Antiparallel β-sheet architecture in Iowa-mutant β-amyloid fibrils

Wei Qiang, Wai Ming Yau, Yongquan Luo, Mark P. Mattson, Robert Tycko

Research output: Contribution to journalArticle

Abstract

Wild-type, full-length (40- and 42-residue) amyloid β-peptide (Aβ) fibrils have been shown by a variety of magnetic resonance techniques to contain cross-β structures in which the β-sheets have an in-register parallel supramolecular organization. In contrast, recent studies of fibrils formed in vitro by the Asp23-to-Asn mutant of 40-residue Aβ (D23N-Aβ 1-40), which is associated with early onset neurodegeneration, indicate that D23N-Aβ 1-40 fibrils can contain either parallel or antiparallel β-sheets. We report a protocol for producing structurally pure antiparallel D23N-Aβ 1-40 fibril samples and a series of solid state nuclear magnetic resonance and electron microscopy measurements that lead to a specific model for the antiparallel D23N-Aβ 1-40 fibril structure. This model reveals how both parallel and antiparallel cross-β structures can be constructed from similar peptide monomer conformations and stabilized by similar sets of interactions, primarily hydrophobic in nature. We find that antiparallel D23N-Aβ 1-40 fibrils are thermodynamically metastable with respect to conversion to parallel structures, propagate less efficiently than parallel fibrils in seeded fibril growth, and therefore must nucleate more efficiently than parallel fibrils in order to be observable. Experiments in neuronal cell cultures indicate that both antiparallel and parallel D23N-Aβ 1-40 fibrils are cytotoxic. Thus, our antiparallel D23N-Aβ 1-40 fibril model represents a specific "toxic intermediate" in the aggregation process of a disease-associated Aβ mutant.

Original languageEnglish (US)
Pages (from-to)4443-4448
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number12
DOIs
StatePublished - Mar 20 2012
Externally publishedYes

Fingerprint

Amyloid
Magnetic Resonance Spectroscopy
Poisons
Hydrophobic and Hydrophilic Interactions
Electron Microscopy
Cell Culture Techniques
Peptides
Growth
In Vitro Techniques
peptide A

Keywords

  • Alzheimer's disease
  • Amyloid structure
  • Solid state NMR

ASJC Scopus subject areas

  • General

Cite this

Antiparallel β-sheet architecture in Iowa-mutant β-amyloid fibrils. / Qiang, Wei; Yau, Wai Ming; Luo, Yongquan; Mattson, Mark P.; Tycko, Robert.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 12, 20.03.2012, p. 4443-4448.

Research output: Contribution to journalArticle

Qiang, Wei ; Yau, Wai Ming ; Luo, Yongquan ; Mattson, Mark P. ; Tycko, Robert. / Antiparallel β-sheet architecture in Iowa-mutant β-amyloid fibrils. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 12. pp. 4443-4448.
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