Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy.
Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy.
Int J Mol Sci. 2020 Oct 19;21(20):7739. doi: 10.3390/ijms21207739.
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.
由于正常衰老，大脑中的葡萄糖摄取量会减少，但在阿尔茨海默病（AD）患者中，这种下降速度会加快。事实上，正电子发射断层扫描（PET）研究表明，AD 患者的代谢减少发生在症状出现前几十年，这表明代谢缺陷可能是至少在一些迟发性病例中某些上游事件。葡萄糖含量的减少会导致糖基化的显著损伤/下调，糖基化是一种重要的翻译后修饰。糖基化是细胞内二级蛋白加工的重要且高度调控的机制，它在调节蛋白质稳定性方面起着至关重要的作用，因为碳水化合物对于实现糖蛋白的适当三维构象很重要。此外，糖基化作为一种代谢传感器，将葡萄糖代谢与正常神经元功能联系起来。所有参与β-淀粉样蛋白（Aβ）前体蛋白代谢的蛋白质都被鉴定为糖基化的候选物，这突出了 Aβ代谢可能受到其糖基化调节的可能性。在这个框架内，本综述旨在总结糖基化在 AD 发病机制中的作用的现有认识，强调葡萄糖代谢途径可能代表一种针对 AD 的替代治疗选择。从这个角度来看，糖基化水平的药理学调节可能代表了一种“甜蜜的方法”，通过靶向独立于淀粉样蛋白级联的新机制来治疗 AD，并且在家族性和散发性 AD 中具有可比的影响。
