Sphingosine kinase-dependent regulation of pro-resolving lipid mediators in Alzheimer's disease

The majority of peripheral and central nervous system disorders are related to hyperactive inflammatory responses, leading to irreversible and persistent cellular defects, functional impairments, and behavioral deficits. Advances in our understanding of these disorders have revealed the disruption of inflammation resolution pathways due to abrogated responses by specialized pro-resolving lipid mediators (SPMs). SPMs comprise a class of bioactive lipids and cell signaling molecules that function to resolve inflammation, pain, and function in host defense and tissue remodeling. Their cellular and systemic levels during physiology and pathology are regulated by sphingosine kinases (especially SphK1) that act by monitoring cyclooxygenase-2 (COX2), a potent inhibitor of SPMs production. This review presents the current understanding of the convergent mechanisms shared by bioactive lipids with SphK1 and COX2 in the etiology of chronic inflammatory disorders, focusing on neuroinflammation, as well as describes the translational directions of this trilogy for the treatment of Alzheimer's disease.