CD1-Mediated Lipid Antigen Presentation Orchestrates Neuroinflammation in Alzheimer’s Disease 2259966

Abstract Introduction Neuroinflammation is a hallmark of neurodegeneration, yet its origins remain unclear in Alzheimer’s disease (AD). The brain’s lipid abundance and the ability of CD1 molecules to present lipid antigens to natural killer T (NKT) cells suggest a lipid-immune axis that could sustain inflammation. While CD1-NKT activity is implicated in several neuroinflammatory diseases, such as multiple sclerosis and Lewy body dementia, its role in AD is largely unexplored. Therefore, we asked whether AD-driven lipid changes activate CD1-dependent antigen presentation in glia and thereby sustain neuroinflammation. Methods 1. human iPSC-derived glia exposed to inflammatory cues, 2. transgenic AD mouse models, and 3. lipidomics to profile CD1 ligands and the “CD1 lipidome” under AD-relevant conditions. We used immunostaining for CD1, NKT, and LD quantification, and targeted mass spectrometry for lipidomics Results 1. Plaque proximal astrocytes in AD mice show higher CD1d than non-AD. 2. hiPSC-derived microglia upregulate CD1 under inflammation. 3. Preliminary lipidomics reveal shifts in glial LD composition in AD brain, with enrichment of candidate glycolipid/phospholipid species under inflammation. Conclusion Our data support a previously underappreciated lipid-immune axis in AD where glial lipid remodeling coincides with CD1-NKT pathway engagement. CD1-mediated lipid antigen presentation offers a mechanistic link between altered brain lipids and neuroinflammation in AD, nominating therapeutic targets along the CD1-NKT axis. Funding Source National Institute of Health, Indiana Clinical & Translational Science Institute, National Institute of Mental Health, National Center for Advancing Translational Sciences, Stark Neurosciences Research Institute, the Indiana Alzheimer Disease Center, Eli Lilly and Company. Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)