New insight into protein glycosylation in the development of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disease that seriously endangers the physical and mental health of patients, however, there are still no effective drugs or methods to cure this disease up to now. Protein glycosylation is the most common modifications of the translated proteins in eukaryotic cells. Recently many researches disclosed that aberrant glycosylation happens in some important AD-related proteins, such as APP, Tau, Reelin and CRMP-2, etc, suggesting a close link between abnormal protein glycosylation and AD. Because of its complexity and diversity, glycosylation is thus considered a completely new entry point for understanding the precise cause of AD. This review comprehensively summarized the currently discovered changes in protein glycosylation patterns in AD, and especially introduced the latest progress on the mechanism of protein glycosylation affecting the progression of AD and the potential application of protein glycosylation in AD detection and treatment, thereby providing a wide range of opportunities for uncovering the pathogenesis of AD and promoting the translation of glycosylation research into future clinical applications.

Fig. 1. Common glycan structures in AD.

The sugar chain of N-glycans is linked to the Asn-X-Ser/Thr consensus sequence in the polypeptide chain and has a common pentasaccharide core composed of GlcNAc and Man. The sugar chain of O-glycan is linked to Ser/Thr in the polypeptide chain and has no fixed core structure. The O-GlcNAc is a single GlcNAc being added to the Ser/Thr in the polypeptide chain. Sialylation modifies the glycan chains in the N-/O-glycan.

Fig. 2. Glycosylation affects the formation of Aβ protein.

A, B APP can be cleaved successively by α-secretase and γ-secretase or β-secretase and γ-secretase. The latter leads to the secretion of Aβ protein, which aggregates to form plaques or more toxic oligomers. APP that undergoes two different cleavage patterns differs in glycosylation. C Except for cleaving APP, β-secretase also affect the sialylation and complex N-glycosylation of APP. And the activity of β-secretase can be influenced by its glycosylation pattern. D Except for cleaving APP, γ-secretase also affect the processing of its complex N-glycosylation in Gorgi as well. Its component, presenilin, affects the ability of glycoprotein production of Golgi and the secretion of several proteins including Aβ protein. Each of the blue shapes (triangles, circles, squares) on the APP in the Fig. 2C and 2D represent a different glycosylation pattern.

Fig. 3. Early N-glycosylation shows a positive regulatory effect on tau phosphorylation, and may affect the further tangles of tau.

When an amino acid of tau is altered from N to Q so that it cannot be glycosylated at that site, the level of tau phosphorylation is altered thereafter. The phosphorylation level of N167Q decreased to 58.3% of that of the control group and the phosphorylation level of N359Q decreased to 61.8%. However, N410Q had nearly no effect (98%). Tau with lower levels of phosphorylation are less likely to form PHF.

Fig. 4. Injecting XXD improves the behavior of SAD rats.

XXD significantly enhanced the expression of OGT and decreased the expression of OGA in the hippocampus of SAD rats. Therefore, the O-GlcNAc glycosylation level of tau protein in the rats treated with XXD was improved. Due to the overall inhibitory effect of O-GlcNAc glycosylation on tau phosphorylation, SAD rats treated with XXD showed reduced levels of tau phosphorylation and improved AD symptoms. This finding confirms that it is feasible to treat AD by altering protein glycosylation patterns with drugs.

Fig. 5. Altered glycosylation patterns of TREM2-R47H in AD.

The expression of TREM2 is increased in AD and TREM2-R47H, a variant of TREM2, on which the Arg in the 47th position mutates to a His, is thought to increase the risk of AD in human. AD-associated R47H variant of TREM2 increases its terminal glycosylation with complex oligosaccharides, including the non-high mannose type glycan, and fucosylated-sialylated complex/hybrid type glycans, etc. This mutation may alter the ability of TREM2 to bind to ligands and its receptor function.

Fig. 6. Changes in glycosylation of key AD proteins.

In AD patient cells, some proteins have abnormal glycosylation patterns, such as tau protein, APP, GFAP, CRMP-2 and TREM. This figure summarizes most of the proteins mentioned in this review and the altered patterns of their glycosylation. The exact mechanism of the effect of abnormal protein glycosylation on AD is still unclear, but glycosylation is considered to be a novel entry point for understanding AD. The protein glycosylation changes shown in this figure do not necessarily occur simultaneously in the same AD cell; this is only a figurative summary.

Fig. 7. The impact of abnormal glycosylation of proteins on AD pathology.

Aberrant glycosylation of APP and its processing enzymes may exacerbate the aggregation of Aβ amyloid plaques. Aberrant glycosylation of tau increases PHF formation by affecting its phosphorylation. Altered glycosylation of Tf and other metalloenzymes affects intracellular oxidative stress by influencing enzyme activity and lifespan. Glycosylation changes of other proteins related to cell signaling, such as TREM2 and Reelin, may affect cell signaling. Together, these changes contribute to neuronal damage in the pathogenesis of AD. The black lines indicate a series of changes following abnormal glycosylation, and the orange lines indicate the interactions between proteins.

Fig. 8. The effects of N-glycosylation/O-glycosylation/O-GlcNAc glycosylation on protein structure and function.

N-glycosylation is associated with protein biorecognition and is involved in the processing and translocation of several AD key proteins to the cytosolic membrane. O-glycosylation mainly affects protein structure, and further affects protein properties such as stability and binding capacity. O-GlcNAc glycosylation exhibits a protective effect on proteins. It may help reduce the dynamic changes and enhances the stability of proteins.