Sphingosine 1‐phosphate receptor signaling is dysregulated in a mouse model of Alzheimer's disease

Sphingosine 1‐phosphate (S1P) through the activation of five G‐protein‐coupled S1P receptors 1‐5 (S1PR1‐5) plays crucial roles in cellular events. Aberrant sphingolipid metabolism has been identified in the brains of Alzheimer’s disease (AD) patients which implies the significance of S1P/S1PR signaling system. Activation of S1PRs with Fingolimod, an analog of S1P that binds to 4 of the 5 S1PRs, provides neuroprotection in animal models of AD i.e., reduces of Aβ neurotoxicity, inhibits the activation of microglia and astrocytes, and increases the production of brain derived neurotrophic factor (BDNF). The pathways by which dysfunctional S1P/S1PR signaling may promote the development of AD pathology remain unknown. Here we examine the changes occurring in the S1P/S1PR signaling system in 5xFAD mice.