Tau Aggregation is Altered by Mutations in its Projection Domain

The intrinsically disordered microtubule-associated protein tau is known for its aberrant aggregation into neurofibrillary tangles as found in neuropathologies such as Alzheimers disease. This study compares three N-terminal isoforms of mutant R5L and of wild type tau to investigate how this mutation and the length of the projection domain affects aggregation behavior. Tau polymers in vitro were examined using atomic force microscopy imaging to compare tau filament lengths and morphologies. In a complementary analysis, the total amount of polymerization was analyzed using a Thioflavin S assay. We observed that the R5L mutation has a greater impact on filament length in shorter N-terminal isoforms of tau, whereas in longer N-terminal isoforms the mutation impacts the total amount of tau aggregation. These observations suggest that the R5L mutation affects the kinetic nucleation-elongation pathway of tau fibrillization, where the mutant impacts polymer nucleation in 2N and 1N isoforms, but has a more significant impact on elongation in the 0N isoform.