title: Tau paired helical filaments from Alzheimer's disease brain and assembled in vitro are based on beta-structure in the core domain.
abstract: 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 alpha-helical structure to mainly beta-sheet, or a mixture of mostly random coil and beta-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 beta-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 beta-structure during aggregation, whereas the N- and C-terminal domains projecting away from the PHF core are mostly random coil.
authors.affiliation: Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Barghorn
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000737:chemistry; D015153:Blotting, Western; D001923:Brain Chemistry; D002942:Circular Dichroism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000648:ultrastructure; D016900:Neurofilament Proteins / Q000737:chemistry* / Q000648:ultrastructure; D020033:Protein Isoforms / Q000737:chemistry / Q000302:isolation & purification / Q000648:ultrastructure; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000648:ultrastructure; D017550:Spectroscopy, Fourier Transform Infrared; D016875:tau Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D016900:Neurofilament Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins; D016875:tau Proteins