Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease.

Wischik, Claude M.; Novák, Michal; Thøgersen, Hans C.; Edwards, Patricia C.; Runswick, Michael J.; Jakes, Ross; Walker, John E.; Milstein, C.; Roth, Martin; Klug, A.

doi:10.1073/pnas.85.12.4506

Cited by 825 publications

(622 citation statements)

References 25 publications

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“…The data underscore the observations that the repeat domain forms the core of the PHFs (21,22), that the aggregation involves the generation of -structure (23,24), and that the N-and C-terminal flanking domains remain largely as an unstructured "fuzzy coat".…”

Section: Spectroscopy Of Alzheimer Phfs and In Vitro Reassembled Pmentioning

confidence: 57%

Tau Paired Helical Filaments from Alzheimer's Disease Brain and Assembled in Vitro Are Based on β-Structure in the Core Domain

2004

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Tau protein, a neuronal microtubule-associated protein, forms insoluble fibers ("paired helical filaments") in Alzheimer's disease and other tauopathies. Conflicting views on the structure of the fibers have been proposed recently, ranging from mainly R-helical structure to mainly -sheet, or a mixture of mostly random coil and -sheet. We have addressed this issue by studying tau fibers immunopurified from Alzheimer brain tissue by a conformation-specific antibody and comparing them with fibers reassembled from recombinant tau or tau constructs in vitro, using a combination of electron microscopy and spectroscopic methods. Brain-derived fibers and reassembled fibers both exhibit a typical twisted appearance when examined by electron microscopy. The soluble tau protein is a natively unfolded protein dominated by random coil structure, whereas Alzheimer PHFs and reassembled fibers show a shift toward an increase in the level of -structure. The results support a model in which the repeat domain of tau (which lies within the core of PHFs) adopts an increasing level of -structure during aggregation, whereas the N-and C-terminal domains projecting away from the PHF core are mostly random coil.

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Section: Spectroscopy Of Alzheimer Phfs and In Vitro Reassembled Pmentioning

confidence: 57%

Tau Paired Helical Filaments from Alzheimer's Disease Brain and Assembled in Vitro Are Based on β-Structure in the Core Domain

2004

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“…During the work providing molecular proof that microtubule associated protein tau is a major (if not sole) constituent of paired helical filaments [2,21], it was noted that tau could be truncated. Molecular mapping of the epitope of monoclonal antibody 423, that recognizes tau protein derived from AD brains, revealed for the first time that tau is truncated at E 391 in Alzheimer's disease [6,12].…”

Section: Discussionmentioning

confidence: 99%

Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo

Žilka¹,

Filipčík²,

Koson³

et al. 2006

FEBS Letters

224

203

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Truncated tau protein is the characteristic feature of human sporadic Alzheimer's disease. We have identified truncated tau proteins conformationally different from normal healthy tau. Subpopulations of these structurally different tau species promoted abnormal microtubule assembly in vitro suggesting toxic gain of function. To validate pathological activity in vivo we expressed active form of human truncated tau protein as transgene, in the rat brain. Its neuronal expression led to the development of the neurofibrillary degeneration of Alzheimer's type. Furthermore, biochemical analysis of neurofibrillary changes revealed that massive sarcosyl insoluble tau complexes consisted of human Alzheimer's tau and endogenous rat tau in ratio 1:1 including characteristic Alzheimer's disease (AD)-specific proteins (A68). This work represents first insight into the possible causative role of truncated tau in AD neurofibrillary degeneration in vivo.

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“…There are several criteria for assessing the difference. (a) PHF tau is aggregated in an abnormal fashion; this effect is probably based on the repeat domain of tau [47,48]. (b) PHF tau has an abnormally high M, due to phosphorylation [6,10].…”

Section: Discussionmentioning

confidence: 99%

Abnormal Alzheimer‐like phosphorylation of tau‐protein by cyclin‐dependent kinases cdk2 and cdk5

et al. 1993

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We have shown earlier that certain proline-directed kinases such as MAP kinase or GSK3 can phosphorylate tau protein in an abnormal manner reminiscent of tau from Alzheimer paired helical filaments ; Mandelkow et al. (199211. Both kinases are abundant in brain tissue and associate physically with microtubules through several cycles of assembly and disassembly. In this report we show that cdk2/cyclinA incorporates =5 Pi into recombinant tau, and that it also induces the Ma shift and antibody reactivity typical of Alzheimer tau. However, since there is no cdk2 in brain [Meyerson et al. (1992)] we looked for other members of this family of kinases. Using an antibody against the conserved N-terminus we isolated a cdk-like kinase from brain which was capable of inducing the Alzheimer-like characteristics in tau by phosphorylation. Its size (31 kDa), target specificity (proline-directed), chromatographic behavior, and abundance in brain suggest that this kinase is similar or identical to the neuronal cdc2-like kinase nclk alias PSSARLE or cdk5 [Hellmich et al. (1992); Meyerson et al. (1992); Xiong et al. (1992);Tsai et al. (1993)]. This was confirmed by an antibody specific for cdk5. Like MAP kinase and GSK3, this kinase is physically associated with microtubules and can be enriched by cycles of microtubule assembly and disassembly. Thus, cdk5 should be regarded as another kinase that could be held responsible for the changes in tau protein during Alzheimer disease progression.

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Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease.

Cited by 825 publications

References 25 publications

Tau Paired Helical Filaments from Alzheimer's Disease Brain and Assembled in Vitro Are Based on β-Structure in the Core Domain

Tau Paired Helical Filaments from Alzheimer's Disease Brain and Assembled in Vitro Are Based on β-Structure in the Core Domain

Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo

Abnormal Alzheimer‐like phosphorylation of tau‐protein by cyclin‐dependent kinases cdk2 and cdk5

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