title: Conformational features of tau fibrils from Alzheimer's disease brain are faithfully propagated by unmodified recombinant protein.
abstract: Fibrils composed of tau protein are a pathological hallmark of several neurodegenerative disorders including Alzheimer's disease (AD). Here we show that when recombinant tau protein is seeded with paired helical filaments (PHFs) isolated from AD brain, the amyloid formed shares many of the structural features of AD PHFs. In contrast, tau amyloids formed with heparin as an inducing agent-a common biochemical model of tau misfolding-are structurally distinct from brain-derived PHFs. Using ultrastructural analysis by electron microscopy, circular dichroism, and chemical denaturation, we found that AD seeded recombinant tau fibrils were not significantly different than tau fibrils isolated from AD brain tissue. Tau fibrils produced by incubating recombinant tau with heparin had significantly narrower fibrils with a longer periodicity, higher chemical stability, and distinct secondary structure compared to AD PHFs. The addition of heparin to the reaction of recombinant tau and AD PHFs also corrupted the templating process, resulting in a mixture of fibril conformations. Our results suggest that AD-isolated PHFs act as a conformational template for the formation of recombinant tau fibrils. Therefore, the use of AD PHFs as seeds to stimulate recombinant tau amyloid formation produces synthetic tau fibers that closely resemble those associated with AD pathology and provides a biochemical model of tau misfolding that may be of improved utility for structural studies and drug screening. These results also demonstrate that post-translational modifications such as phosphorylation are not a prerequisite for the propagation of the tau fibril conformation found in AD.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Delaware , Newark, Delaware 19716, United States.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Morozova
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: March
authors.forename: Anne S
authors.initials: AS
authors.lastname: Robinson
authors.forename: David W
authors.initials: DW
authors.lastname: Colby
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002942:Circular Dichroism; D006493:Heparin / Q000737:chemistry; D008854:Microscopy, Electron; D016874:Neurofibrillary Tangles / Q000473:pathology / Q000648:ultrastructure*; D011487:Protein Conformation / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry* / Q000648:ultrastructure
chemical_list: D011994:Recombinant Proteins; D016875:tau Proteins; D006493:Heparin
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