Dysregulation of sphingosine-1-phosphate (S1P) and S1P receptor 1 signaling in the 5xFAD mouse model of Alzheimer's disease.

Sphingolipid-1-phosphate (S1P) signaling through the activation S1P receptors (S1PRs) plays critical 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, provides neuroprotective effects in five familiar Alzheimer disease (5xFAD) transgenic mice, resulting in the reduction of amyloid-β (Aβ) neurotoxicity, inhibition of activation of microglia and astrocytes, increased hippocampal neurogenesis, and improved learning and memory. 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 signaling of S1P/S1P receptor 1 (S1PR1), the most abundant S1PR subtype in the brain, in the cortex of 5xFAD transgenic mice at 3, 8, and 14 months of age. Compared to non-transgenic wildtype (WT) littermates, we found significant decreased levels of 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 SphKs, S1PL, and furthermore, those 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.