Amyloid β1-42 Oligomers Induce Galectin-1S8 O-GlcNAcylation Leading to Microglia Migration.

Abstract

Protein O-GlcNAcylation has been associated with neurodegenerative diseases such as Alzheimer's disease (AD). The O-GlcNAcylation of the Amyloid Precursor Protein (APP) regulates both the trafficking and the processing of the APP through the amyloidogenic pathway, resulting in the release and aggregation of the Aβ1-42 peptide. Microglia clears Aβ aggregates and dead cells to maintain brain homeostasis. Here, using LC-MS/MS, we revealed that the Aβ1-42 oligomers modify the microglia O-GlcNAcome. We identified 55 proteins, focusing our research on Galectin-1 protein since it is a very versatile protein from a functional point of view. Combining biochemical with genetic approaches, we demonstrated that Aβ1-42 oligomers specifically target Galectin-1S8 O-GlcNAcylation via OGT. In addition to this, the Gal-1-O-GlcNAcylated form, in turn, controls human microglia migration. Given the importance of microglia migration in the progression of AD, this study reports the relationship between the Aβ1-42 oligomers and Serine 8-O-GlcNAcylation of Galectin-1 to drive microglial migration.