Glycation alter the process of Tau phosphorylation to change Tau isoforms aggregation property

• Different glycated Tau proteins have different aggregation property in vitro.
• Different phosphorylated Tau proteins have different aggregation property in vitro.
• Glycation could modulate Tau phosphorylation and change the protein aggregation property in vitro.

The risk of tauopathies depends in part on the levels and modified composition of six Tau isoforms in the human brain. Abnormal phosphorylation of the Tau protein and the shift of the ratio of 3R Tau to 4R Tau are presumed to result in neurofibrillary pathology and neurodegeneration. Glycation has recently been linked to dementia and metabolic syndrome. To determine the contribution of Tau protein glycation and phosphorylation on Tau aggregation propensity, the assembled kinetics were examined in vitro using Thioflavin T fluorescence assays. We found that glycation and phosphorylation have different effects on aggregation propensity in different Tau isoforms. Different Tau proteins play important parts in each tauopathies, but 3R0N, fetal Tau protein, has no effect on tauopathies. Conversely, 4R2N has more modified sites and a higher tendency to aggregate, playing the most important role in 4R tauopathies. Finally, Glycation, which could modulate Tau phosphorylation, may occur before any other modification. It also regulates the 3R to 4R ratio and promotes 4R2N Tau protein aggregation. Decreasing the sites of glycation, as well as shifting other Tau proteins to 3R0N Tau proteins has potential therapeutic implications for tauopathies.