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

Abstract

AbstractBackgroundSphingosine 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.MethodThe gene and protein expression of S1P receptors and S1PR1 signaling pathways were examined in the cortex of male wild‐type mice (WT, n=5) and 5xFAD mice (n=5) at 3, 8, and 14 months of age using quantitative real‐time polymerase chain reaction (real‐time PCR) and Western blots. Statistical analyses of the data were performed using one‐ or two‐way ANOVAs with Sidak's multiple‐comparisons test.ResultS1PR1 gene expression is the most abundant S1PRs in the cortex of both WT and 5xFAD mice. The protein level of S1PR1 is significantly increased in 5xFAD mice compared to WT mice at 3, 8, and 14 months of age. The level of SphK2 that is involved in the activation of S1P as a signaling molecule is also increased in 5xFAD mice at the ages studied. Together with increased level of the truncated form of TrkB, the specific receptor of BDNF, we detected increased levels of the phosphorylated forms of Akt and mTor in 5xFAD mice.ConclusionOur previous findings on the neuroprotective effects of Fingolimod in 5xFAD mice directly support the new findings that increased expression of S1PR1 is associated with the development of AD‐like pathology in 5xFAD mice. Our results presage that S1PR1 regulates the activation of downstream signaling pathways Akt and mTor known to contribute to AD‐related pathogenesis and behavior. Together, these studies suggest that S1PR modulators may potentially have therapeutic benefits in AD.