Transcriptomic and glycomic analyses highlight pathway-specific glycosylation alterations unique to Alzheimer’s disease

Abstract

Glycosylation has been found to be altered in the brains of individuals with Alzheimer’s disease (AD). However, it is unknown which specific glycosylation-related pathways are altered in AD dementia. Using publicly available RNA-seq datasets covering seven brain regions and including 1724 samples, we identified glycosylation-related genes ubiquitously changed in individuals with AD. Several differentially expressed glycosyltransferases found by RNA-seq were confirmed by qPCR in a different set of human medial temporal cortex (MTC) samples (n = 20 AD vs. 20 controls). N-glycan-related changes predicted by expression changes in these glycosyltransferases were confirmed by mass spectrometry (MS)-based N-glycan analysis in the MTC (n = 9 AD vs. 6 controls). About 80% of glycosylation-related genes were differentially expressed in at least one brain region of AD participants (adjusted p-values < 0.05). Upregulation of MGAT1 and B4GALT1 involved in complex N-linked glycan formation and galactosylation, respectively, were reflected by increased concentrations of corresponding N-glycans. Isozyme-specific changes were observed in expression of the polypeptide N-acetylgalactosaminyltransferase (GALNT) family and the alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase (ST6GALNAC) family of enzymes. Several glycolipid-specific genes (UGT8, PIGM) were upregulated. The critical transcription factors regulating the expression of N-glycosylation and elongation genes were predicted and found to include STAT1 and HSF5. The miRNA predicted to be involved in regulating N-glycosylation and elongation glycosyltransferases were has-miR-1-3p and has-miR-16-5p, respectively. Our findings provide an overview of glycosylation pathways affected by AD and potential regulators of glycosyltransferase expression that deserve further validation and suggest that glycosylation changes occurring in the brains of AD dementia individuals are highly pathway-specific and unique to AD.

Whole genome methylation sequencing in blood identifies extensive differential DNA methylation in late‐onset dementia due to Alzheimer's disease

“…Comparison of these data with published differential RNA expression data in blood from persons with and without AD shows that 173 of the 1568 DMP‐containing enhancers have long‐range interactions with 95 promoters of genes known to be differentially expressed in blood of AD patients, including B4GALT1 (Figure 6 , Tables S5 and S6 in supporting information). 33 , 49 Differentially methylated enhancers interact with the promoters of 13 out of 75 AD genetic risk loci, 38 including 7 AD genes not otherwise found to be differentially methylated in our analysis (Section 3.3 ). Accordingly, either the gene bodies or the enhancers of 55 of 75 AD genetic risk loci are differentially methylated in blood.…”

Core-N-glycans are atypically abundant at the neuronal surface and regulate glutamate receptor signaling

“…One possible explanation is that, due to their gigantic surface area, neuron needs for membrane protein synthesis exceed the upper bound of N-glycan processing capacity in the Golgi apparatus. As shown in mice and humans, MGAT1 mRNA appears to be downregulated in the brain compared to other tissues (25), which could potentially contribute to limit this capacity. However, this lower expression in the brain seems to be a general trend for glycosylation enzymes and is not specific to proteins controlling the maturation of core-glycans (9, 25).…”

“…As shown in mice and humans, MGAT1 mRNA appears to be downregulated in the brain compared to other tissues (25), which could potentially contribute to limit this capacity. However, this lower expression in the brain seems to be a general trend for glycosylation enzymes and is not specific to proteins controlling the maturation of core-glycans (9, 25).…”

“…Changes of the N-glycosylation of synaptic proteins, including glutamate receptors, have been reported in multiple debilitating brain diseases, in particular schizophrenia and Alzheimer’s disease (AD)(3–5). Interestingly, recent studies have reported concomitant increases of the levels of MGAT1 mRNA and the expression of hybrid/complex N-glycans in the brain AD patients (5, 25). It is not clear at present whether these changes participate to the pathogenesis of the disease or merely reflect compensatory mechanisms.…”

A Personalized Metabolic Modelling Approach through Integrated Analysis of RNA-Seq-Based Genomic Variants and Gene Expression Levels in Alzheimer’s Disease

“…They comprise a high amount of the brain lipid composition. Tang et al (Tang, et al, 2023) analysed the expression levels of glycosylation related genes in the AD brains and found alterations in the levels of the genes that play a role in glycosphingolipid biosynthesis in human.…”