Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 12, Pages 4443-4448Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1111305109
Keywords
Alzheimer's disease; amyloid structure; solid state NMR
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute on Aging, within the National Institutes of Health
Ask authors/readers for more resources
Wild-type, full-length (40- and 42-residue) amyloid beta-peptide (A beta) fibrils have been shown by a variety of magnetic resonance techniques to contain cross-beta structures in which the beta-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 A beta (D23N-A beta(1-40)), which is associated with early onset neurodegeneration, indicate that D23N-A beta(1-40) fibrils can contain either parallel or antiparallel beta-sheets. We report a protocol for producing structurally pure antiparallel D23N-A beta(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-A beta(1-40) fibril structure. This model reveals how both parallel and antiparallel cross-beta 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-A beta(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-A beta(1-40) fibrils are cytotoxic. Thus, our antiparallel D23N-A beta(1-40) fibril model represents a specific toxic intermediate in the aggregation process of a disease-associated A beta mutant.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available