue Bank, University of Miami Brain Endowment Bank for the postmortem human tissue samples, and the anonymous donors. The University of Kentucky Alzheimer’s Disease Center Tissue Bank is supported by NIH (NIA P30 AG028383).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no competing interests.
The information in these materials is not a formal dissemination of information by FDA and does not represent agency position or policy.
- 1.Moore BW, Perez VJ (1967) Specific acidic proteins of the nervous system. In: Carlson FD (ed) Physiological and biochemical aspects of nervous integration. Prentice-Hall, Englewood Cliffs, pp. 343–359Google Scholar
- 20.Plotegher N, Kumar D, Tessari I, Brucale M, Munari F, Tosatto L, Belluzzi E, Greggio E et al (2014) The chaperone-like protein 14-3-3η interacts with human α-synuclein aggregation intermediates rerouting the amyloidogenic pathway and reducing α-synuclein cellular toxicity. Hum Mol Genet 23:5615–5629. https://doi.org/10.1093/hmg/ddu275 CrossRefGoogle Scholar
- 21.Halskau Ø Jr, Ying M, Baumann A, Kleppe R, Rodriguez-Larrea D, Almås B, Haavik J, Martinez A (2009) Three-way interaction between 14-3-3 proteins, the N-terminal region of tyrosine hydroxylase, and negatively charged membranes. J Biol Chem 284:32758–32769. https://doi.org/10.1074/jbc.M109.027706 CrossRefGoogle Scholar
- 29.Kawamoto Y, Akiguchi I, Tomimoto H, Shirakashi Y, Honjo Y, Budka H (2006) Upregulated expression of 14-3-3 proteins in astrocytes from human cerebrovascular ischemic lesions. Stroke 37:830–835. https://doi.org/10.1161/01.STR.0000202587.63936.37 CrossRefGoogle Scholar
- 30.Schindler CK, Heverin M, Henshall DC (2006) Isoform- and subcellular fraction-specific differences in hippocampal 14-3-3 levels following experimentally evoked seizures and in human temporal lobe epilepsy. J Neurochem 99:561–569. https://doi.org/10.1111/j.1471-4159.2006.04153.x CrossRefGoogle Scholar
- 34.Murphy N, Bonner HP, Ward MW, Murphy BM, Prehn JH, Henshall DC (2008) Depletion of 14-3-3 zeta elicits endoplasmic reticulum stress and cell death, and increases vulnerability to kainate-induced injury in mouse hippocampal cultures. J Neurochem 106:978–988. https://doi.org/10.1111/j.1471-4159.2008.05447.x CrossRefGoogle Scholar
- 37.Wu JS, Cheung WM, Tsai YS, Chen YT, Fong WH, Tsai HD, Chen YC, Liou JY et al (2009) Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation. Circulation 119:1124–1134. https://doi.org/10.1161/CIRCULATIONAHA.108.812537 CrossRefGoogle Scholar
- 39.Ding H, Underwood R, Lavalley N, Yacoubian TA (2015) 14-3-3 inhibition promotes dopaminergic neuron loss and 14-3-3θ overexpression promotes recovery in the MPTP mouse model of Parkinson's disease. Neuroscience 307:73–82. https://doi.org/10.1016/j.neuroscience.2015.08.042 CrossRefGoogle Scholar
- 42.Fountoulakis M, Cairns N, Lubec G (1999) Increased levels of 14-3-3 gamma and epsilon proteins in brain of patients with Alzheimer’s disease and Down syndrome. J Neural Transm Suppl 57:323–335Google Scholar
- 46.Brennan GP, Jimenez-Mateos EM, McKiernan RC, Engel T, Tzivion G, Henshall DC (2013) Transgenic overexpression of 14-3-3 zeta protects hippocampus against endoplasmic reticulum stress and status epilepticus in vivo. PLoS One 8:e54491. https://doi.org/10.1371/journal.pone.0054491 CrossRefGoogle Scholar