Differential effects of putative N-glycosylation sites in human Tau on Alzheimer's disease-related neurodegeneration

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 whereasN-glycosylation occurs in the ER-Golgi. Previous in vitro studies indicated thatN-glycosylation of Tau facilitated its phosphorylation and contributed to maintenance of its Paired Helical Filament structure. However, the specific Tau residue(s) that undergoN-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 wereN-glycosylated in wild-type (WT) human Tau (hTau) expressed in human SH-SY5Y cells. Asparagine to glutamine mutants, which cannot undergoN-glycosylation, at each of three putativeN-glycosylation sites inhTau (N167Q, N359Q, and N410Q) were generated and expressed in SH-SY5Y cells and in transgenicDrosophila. The mutants modulated the levels ofhTau phosphorylation in a site-dependent manner in both cell and fly models. Additionally, N359Q ameliorated, whereas N410Q exacerbated various aspects ofhTau-engendered neurodegeneration in transgenic flies.

Automated summary

Tau protein undergoes abnormal post-translational modifications in Alzheimer's disease, such as hyperphosphorylation and glycosylation, impacting disease progression. N-glycosylated Tau has been found in AD brain tissues and specific residues N359 and N410 were identified as undergoing N-glycosylation in wild-type human Tau. Mutants at these glycosylation sites modulate Tau phosphorylation levels and affect neurodegeneration in cell and fly models.