Dissecting the role of tau glycosylation in Alzheimer's disease

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Multiple neurodegenerative conditions including Alzheimer’s disease (AD) are characterized by the accumulation of in the brain. Tau is a heavily modified protein, and SUMMARY. Microtubule-Associated Protein Tau (MAPT) specific to glycosylation, it has been found to be N-glycosylated in AD samples but not in healthy controls. Three N-glycosylation sites were identified in hTau40, but the exact impact of glycosylation on biophysical properties and cellular uptake is poorly understood. In this proposal, we aim to understand how the structure, topology, and location of glycans impact biological functions of Tau. Based on the preliminary data presented in this application, we will pursue the following three aims: In Aim 1, we will study the effects on N-glycosylation together with other modifications modulating the phase behavior of Tau. In Aim 2, we will study synergistic and antagonistic effects of Tau glycosylation and other posttranslational modifications. In Aim 3, we will investigate cellular uptake, toxicity, and stability of Tau glycoproteins in hiPSC-derived neurons. Taken together, this project will address an important knowledge gap regarding the role of glycans and enable the design of novel therapeutic and diagnostic strategies.