Glycosylation Mechanisms in Alzheimer's Disease Pathogenesis

Protein glycosylation, the enzymatic attachment of carbohydrate moieties to target proteins, has emerged as a pivotal factor in the onset and progression of Alzheimer's disease. Alterations in both N-linked and O-linked glycosylation of key proteins such as the amyloid precursor protein (APP) and microtubule-associated tau influence their folding, trafficking and clearance. Aberrant glycan structures can promote pathological amyloid-β accumulation by altering secretase accessibility to APP, while changes in tau glycosylation impact its propensity to form neurofibrillary tangles. Furthermore, glycosylation acts as a metabolic sensor, linking disturbed glucose utilisation in ageing brain regions to impaired glycoprotein stability and synaptic dysfunction. Emerging evidence also indicates that glycan patterns modulate neuroinflammatory responses, by regulating microglial cell surface receptors and cytokine signalling. Collectively, these findings underscore the global significance of glycosylation pathways in disease pathogenesis and point to carbohydrate-processing enzymes as novel biomarkers and therapeutic targets capable of refining diagnosis and attenuating neurodegeneration.

Research from Nature Portfolio

Recent studies have harnessed a cellular model in which human tau is directed through the secretory pathway to examine the effects of N-glycosylation on its aggregation propensity. It was observed that tau modified with N-glycans forms shorter, thinner fibrils and exhibits reduced aggregation in vitro compared with enzymatically de-glycosylated tau. These findings suggest that physiological N-glycosylation may confer a protective effect by hindering tau filament assembly and so offer insight into strategies for stabilising tau and delaying tangle formation during disease progression.

Glycosylation Mechanisms in Alzheimer's Disease Pathogenesis publication trend

The graph below shows the total number of articles in glycosylation mechanisms in alzheimer's disease pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

Glycosylation: Enzymatic addition of carbohydrate chains to proteins or lipids, affecting their structure and function.

N-glycosylation: Attachment of glycans to the nitrogen atom of asparagine side chains, occurring in the ER and Golgi apparatus.

O-glycosylation: Linking of sugar moieties to the oxygen atom of serine or threonine residues, typically in the Golgi.

Amyloid precursor protein (APP): Transmembrane protein whose proteolysis generates amyloid-β peptides implicated in plaque formation.

Tau protein: Microtubule-associated protein that undergoes post-translational modifications and forms neurofibrillary tangles when dysregulated.

References

1. New insight into protein glycosylation in the development of Alzheimer’s disease. Cell Death Discovery (2023).
2. Implications of Glycosylation in Alzheimer’s Disease. Frontiers in Neuroscience (2021).
3. The Glucose Metabolic Pathway as A Potential Target for Therapeutics: Crucial Role of Glycosylation in Alzheimer’s Disease. International Journal of Molecular Sciences (2020).
4. Novel model of secreted human tau protein reveals the impact of the abnormal N-glycosylation of tau on its aggregation propensity. Scientific Reports (2019).