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.