Regulation of microglial function in Alzheimer's disease by sphingolipid metabolism and transport

Veterans are twice as likely to develop Alzheimer’s disease (AD) compared to persons without military service. While it is well established that post-traumatic stress disorder (PTSD) or traumatic brain injury (TBI) significantly contribute to the increased risk of developing AD in Veterans, it is not clear which molecular mechanism is associated with this exposome and how to target it. Neuroinflammation due to dysregulation of microglia, the primary innate immune cells of the brain, is a key pathogenic factor shared by PTSD, TBI, and AD. In AD, microglia are activated by protein aggregates that are hallmarks of AD pathogenesis such as amyloid β (Aβ) plaques and tau neurofibrillary tangles. Activated microglia can be beneficial by removing these protein aggregates, but they can also adopt a harmful phenotype by damaging neurons and secreting neuroinflammatory cytokines. Despite the enormous progress in defining subgroups of microglia through RNA sequencing, the critical barrier to progress is the knowledge gap in understanding the signals that regulate microglial function. Knowing these signals is vital to our understanding of the functional plasticity of microglia and to develop novel therapies that empower microglia to combat AD. We have identified sphingosine-1-phosphate (S1P), a key signaling sphingolipid, as a crucial regulator of microglial function. Our research demonstrated that S1P drives microglial activation toward a dysregulated “neuroinflammatory” phenotype via S1P receptor 1 (S1PR1) signaling. Reducing this signaling enhances Aβ phagocytosis and ameliorates AD pathology in 5XFAD mice. Further, we discovered that the dysfunctional microglial activation is driven by the extracellular secretion of S1P through spinster homolog 2 (Spns2), a plasma membrane-resident S1P transporter. In addition to being secreted, S1P can also be synthesized in the nucleus. In this proposal, we hypothesize that the microglial function in AD is regulated by both extracellular and nuclear pools of S1P, with their balance controlled by sphingolipid metabolism and Spns2. In our specific aims, we will utilize the 5XFAD mouse model with microglia-specific knockout of Spns2 to investigate: 1) how S1P metabolism and transport regulate extracellular and nuclear S1P pools in microglia (Aim 1); 2) how these S1P pools influence distinct microglial phenotypes (Aim 2); and 3) how different S1P pools affect Aβ phagocytosis and neuroinflammation, which can be targeted to mitigate AD pathology (Aim 3). Our current priority is targeting S1P with clinically approved drugs, which has the greatest potential for impact in quickly aiding Veterans in managing AD. Project Number: 1I01BX007282-01 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Erhard Bieberich | Institution: VA MEDICAL CENTER - LEXINGTON, KY, LEXINGTON, KY | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NURD-E (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11187305