Alzheimer’s disease is the most common form of dementia and is growing in prevalence. Because Alzheimer’s disease starts many decades before symptoms appear, and because many drugs attempting to treat Alzheimer’s disease once symptoms have already started show either no or very small effects, the search is on for new ways to treat and prevent this devastating disease.
Glycosylation is a biological process where different types of sugars are added to proteins. This process is important for the proteins to fold correctly and function properly. Scientists have noticed changes in the glycosylation patterns in the brains of people with Alzheimer’s disease. In our recently published paper our group explored how glycosylation is affected in the brain of individuals with Alzheimer’s disease, in the hope that our findings might lead to future discoveries for potential treatments.
In this study, we performed four different types of analyses to understand the main pathways of glycosylation that are altered in the brains of Alzheimer’s disease patients. First, we mined publicly available transcriptomic data to determine how gene expression of the genes specifically involved in glycosylation was different in Alzheimer’s patients compared with controls. We then performed quantitative PCR on a subset of those genes in a separate set of brain samples to determine whether the gene expression changes observed in the transcriptomic data could also be seen by qPCR. We used an additional set of brain samples to measure the actual glycans (the sugars themselves) by mass spectrometry to see if the changes predicted by gene expression could be measured directly in the resulting glycans. Finally, we used computational approaches and databases to explore the possible regulatory factors that control the specific glycosylation pathways that were found to be altered by transcriptomics and glycomics.
We found two genes, MGAT1 and B4GALT1, involved in complex N-linked glycan formation and galactosylation, upregulated in the brains of Alzheimer’s patients. Concentrations of glycans that are synthesized by these genes were also increased in Alzheimer’s patients. We also observed that the isoforms of particular enzymes changed differently in AD. For example, ST6GALNAC2, 3, and 5 are isoforms of alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase (ST6GALNAC), but the expression of ST6GALNAC2 and 3 increased in AD, while ST6GALNAC5 decreased. A similar pattern was also found in isoforms of polypeptide N-acetylgalactosaminyltransferase (GALNT). These isoforms perform the same function (i.e. add a sialic acid to the end of the glycan structure in the case of the ST6GALNAC isoforms) but they act on different target proteins. These results suggested that the glycosylation changes observed in Alzheimer’s disease patient brains are highly specific. Additionally, we noticed that certain genes related to glycolipids (UGT8 and PIGM) were more active in AD brains. Considering the regulation of these enzymes, we predicted that certain transcription factors, such as STAT1 and HSF5, and microRNAs, such as hsa-miR-1-3p and hsa-miR-16-5p, may play a crucial role in regulating the expression of glycosyltransferases.
These findings help us gain insights into the underlying mechanisms of Alzheimer’s disease and may contribute to the development of potential treatments in the future. This study was a collaboration with Carlito Lebrilla and his team, who specialize in the measurement of glycans by mass spectrometry, and the laboratories of Lee-Way Jin and Izumi Maezawa, who are experts in neurodegenerative disease.