Brain‐region‐specific, glycosylation‐related transcriptomic alterations in Alzheimer's disease

Abstract

Glycosylation aberrations have been found to be associated with Alzheimer's Disease (AD). In this study, three large public datasets that include RNA-seq data were used to investigate which glycosylation pathways are differentially expressed in AD patients in the brain. RNA-Seq data for six brain regions from hundreds of control, AD, and other neurodegenerative disease cases from Mayo RNASeq, MSBB, and ROSMAP were analyzed. The differential expression of glycosylation-related mRNAs between control and disease groups was analyzed for each brain region using the negative binomial model and a quasi-likelihood F-test using the edgeR package. The TMM method was used for normalization and the Benjamini-Hochberg method was used for multiple testing correction. The total number of genes involved in glycosylation or proteoglycans for each brain region varied from 457 to 467. The number of genes found to be differentially expressed exclusively in controls vs. AD varied between brain regions, with the dorsolateral prefrontal cortex (DLPFC), anterior prefrontal cortex (aPFC), primary auditory cortex, and temporal cortex (TC) having 83, 105, 61, and 99 differentially expressed genes respectively, while in Broca's area and the perirhinal cortex, only 12 and 27 genes were differential respectively. Polypeptide N-acetylgalactosaminyltransferase like 6 (GALNTL6), a gene involved in the initiation of O-glycosylation, was found differentially expressed exclusively in AD in four brain regions (adjusted p-value): DLPFC (p=2.88e-6), TC (p=0.00346), aPFC (p=0.000507) and primary auditory cortex (p=0.00446). GALNTL6 was down-regulated in DLPFC (logFC=-0.29) and TC (logFC=-0.40) and up-regulated in aPFC (logFC=0.24) and primary auditory cortex (logFC=0.27). Alpha-2,3-sialyltransferase 3 (ST3GAL3) and alpha-2,6-sialyltransferase 2 (ST6GAL2) are involved in the sialylation of both N- and O-glycans, and their mRNA was exclusively down-regulated in AD in DLPFC (ST3GAL3, logFC=-0.10, adjusted p-value=0.00275; ST6GAL2, logFC=-0.24, adjusted p-value=6.43-e-06) and TC (ST3GAL3, logFC=-0.22, adjusted p-value=0.000250; ST6GAL2, logFC=-0.41, adjusted p-value=1.30e-06). mRNAs for other O-glycan biosynthesis genes, such as GALNT17, POMT2, GXYLT1, and B3GAT2 were altered in AD in multiple brain regions. Interestingly several enzymes involved in O- and N- glycosylation were significantly down regulated in the dorsolateral prefrontal cortex and temporal cortex, areas significantly impaired in AD. These findings may facilitate future development of AD therapeutics.