Alzheimer disease hyperphosphorylated tau aggregates hydrophobically

Ruben, George C.; Ciardelli, Thomas L.; Grundke‐Iqbal, Inge; Iqbal, Khalid

doi:10.1002/(sici)1098-2396(199711)27:3<208::aid-syn7>3.0.co;2-h

Cited by 23 publications

(15 citation statements)

References 41 publications

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“…The binding between AD P-tau and MAPs seemed to be of hydrophobic nature because it is stimulated at 200 mM NaCl and inhibited at 2 M NaCl; also, it is completely inhibited by Ϸ0.5% Triton X-100 (15,18). AD P-tau can sequester the six isoforms of tau with different affinity; fetal tau binds the least of the six isoforms (19).…”

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confidence: 64%

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Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity

Alonso¹,

Li²,

Grundke‐Iqbal³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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175

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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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confidence: 64%

“…The portion of tau molecule involved in tau-tau interaction seems to be the microtubule-binding domain (17,19,(37)(38)(39) and of hydrophobic nature (15,18). The involvement of this tau region in the interaction is suggested because the interaction improves when the second microtubule-binding domain (i.e., four-repeat tau) is present (17).…”

Section: Discussionmentioning

confidence: 99%

Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity

Alonso¹,

Li²,

Grundke‐Iqbal³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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175

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“…is an unusual protein that has long stretches of charged (positively and negatively) regions that are not conducive for intermolecular hydrophobic association (47). Of the four microtubule binding repeats in , the predicted amino acids having ␤-structure are concentrated in R2 and R3 (33) and can selfassemble into filaments in vitro; R2 and R3 have also been shown to coassemble with heparin into PHF (48).…”

Section: Discussionmentioning

confidence: 99%

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

Alonso

Zaidi

Novák

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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854

627

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The microtubule-associated protein 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 from AD brain cytosol (AD P-) 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-inhibits its self-association into PHF. Furthermore, hyperphosphorylation induces self-assembly of each of the six isoforms into tangles of PHF and straight filaments, and the microtubule binding domains͞repeats region in the absence of the rest of the molecule can also self-assemble into PHF. Thus, it appears that self-assembles by association of the microtubule binding domains͞repeats and that the abnormal hyperphosphorylation promotes the self-assembly of into tangles of PHF and straight filaments by neutralizing the inhibitory basic charges of the flanking regions.

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“…Although disulfide bonds resistant to cytoplasmic reduction are found in globular proteins, they are not expected in a protein like tau, which is believed to exist in an extended conformation with limited secondary structure (Cleveland et al, 1977b. Since the region of tau that contains the cysteine residues is known to be a relatively hydrophobic part of the molecule (Ruben et al, 1991), however, it is possible that conformational changes associated with dimerization and/or polymerization trap the relevant cysteines in a central hydrophobic domain not easily accessed by reducing agents.…”

Section: Figmentioning

confidence: 99%

“…The average total polymer length/field Ϯ S.E. is plotted as a function of the initial cation concentration, n Ն 10. demonstrated that the secondary structure content of tau also increased as a function of temperature (Ruben et al, 1991). It is likely, therefore, that prior to polymerization the tau molecule assumes a more highly ordered conformation.…”

Section: Figmentioning

confidence: 99%

Polymerization of Microtubule-associated Protein Tau under Near-physiological Conditions

Wilson

Binder²

1995

Journal of Biological Chemistry

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Neurofibrillary tangles, which form in certain degenerating neurons in the brains of patients with Alzheimer's disease, are amassed from filaments having a straight or paired helical morphology. Solubilization of these filaments reveals that they are composed of the microtubule-associated protein tau. It has not previously been shown, however, that tau will assemble to form filaments of similar morphology under conditions representative of the intracellular environment. We have succeeded in forming such filaments using tau purified from porcine or rat microtubules. The filaments are relatively straight with narrowing at irregular intervals, and are about 10 nm wide, a morphology similar to that of straight filaments seen in Alzheimer's disease neurofibrillary tangles. At tau concentrations of 1-10 M, in vitro assembly occurs at physiological pH, ionic strength, temperature, and reducing potential, and each one of these factors modulates the reaction. Assembly is judged to be only slowly reversible by the exponential rather than normal distribution of filament lengths, and by the limited disassembly observed under conditions which inhibit polymerization. Tau purified directly from whole brain tissue rather than from microtubules does not polymerize under conditions described in this report.

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Alzheimer disease hyperphosphorylated tau aggregates hydrophobically

Cited by 23 publications

References 41 publications

Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity

Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity

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

Polymerization of Microtubule-associated Protein Tau under Near-physiological Conditions

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