Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity

Abstract

Accumulation of abnormally hyperphosphorylated tau (P-tau) in the form of tangles of paired helical filaments and͞or straight filaments is one of the hallmarks of Alzheimer's disease (AD) and other tauopathies. P-tau is also found unpolymerized in AD. Although the cognitive decline is known to correlate with the degree of neurofibrillary pathology, whether the formation of filaments or the preceding abnormal hyperphosphorylation of tau is the inhibitory entity that leads to neurodegeneration has been elusive. We have previously shown that cytosolic abnormaly hyperphosphorylated tau in AD brain (AD P-tau) sequesters normal tau (N-tau), microtubule-associated protein (MAP) 1, and MAP2, which results in the inhibition of microtubule assembly and disruption of microtubules. Here, we show that polymerization of AD P-tau into filaments inhibits its ability to bind N-tau and as well as the ability to inhibit the assembly of tubulin into microtubules in vitro and in the regenerating microtubule system from cultured cells. Like AD P-tau, the in vitro abnormally hyperphosphorylated recombinant brain N-tau binds N-tau and loses this binding activity on polymerization into filaments. Dissociation of the hyperphosphorylated N-tau filaments by ultrasonication restores its ability to bind N-tau. These findings suggest that the nonfibrillized P-tau is most likely the responsible entity for the disruption of microtubules in neurons in AD. The efforts in finding a therapeutic intervention for tau-induced neurodegeneration need to be directed either to prevent the abnormal hyperphosphorylation of this protein or to neutralize its binding to normal MAPs, rather than to prevent its aggregation into filaments.abnormal hyperphosphorylation of tau ͉ microtubule assembly ͉ microtubule-associated proteins ͉ neurofibrillary degeneration ͉ paired helical filaments A common feature of the dementia disorders that are known as tauopathies [which include Alzheimer's disease (AD) 1 and frontotemporal dementia with Parkinsonism-linked to chromosome 17 ] is the accumulation in the brain neurons of abnormally hyperphosphorylated tau (P-tau), mostly polymerized into tangles of paired helical filaments (PHFs) and/or straight filaments (SF) (1). Besides hyperphosphorylation, tau in PHF͞SF has been shown to be glycated (2), truncated (3), and immunoreactive with an Ab to a stable 4-hydroxy-2-nonenal (HNE)-lysine adduct (4). The number of neurofibrillary tangles is known to correlate directly with the degree of dementia in AD patients (5-7). Also, the recent discovery of the cosegregation of specific mutations in the tau gene with disease in some pedigrees of FTDP-17 has confirmed that the tau pathology can be a primary cause of neurodegeneration and dementia (8-10). Up to 40% of the abnormally hyperphosphorylated tau in AD brain (AD P-tau) is in the cytosol (11-13). Understanding whether this AD P-tau or its polymer, PHF͞SF, initiates the neurodegeneration is critical for developing a rational therapeutic treatment of AD and related tauopathies.The AD...

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