NDLI: Direct evidence for self-propagation of different amyloid-ß fibril conformations.

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Direct evidence for self-propagation of different amyloid-ß fibril conformations.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Spirig, Thomas Ovchinnikova, Oxana Vagt, Toni Glockshuber, Rudi
Description	Country affiliation: Switzerland Author Affiliation: Spirig T ( Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.)
Abstract	BACKGROUND: Amyloid fibrils formed by amyloid-ß (Aß) peptides are associated with Alzheimer's disease and can occur in a range of distinct morphologies that are not uniquely determined by the Aß sequence. Whether distinct conformations of Aß fibrils can be stably propagated over multiple cycles of seeding and fibril growth has not been established experimentally. OBJECTIVE: The ability of the 40-residue peptide Aß1-40 to assemble into fibrils with the conformation of the mutant Aß1-40 peptide containing the 'Osaka' mutation E22Δ was investigated. METHODS: Fibril formation of highly pure, recombinant Aß1-40 in the presence of distinct, preformed seeds in vitro was recorded with thioflavin T fluorescence, and distinct fibrillar structures were identified and distinguished by fluorescence spectroscopy and electron microscopy. RESULTS: We propagated the specific quaternary structure of Aß1-40 E22Δ fibrils with wild-type Aß1-40 over up to seven cycles of seeding and fibril elongation. As a result of a 10(7)-fold dilution of the initially present Aß1-40 E22Δ seeds, the vast majority of fibrils formed after the seventh propagation cycle with Aß1-40 did not contain a single molecule of Aß1-40 E22Δ, but still retained the conformation of the initial Aß1-40 E22Δ seeds. Increased critical concentrations of Aß1-40 fibrils formed in the presence of Aß1-40 E22Δ nuclei suggest that these fibrils are less stable than homologously seeded Aß1-40 fibrils, consistent with a kinetically controlled mechanism of fibril formation. CONCLUSION: The propagation of a distinct Aß fibril conformation over multiple cycles of seeded fibril growth demonstrates the basic ability of the Aß peptide to form amyloid strains that in turn may cause phenotypes in Alzheimer's disease.
File Format	HTM / HTML
ISSN	16602854
Issue Number	3
Volume Number	14
e-ISSN	16602862
Journal	Neurodegenerative Diseases
Language	English
Publisher	Karger
Publisher Date	2014-01-01
Publisher Place	Switzerland
Access Restriction	Subscribed
Subject Keyword	Discipline Neurology Amyloid Beta-peptides Metabolism Amyloid Peptide Fragments Genetics Escherichia Coli Humans Kinetics Microscopy, Electron, Transmission Mutation Protein Structure, Quaternary Recombinant Proteins Spectrometry, Fluorescence Thermodynamics Journal Article
Content Type	Text
Resource Type	Article
Subject	Neurology Neurology (clinical)

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