Sphingolipid-1-phosphate (S1P) and S1P receptors (S1PRs) play crucial roles in cellular events in the brain. Aberrant S1P metabolism has been identified in the brains of Alzheimer’s disease (AD) patients. Our recent studies have shown that treatment with fingolimod, an analog of sphingosine known to activate S1PRs in vivo, provides neuroprotective effects in 5xFAD mice, resulting in the reduction of Aβ neurotoxicity, inhibition of activation of microglia and astrocytes, and increased hippocampal neurogenesis. However, the pathways by which dysfunctional S1P and S1PR signaling may associate with the development of AD-like pathology remain unknown. In this study, we investigated the alteration of S1P and S1PR1 signaling in the brain of 5xFAD transgenic mice compared to non-transgenic wildtype (WT) littermates at 3, 8, and 14 months of age. Compared to WT mice, we found significantly decreased levels of S1P concomitant with decreased sphingosine kinases (SphKs), increased S1P lyase (S1PL), and increased S1PR1 in 8- and 14-month-old, but not in 3-month-old 5xFAD mice. Furthermore, we detected increased activation of the S1PR1 downstream pathway of Akt/mTor/Tau signaling in aging 5xFAD mice. Treatment with fingolimod from 1 to 8 months of age reversed the levels of S1P, SphKs, and S1PL, and that of S1PR1 and its downstream pathway of Akt/mTor/Tau signaling. Together the data reveal that dysregulation of S1P and S1PR signaling may associate with the development of AD-like pathology through Akt/mTor/Tau signaling.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.