Abstract
Glucose uptake in the brain decreases because of normal aging but this decline is accelerated in Alzheimer’s disease (AD) patients. In fact, positron emission tomography (PET) studies have shown that metabolic reductions in AD patients occur decades before the onset of symptoms, suggesting that metabolic deficits may be an upstream event in at least some late-onset cases. A decrease in availability of glucose content induces a considerable impairment/downregulation of glycosylation, which is an important post-translational modification. Glycosylation is an important and highly regulated mechanism of secondary protein processing within cells and it plays a crucial role in modulating stability of proteins, as carbohydrates are important in achieving the proper three-dimensional conformation of glycoproteins. Moreover, glycosylation acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. All the proteins involved in β-amyloid (Aβ) precursor protein metabolism have been identified as candidates of glycosylation highlighting the possibility that Aβ metabolism could be regulated by their glycosylation. Within this framework, the present review aims to summarize the current understanding on the role of glycosylation in the etiopathology of AD, emphasizing the idea that glucose metabolic pathway may represent an alternative therapeutic option for targeting AD. From this perspective, the pharmacological modulation of glycosylation levels may represent a ‘sweet approach’ to treat AD targeting new mechanisms independent of the amyloid cascade and with comparable impacts in familial and sporadic AD.
Highlights
Glycans are essential for life along with DNA, proteins and lipids
Further studies demonstrated that this type of glycosylation consisted in O-linked β-N-acetylglucosaminylation (O-GlcNAcylation), where GlcNAc was added on the oxygen of Ser or Thr residues of proteins located in specific cellular compartments including cytoplasmatic membranes, mitochondria and nucleus [9,13,15,16]
This review aims to summarize the molecular and cellular mechanisms of glycosylation focusing on specific proteins, which play a crucial role on the onset and progression of Alzheimer’s disease (AD)
Summary
Glycans are essential for life along with DNA, proteins and lipids. They are one of the four basic components of the cell and contribute significantly to all physiological processes [1]. Further studies demonstrated that this type of glycosylation consisted in O-linked β-N-acetylglucosaminylation (O-GlcNAcylation), where GlcNAc was added on the oxygen of Ser or Thr residues of proteins located in specific cellular compartments including cytoplasmatic membranes, mitochondria and nucleus [9,13,15,16]. Unlike the complex N- and O-linked glycosylation that is able to induce stable modifications of substrates, O-GlcNAcylation causes a more dynamic PTM and is rapidly reversible in response to various environment stresses [17] To this regard, O-GlcNAc interplays with other PTMs including O-phosphorylation in a reciprocal manner, which modulates other PTM’s functional interactions with common substrates [17,18,19].
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