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

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.