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

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Abstract

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.

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Acknowledgments

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).

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  1. Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, HFT-132, 3900 NCTR Road, Jefferson, AR, 72079, USA

    Qiang Gu, Elvis Cuevas, James Raymick, Jyotshna Kanungo & Sumit Sarkar

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  1. Qiang Gu
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Correspondence to Qiang Gu.

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Gu, Q., Cuevas, E., Raymick, J. et al. Downregulation of 14-3-3 Proteins in Alzheimer’s Disease. Mol Neurobiol 57, 32–40 (2020). https://doi.org/10.1007/s12035-019-01754-y

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