Abstract
Life expectancy of individuals in both developed and undeveloped nations continues to rise at an unprecedented rate. Coupled to this increase in longevity for individuals is the rise in the incidence of chronic neurodegenerative disorders that includes Alzheimer’s disease (AD). Currently, almost ten percent of the population over the age of 65 suffers from AD, a disorder that is presently without definitive therapy to prevent the onset or progression of cognitive loss. Yet, it is estimated that AD will continue to significantly increase throughout the world to impact millions of individuals and foster the escalation of healthcare costs. One potential target for the development of novel strategies against AD and other cognitive disorders involves the mammalian forkhead transcription factors of the O class (FoxOs). FoxOs are present in “cognitive centers” of the brain to include the hippocampus, the amygdala, and the nucleus accumbens and may be required for memory formation and consolidation. FoxOs play a critical role in determining survival of multiple cell types in the nervous system, drive pathways of apoptosis and autophagy, and control stem cell proliferation and differentiation. FoxOs also interface with multiple cellular pathways that include growth factors, Wnt signaling, Wnt1 inducible signaling pathway protein 1 (WISP1), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) that ultimately may control FoxOs and determine the fate and function of cells in the nervous system that control memory and cognition. Future work that can further elucidate the complex relationship FoxOs hold over cell fate and cognitive function could yield exciting prospects for the treatment of a number of neurodegenerative disorders including AD.
Highlights
Life expectancy of individuals in both developed and undeveloped nations continues to rise at an unprecedented rate
In light of the multiple pathways that may be responsible for the onset of Alzheimer’s disease (AD), developing therapies are designed to focus on a variety of targets that include DNA methylation, deployment of monoclonal antibodies against Aβ, prevention of Aβ and tau aggregation, increased cytokine and growth factor signal transduction, mammalian target of rapamycin modulation, and the application of metal chelators [14,15,17,18,21,22,23,24,25,26,27]
Since Akt and serum- and glucocorticoid-inducible protein kinase (SgK) phosphorylate FoxO proteins at different sites, it may be possible to exploit this knowledge to allow for increased options for controlling forkhead protein activity. Some protein kinases such as mammalian sterile 20-like kinase-1 (MST1) can phosphorylate FOXO proteins and disrupt the binding to 14-3-3 which allows FOXO nuclear translocation and subsequent death in neurons [38], further suggesting that the phosphorylation site of FoxO proteins is crucial in determining the activity of forkhead transcription factors
Summary
Life expectancy of individuals in both developed and undeveloped nations continues to rise at an unprecedented rate. Phosphorylation or acetylation of forkhead proteins can block FoxO activity and alter the binding of the C-terminal basic region to DNA to prevent transcriptional activity [42]. Some protein kinases such as mammalian sterile 20-like kinase-1 (MST1) can phosphorylate FOXO proteins and disrupt the binding to 14-3-3 which allows FOXO nuclear translocation and subsequent death in neurons [38], further suggesting that the phosphorylation site of FoxO proteins is crucial in determining the activity of forkhead transcription factors.
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