Regulation of Microglial Activation State in Neurodegeneration

Functional and 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) is an age-related neurodegenerative 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 plays important roles in disease onset, evidenced by the approval of multiple sclerosis drug, FTY720, a S1P receptor modulator. Although FTY720 has been tested in AD animal models, the role of S1P-signaling in microglia biology in AD is still elusive since FTY720 plays multiple functions in cells such as being an agonist or functional antagonist of the S1PR1 or a ceramide mimic depending cell types and cellular context. Our preliminary studies suggest that Spinster homolog 2 (Spns2), an S1P transporter, critically modulates microglial transition from inflammatory to anti-inflammatory states. Our overarching hypothesis is that Spns2 promotes microglial inflammatory activation through S1P/S1PR-signaling in AD. We will (1) test that Spns2-mediated S1P transport enhances inflammatory responses in microglia in AD models in vitro, (2) determine the downstream signaling mediated by Spns2/S1P in inflammatory response in AD models in vitro, and (3) test that Spns2KO ameliorates AD-related phenotypes in a murine AD model. By focusing on the S1P transporter Spns2 in microglia biology, this proposal holds a unique premise to reveal novel aspects of the function of Spns2 and S1P in AD.