Amyloid assemblies of Tau are associated with Alzheimer’s disease (AD). In AD Tau undergoes several abnormal post-translational modifications, including hyperphosphorylation and glycosylation, which impact disease progression. N-glycosylated Tau was reported to be found in AD brain tissues but not in healthy counterparts. This is surprising since Tau is a cytosolic protein whereas N-glycosylation occurs in the ER-Golgi. Previous in vitro studies indicated that N-glycosylation of Tau facilitated its phosphorylation and contributed to maintenance of its Paired Helical Filament structure. However, the specific Tau residue(s) that undergo N-glycosylation and their effect on Tau-engendered pathology are unknown. High-performance liquid chromatography and mass spectrometry (LC–MS) analysis indicated that both N359 and N410 were N-glycosylated in wild-type (WT) human Tau (hTau) expressed in human SH-SY5Y cells. Asparagine to glutamine mutants, which cannot undergo N-glycosylation, at each of three putative N-glycosylation sites in hTau (N167Q, N359Q, and N410Q) were generated and expressed in SH-SY5Y cells and in transgenic Drosophila. The mutants modulated the levels of hTau phosphorylation in a site-dependent manner in both cell and fly models. Additionally, N359Q ameliorated, whereas N410Q exacerbated various aspects of hTau-engendered neurodegeneration in transgenic flies.

Tau 淀粉样蛋白组装与阿尔茨海默病 (AD) 相关。在 AD 中，Tau 蛋白经历了几种异常的翻译后修饰，包括过度磷酸化和糖基化，这会影响疾病的进展。据报道，在 AD 脑组织中发现了N-糖基化 Tau，但在健康脑组织中却没有发现。这是令人惊讶的，因为 Tau 是一种胞质蛋白，而N-糖基化发生在 ER-高尔基体中。先前的体外研究表明，Tau 的N-糖基化促进其磷酸化，并有助于维持其配对螺旋丝结构。然而，经历N-糖基化的特定 Tau 残基及其对 Tau 引起的病理学的影响尚不清楚。高效液相色谱和质谱 (LC-MS) 分析表明，在人 SH-SY5Y 细胞中表达的野生型 (WT) 人 Tau ( h Tau) 中，N359 和 N410 均被N-糖基化。在h Tau 中三个假定的N-糖基化位点（N167Q、N359Q 和 N410Q）中的每一个处生成不能进行N-糖基化的天冬酰胺至谷氨酰胺突变体，并在 SH-SY5Y 细胞和转基因果蝇中表达。在细胞和果蝇模型中，突变体以位点依赖性方式调节h Tau 磷酸化水平。此外，N359Q 改善了转基因果蝇中h Tau 引起的神经变性的各个方面，而 N410Q 则加剧了这些神经变性。