Abstract

Alzheimer's disease is associated with the abnormal deposits of amyloid beta protein (Ab) which occurs as fibrils within the cerebral neuropil. To characterize the way in which these fibrils assemble we have performed in vitro structural studies on synthetic peptides including the full-length Ab(1-40) as well as Ab(10-35) and Ab(16-22) which all contain the motif KLVFFAE associated with beta-sheet formation. We have used negative-stain transmission electron microscopy to show the presence of fibril formation in these samples which are then analyzed by solid state NMR to determine higher resolution structural information about the organization of the beta-sheets. We have also used scanning transmission electron microscopy (STEM) to map the mass-per-length of the fibrils to obtain information about the numbers of beta-sheets within fibrils formed under different pH conditions. Our results demonstrate how the structure of fibrils grown from Alzheimer-related Ab peptides depends on the peptide length and on the growth conditions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Intramural Research (Z01)
Project #
1Z01OD011017-02
Application #
6432979
Study Section
(BEPS)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
Indirect Cost

  Institution

Name
Office of the Director, NIH
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Petkova, Aneta T; Leapman, Richard D; Guo, Zhihong et al. (2005) Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils. Science 307:262-5
Petkova, A T; Buntkowsky, G; Dyda, F et al. (2004) Solid state NMR reveals a pH-dependent antiparallel beta-sheet registry in fibrils formed by a beta-amyloid peptide. J Mol Biol 335:247-60
Antzutkin, Oleg N; Leapman, Richard D; Balbach, John J et al. (2002) Supramolecular structural constraints on Alzheimer's beta-amyloid fibrils from electron microscopy and solid-state nuclear magnetic resonance. Biochemistry 41:15436-50
Petkova, Aneta T; Ishii, Yoshitaka; Balbach, John J et al. (2002) A structural model for Alzheimer's beta -amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci U S A 99:16742-7
Antzutkin, O N; Balbach, J J; Leapman, R D et al. (2000) Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of beta-sheets in Alzheimer's beta-amyloid fibrils. Proc Natl Acad Sci U S A 97:13045-50
Balbach, J J; Ishii, Y; Antzutkin, O N et al. (2000) Amyloid fibril formation by A beta 16-22, a seven-residue fragment of the Alzheimer's beta-amyloid peptide, and structural characterization by solid state NMR. Biochemistry 39:13748-59