A nucleated assembly mechanism of Alzheimer paired helical filaments

Alzheimer's disease is characterized by two types of fibrous aggregates in the affected brains, the amyloid fibers (consisting of the A beta-peptide, generating the amyloid plaques), and paired helical filaments (PHFs; made u p of tau protein, forming the neurofibrillary tangles). Hence, tau protein, a highly soluble protein that normally stabilizes microtubules, becomes ag gregated into insoluble fibers that obstruct the cytoplasm of neurons and c ause a loss of microtubule stability. We have developed recently a rapid as say for monitoring PHF assembly and show here that PHFs arise from a nuclea ted assembly mechanism. The PHF nucleus comprises about 8-14 tau monomers. A prerequisite for nucleation is the dimerization of tau because tau dimers act as effective building blocks. PHF assembly can be seeded by preformed filaments (made either in vitro or isolated from Alzheimer brain tissue). T hese results suggest that dimerization and nucleation are the rate-limiting steps for PHF formation in vivo.