Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments

The microtubule-associated protein T is a family of six isoforms that becom es abnormally hyperphosphorylated and accumulates in the form of paired hel ical filaments (PHF) in the brains of patients with Alzheimer's disease (AD ) and patients with several other tauopathies, Here. we show that the abnor mally hyperphosphorylated tau from AD brain cytosol (AD P-tau) self-aggrega tes into PHF-like structures on incubation at pH 6.9 under reducing conditi ons at 35 degreesC during 90 min. In vitro dephosphorylation, but not degly cosylation, of AD P-tau inhibits its self-association into PHF. Furthermore , hyperphosphorylation induces self-assembly of each of the six tau isoform s into tangles of PHF and straight filaments, and the microtubule binding d omains/repeats region in the absence of the rest of the molecule can also s elf-assemble into PHF. Thus, it appears that tau self-assembles by associat ion of the microtubule binding domains/repeats and that the abnormal hyperp hosphorylation promotes the self-assembly of tau into tangles of PHF and st raight filaments by neutralizing the inhibitory basic charges of the flanki ng regions.