Decoding the role of glucocorticoid-regulated kinase 1 in Alzheimer's disease: a promising path toward novel therapeutic strategies.

Serum glucocorticoid-regulated kinase 1 (SGK1) is a ubiquitous serine and threonine kinase and has been implicated in many physiological processes including cell survival, proliferation, metabolism, and ion transport. The dysregulation of SGK1 has also been linked to various diseases including cardiometabolic diseases, cancer, and neurological disorders. Recent evidence indicates that SGK1 is influential in the key Alzheimer's disease (AD) pathologic mechanisms including memory and cognitive dysfunction and AD hallmarks such as amyloid beta (Aβ) plaques and neurofibrillary tangles. Overexpression of SGK1 affects the Aβ metabolism and affects the pathway and enzymes disserting Aβ. SGK1 also increases dendritic spine density through regulation of actin polymerization, which increases the ratio of synaptic contacts leading to possible enhancement of memory and cognitive function. The modulation of SGK1 dysfunction in AD pathology leads to tau hyperphosphorylation through glycogen synthase kinase-3 (GSK-3β), thereby promoting the formation of neurofibrillary tangles (NFTs). In addition, SGK1 enhances neuroinflammation through the activation of microglia as well as astrocytes into the release of pro-inflammatory cytokines and neuronal damage. Consequently, SGK1 has been implicated in pathological processes in neurodegeneration and further research is required to delineate its dual role. In this review, we focus on the role of SGK1 in neurodegenerative diseases, specifically in AD. In addition, it discusses the role of SGK1 signaling pathways and the possible SGK1 as a therapeutic target in memory formation and Aβ metabolism.