Stressed and Inflamed, Can GSK3 Be Blamed?

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 42; no. 3; pp. 180 - 192
• Main Authors: Jope, Richard S., Cheng, Yuyan, Lowell, Jeffrey A., Worthen, Ryan J., Sitbon, Yoel H., Beurel, Eleonore
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2017
• Subjects: Alzheimer's disease; Animals; depression; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; glycogen synthase kinase-3; Humans; inflammation; Inflammation - drug therapy; Inflammation - metabolism; learning; Protein Kinase Inhibitors - pharmacology; stress; Stress, Psychological - drug therapy; Stress, Psychological - metabolism; stress; learning; glycogen synthase kinase-3; depression; inflammation; Alzheimer's disease
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2016.10.009

Psychological stress has a pervasive influence on our lives. In many cases adapting to stress strengthens organisms, but chronic or severe stress is usually harmful. One surprising outcome of psychological stress is the activation of an inflammatory response that resembles inflammation caused by infection or trauma. Excessive psychological stress and the consequential inflammation in the brain can increase susceptibility to psychiatric diseases, such as depression, and impair learning and memory, including in some patients with cognitive deficits. An emerging target to control detrimental outcomes of stress and inflammation is glycogen synthase kinase-3 (GSK3). GSK3 promotes inflammation, partly by regulating key transcription factors in the inflammation signaling pathway, and GSK3 can impair learning by promoting inflammation and by inhibiting long-term potentiation (LTP). Drugs inhibiting GSK3 may prove beneficial for controlling mood and cognitive impairments caused by excessive stress and the associated neuroinflammation.
Psychological stress and inflammation can generate healthy responses, but if they are chronic or excessive, they can have deleterious consequences for mood regulation and for learning and memory.
Inflammation is induced by psychological stress by many of the same signaling pathways that activate inflammation after infection or trauma, including the activation of TLRs and GSK3.
A signaling pathway involving stress-induced activation of GSK3 that promotes inflammation may be a central facet of mood disorders and thus be a potential therapeutic target.
Stress-induced activation of GSK3 and inflammation impair LTP and some facets of learning and memory.
A vicious cycle may be established in Alzheimer's disease because the initial formation of plaques and tangles associated with early Alzheimer's disease induces local inflammation that is augmented by stress and by GSK3 activation, which further amplify plaque and tangle formation.