Crosstalk between tau protein autoproteolysis and amyloid fibril formation

Tau cleavage has been shown to have a significant effect on protein aggregation. Tau truncation results in the formation of aggregation-prone fragments leading to toxic aggregates and also causes the formation of harmful fragments that do not aggregate. Thus, targeting proteolysis of tau would be beneficial for the development of therapeutics for Alzheimer's disease and related tauopathies. In this study, amino-terminal quantification and ThT fluorimetry were respectively used to analyze the kinetics of tau fragmentation and fibril formation. SDS-PAGE analysis of tau protein incubated with a disulfide-reducing agent demonstrated that the cysteines of tau have a crucial role in the fibrillation and autoproteolysis. However, the structures converted to amyloid fibrils were different with conformations that led to autoproteolysis. The quantification of the amino terminal indicated that the double-disulfide parallel structures formed in the presence of heparin did not have protease activity. The survey of possible tau disulfide-mediated dimer configurations suggested that the non-register single disulfide bound conformations were involved in the tau autoproteolysis process. Moreover, the inhibition of autoproteolysis resulted in the increment of aggregation rate; hence it seems that the tau auto-cleavage is the cellular defense mechanism against protein fibrillation.