Abstract

Alzheimers 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 the Ab(10-35) which both contain the motif KLVFFAE associated with beta-sheet formation. We have used mass mapping in the scanning transmission electron microscope to determine the packing of beta-sheets within fibrils formed from these peptides under different pH conditions. Measurements of Ab(10-35) fibrils grown at pH 3.7 reveal protofilaments that contain just two stacked beta-sheets. At pH 7.4, Ab(10-35) forms a heterogeneous population of fibrils with a helically twisted structure. Measurements of fibrils grown from the naturally occurring full-length Ab(1-40) peptide at pH 7.4 reveal a different type of helically twisted protofilament containing three beta-sheets stacked together as a lamina. Our results demonstrate how the structure of fibrils grown from Alzheimer-related Ab peptides depends on the peptide length and on the growth conditions. - Alzheimer's disease, amyloid beta protein, scanning transmission electron microscopy, mass mapping

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Intramural Research (Z01)
Project #
1Z01OD011017-01
Application #
6228079
Study Section
Special Emphasis Panel (BE)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Office of the Director, National Institutes of Health
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