Fig. 5

The functional domains of tau and its aggregation process. The alternative splicing of human MAPT gene generates six isoforms of tau proteins. They differ from each other by the presence or absence of one or two N-terminal inserts (N1, N2) and by bearing either three (R1, R3, R4) or four (R1, R2, R3 and R4) repeat domains. The structure of the longest isoform is shown here. The repeat domains are important for microtubule binding as well as aggregation under pathological conditions. It is believed that tau stabilizes microtubules in neurons and this process is regulated by kinases and phosphatases. Abnormally hyperphosphorylated tau (p-tau) dissociates from microtubules and form oligomers. The aggregation continues and leads to the assembly of paired helical filaments or straight filaments, and eventually forming neurofibrillary tangles [170, 171]