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

TLDR

The microtubule‑associated protein tau becomes abnormally hyperphosphorylated and accumulates as paired helical filaments in the brains of patients with Alzheimer’s disease and other tauopathies. Hyperphosphorylated tau from AD brain cytosol self‑assembles into paired helical and straight filaments under mildly acidic, reducing conditions, and this aggregation is inhibited by dephosphorylation, indicating that hyperphosphorylation neutralizes inhibitory charges on microtubule‑binding domains to drive filament formation.

Abstract

The microtubule-associated protein τ is a family of six isoforms that becomes abnormally hyperphosphorylated and accumulates in the form of paired helical filaments (PHF) in the brains of patients with Alzheimer's disease (AD) and patients with several other tauopathies. Here, we show that the abnormally hyperphosphorylated τ from AD brain cytosol (AD P-τ) self-aggregates into PHF-like structures on incubation at pH 6.9 under reducing conditions at 35°C during 90 min. In vitro dephosphorylation, but not deglycosylation, of AD P-τ inhibits its self-association into PHF. Furthermore, hyperphosphorylation induces self-assembly of each of the six τ isoforms into tangles of PHF and straight filaments, and the microtubule binding domains/repeats region in the absence of the rest of the molecule can also self-assemble into PHF. Thus, it appears that τ self-assembles by association of the microtubule binding domains/repeats and that the abnormal hyperphosphorylation promotes the self-assembly of τ into tangles of PHF and straight filaments by neutralizing the inhibitory basic charges of the flanking regions.