The Glucose Metabolic Pathway as A Potential Target for Therapeutics: Crucial Role of Glycosylation in Alzheimer’s Disease

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.