β-Amyloid Fibril Structures, In Vitro and In Vivo
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Since 1998, a great deal of progress has been made towards determining and understanding the molecular structures of amyloid fibrils, including fibrils formed by the β-amyloid peptide that is associated with Alzheimer’s disease. Much of this progress has resulted from solid state nuclear magnetic resonance (NMR) measurements, which provide experimental constraints on molecular conformations and interatomic distances without requiring solubility or crystallinity. In general, amyloid fibrils are polymorphic, meaning that fibrils formed by a given peptide or protein can have multiple, distinct molecular structures, depending on the precise conditions under which the fibrils grow. From solid state NMR, electron microscopy, and other measurements, we have developed two detailed molecular structural models for fibrils formed by the 40-residue wild-type β-amyloid (Aβ1–40) peptide. These two Aβ1–40 fibril polymorphs share a common, parallel β-sheet organization and contain similar peptide conformations but differ in overall symmetry and in other structural aspects. We have also identified and characterized a surprising antiparallel β-sheet structure in metastable fibrils formed by a disease-associated mutant, D23N-Aβ1–40, which reveals how similar sets of interactions can stabilize both parallel and antiparallel β-sheets within amyloid fibrils. We are currently extending our structural studies to β-amyloid fibrils that develop in human brain tissue, with the goal of testing whether variations in fibril structure correlate with variations in severity, progression rate, or other characteristics of Alzheimer’s disease.
KeywordsAmyloid Fibril Solid State Nuclear Magnetic Resonance Fibril Structure Amyloid Disease Mature Fibril
This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, a component of the U.S. National Institutes of Health. I thank present and past members of my research group, including Drs. Oleg Antzutkin, Yoshitaka Ishii, John Balbach, Nathan Oyler, Jerry Chan, Aneta Petkova, Anant Paravastu, Kent Thurber, Junxia Lu, and Wei Qiang, for their many contributions to this work. I also thank Prof. Stephen C. Meredith of the University of Chicago for collaborating on several aspects of this work.
- Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, Bi WZ, Cohen AD, Lopresti BJ, DeKosky ST, Halligan EM, Klunk WE (2008) Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 65:1509–1517PubMedCrossRefGoogle Scholar
- Chen B, Thurber KR, Shewmaker F, Wickner RB, Tycko R (2009) Measurement of amyloid fibril mass-per-length by tilted-beam transmission electron microscopy. Proc Natl Acad Sci USA 106:14339–14344Google Scholar
- Klunk WE, Engler H, Nordberg A, Wang YM, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Langstrom B (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound B. Ann Neurol 55:306–319PubMedCrossRefGoogle Scholar
- Lansbury PT, Costa PR, Griffiths JM, Simon EJ, Auger M, Halverson KJ, Kocisko DA, Hendsch ZS, Ashburn TT, Spencer RGS, Tidor B, Griffin RG (1995) Structural model for the β-amyloid fibril based on interstrand alignment of an antiparallel sheet comprising a C-terminal peptide. Nat Struct Biol 2:990–998PubMedCrossRefGoogle Scholar
- Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M (2006) Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313:1781–1784PubMedCrossRefGoogle Scholar
- Tycko R, Savtchenko R, Ostapchenko VG, Makarava N, Baskakov IV (2010) The α-helical C-terminal domain of full-length recombinant PrP converts to an in-register parallel β-sheet structure in PrP fibrils: evidence from solid state nuclear magnetic resonance. Biochemistry 49:9488–9497PubMedCrossRefGoogle Scholar
- Wong DF, Rosenberg PB, Zhou Y, Kumar A, Raymont V, Ravert HT, Dannals RF, Nandi A, Brasic JR, Ye WG, Hilton J, Lyketsos C, Kung HF, Joshi AD, Skovronsky DM, Pontecorvo MJ (2010) In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (Flobetapir F 18). J Nucl Med 51:913–920PubMedCrossRefGoogle Scholar