Figure 2.

Sphk1–COX2–SPM trilogy in homeostasis and Alzheimer’s disease. (a). Under homeostatic conditions, neuronal cells express sphingosine kinase 1 (Sphk1), which is a potent regulator of COX2 acetylation (A-COX2) and subsequent SPM synthesis. This Sphk1–COX2–SPM trilogy maintains the central nervous system (CNS) homeostatic environment, improves cognition, and maintains healthy neurons. (b). In a parallel manner, the microglial compartment in the CNS expresses N-AS, which also acetylates COX2 and monitors SPM expression. This N-AS signaling maintains the microglial activity in balance and participates in CNS surveillance. (c,d). In Alzheimer’s disease pathology, amyloid beta (Aβ) deposition results in the disruption of Sphk1 signaling in neurons and N-AS expression in microglia, leading to neuronal loss (degenerating neurons), defective microglia (dystrophic microglia), cognitive impairment, and overall inflammatory and neurodegenerative environment.