Protein O-GlcNAcylation is a nutrient-related post-translational modification that, since its discovery some 30 years ago, has been associated with the development of neurodegenerative diseases. As reported in Alzheimer’s disease (AD), flaws in the cerebral glucose uptake translate into reduced hexosamine biosynthetic pathway flux and subsequently lead to aberrant protein O-GlcNAcylation. Notably, the reduction of O-GlcNAcylated proteins involves also tau and APP, thus promoting their aberrant phosphorylation in AD brain and the onset of AD pathological markers. Down syndrome (DS) individuals are characterized by the early development of AD by the age of 60 and, although the two conditions present the same pathological hallmarks and share the alteration of many molecular mechanisms driving brain degeneration, no evidence has been sought on the implication of O-GlcNAcylation in DS pathology. Our study aimed to unravel for the first time the role of protein O-GlcNacylation in DS brain alterations positing the attention of potential trisomy-related mechanisms triggering the aberrant regulation of OGT/OGA cycle. We demonstrate the disruption of O-GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and confirm the relevance of O-GlcNAcylation in the appearance of AD hallmarks in the brain of a murine model of DS. Furthermore, we provide evidence for the neuroprotective effects of brain-targeted OGA inhibition. Indeed, the rescue of OGA activity was able to restore protein O-GlcNAcylation, and reduce AD-related hallmarks and decreased protein nitration, possibly as effect of induced autophagy.

蛋白质 O-GlcNAcylation 是一种营养相关的翻译后修饰，自大约 30 年前发现以来，它与神经退行性疾病的发展有关。正如在阿尔茨海默病 (AD) 中报道的那样，大脑葡萄糖摄取的缺陷转化为己糖胺生物合成途径通量的减少，并随后导致蛋白质 O-GlcNAcylation 异常。值得注意的是，O-GlcNAcylated 蛋白的减少还涉及 tau 和 APP，从而促进它们在 AD 脑中的异常磷酸化和 AD 病理标志物的出现。唐氏综合症 (DS) 个体的特征是在 60 岁时早期发展为 AD，尽管这两种情况呈现出相同的病理特征并共享许多驱动脑退化的分子机制的改变，没有证据表明 O-GlcNAcylation 在 DS 病理学中的意义。我们的研究旨在首次阐明蛋白质 O-GlcNacylation 在 DS 脑改变中的作用，从而引起对触发 OGT/OGA 循环异常调节的潜在三体相关机制的关注。我们证明了 O-GlcNAcylation 稳态的破坏，这是 OGT 和 OGA 调节机制改变的影响，并证实了 O-GlcNAcylation 与 DS 小鼠模型大脑中 AD 标志出现的相关性。此外，我们为脑靶向 OGA 抑制的神经保护作用提供了证据。事实上，OGA 活性的拯救能够恢复蛋白质 O-GlcNAcylation，并减少 AD 相关标志和减少蛋白质硝化，这可能是诱导自噬的作用。