Single-cell Glycogenomics Deciphers Links Between Altered Transcriptional Regulation and Aberrant Glycosylation in Alzheimer’s Disease

Abstract

SummaryGlycosylation is increasingly recognized as a potential new therapeutic target in Alzheimer’s disease. In recent years, evidence for Alzheimer’s disease-specific glycoproteins has been established. However, the mechanisms of their dysregulation, including tissue and cell type specificity, are not fully understood. We aimed to explore upstream regulators of aberrant glycosylation by integrating multiple data sources and using a glycogenomics approach. We identified dysregulation by the glycosyltransferase PLOD3 in oligodendrocytes as an upstream regulator in cerebral vessels, and found that it is involved in COL4A5 synthesis, which is strongly correlated with amyloid fiber formation. Furthermore, COL4A5 was suggested to interact with astrocytes via ECM receptors as a ligand. This study suggests directions for new therapeutic strategies for Alzheimer’s disease targeting glycosyltransferases.Graphical Abstract