Self-propagating, molecular-level polymorphism in Alzheimer's beta-amyloid fibrils.
Amyloid fibrils commonly exhibit multiple distinct morphologies in electron microscope and atomic force microscope images, often within a single image field. By using electron microscopy and solid-state nuclear magnetic resonance measurements on fibrils formed by the 40-residue beta-amyloid peptide of Alzheimer's disease (Abeta(1-40)), we show that different fibril morphologies have different underlying molecular structures, that the predominant structure can be controlled by subtle variations in fibril growth conditions, and that both morphology and molecular structure are self-propagating when fibrils grow from preformed seeds. Different Abeta(1-40) fibril morphologies also have significantly different toxicities in neuronal cell cultures. These results have implications for the mechanism of amyloid formation, the phenomenon of strains in prion diseases, the role of amyloid fibrils in amyloid diseases, and the development of amyloid-based nano-materials.
Petkova
Aneta T
AT
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, MD 20892-0520, USA.
Leapman
Richard D
RD
Guo
Zhihong
Z
Yau
Wai-Ming
WM
Mattson
Mark P
MP
Tycko
Robert
R
D020816:Amino Acid Motifs; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure*; D000818:Animals; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D006860:Hydrogen Bonding; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)