Functional genome wide association studies have indicated that dysregulated microglia activation is a major contributing factor for neurodegeneration and cognitive decline in Alzheimer's disease (AD). Thus, regulating the microglia activation state could have profound therapeutic potential for AD. However, the underlying mechanisms by which microglia transition between different states during normal and disease conditions are largely unknown. S1P-signaling has been implicated to play important roles in AD. Yet the function of S1P in AD is not clear due to conflicting reports. On one hand, the level of S1P is reduced in postmortem AD patient brains, suggesting a protective role of S1P. On the other hand, there are also reports indicating that S1P might play the opposite. Although has been tested in A?-related AD mouse models, the role of FTY720 in tau pathology is elusive. Further, FTY720 can have different function depending on the cellular context and treatment procedure, which makes interpretation of S1P's role challenging. Thus, the function of S1P-signaling in AD is more complex than assumed and demands further investigation Our preliminary studies suggest that Spinster homolog 2 (Spns2), an S1P transporter, critically modulates microglial transition from inflammatory to anti-inflammatory states when treated with A? peptide. This data is interesting in that it reveals microglia states could be regulated through Spns2 and/or S1P. Since microglia form the first and major line of immune defense in the central nervous system, we will mainly investigate the function of Spns2 on microglia activation in this application. The role of astrocytes, the other major glial cell type, and other S1P transporters such as ABCA1, will also be evaluated. Our goal is to define the function and underlying mechanism of Spns2 in microglial responses in AD. Our goal is to define the function and underlying mechanism of Spns2 in microglial responses in AD. Our overarching hypothesis is that Spns2 contributes to AD pathogenesis by promoting microglial pro-inflammatory activation induced by AD-related stimuli. We will Test that (1) Spns2 enhances pro-inflammatory responses in microglia induced by AD-related stimuli, (2) Spns2/S1P promotes NF?B and p38 MAPK pro-inflammatory signaling induced by A? and tau in microglia, and (3) Spns2 deficiency ameliorates AD-related phenotypes in murine AD models. By focusing on the S1P transporter Spns2, this proposal holds a unique premise to reveal novel aspects of S1P-signaling in AD pathogenesis.
The function of S1P-signaling in AD is more complex than assumed and demands further investigation. Our research will test a novel hypothesis that the S1P transporter Spns2 contributes to AD pathogenesis by promoting microglial pro-inflammatory activation induced by AD-related stimuli. By focusing on Spns2, this proposal holds a unique premise to reveal novel aspects of S1P-signaling in AD