Structural basis of biological active β-amyloid conformers
Molecular and Cellular Neurology and Neuropathology
Final Report Abstract
The deposition of beta-amyloid (Abeta) peptide as amyloid fibrils is a hallmark of neurodegenerative conditions, such as cerebral amyloid angiopathy (CAA) and Alzheimer´s disease (AD). Increasing evidence shows that CAA is provoked by Abeta fibrils while AD may rather depend on the toxic effect of Abeta’s fibrillation intermediates. In this project we have purified Abeta fibrils from diseased human tissue to make them available for direct structural analysis with high end biophysical methods and in vivo seedings studies in mice. Using cryoelectron microscopy we could determine the polymorphism and the structure of Abeta amyloid fibrils, which were purifed from AD patients. We found that the fibrils differed structurally from all previously known Abeta amyloid fibrils that were formed in vitro. In particular, they showed a right handed fibril supertwist. This project pprovided one of the major pieces of evidence that led to a new view on the molecular basis of amyloid diseases. According to this view, pathologically relevant amyloid fibrils show a relatively high resistance of proteolysis, which enables these fibrils to accumulate and to cause trouble inside the body (proteolytic selection hypothesis).
Publications
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Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer’s brain tissue. Nature Communications, 10(1).
Kollmer, Marius; Close, William; Funk, Leonie; Rasmussen, Jay; Bsoul, Aref; Schierhorn, Angelika; Schmidt, Matthias; Sigurdson, Christina J.; Jucker, Mathias & Fändrich, Marcus
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A molecular view of human amyloid-β folds. Science, 375(6577), 147-148.
Willem, Michael & Fändrich, Marcus
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Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae. Nature Communications, 13(1).
Rother, Christine; Uhlmann, Ruth E.; Müller, Stephan A.; Schelle, Juliane; Skodras, Angelos; Obermüller, Ulrike; Häsler, Lisa M.; Lambert, Marius; Baumann, Frank; Xu, Ying; Bergmann, Carina; Salvadori, Giulia; Loos, Maarten; Brzak, Irena; Shimshek, Derya; Neumann, Ulf; Walker, Lary C.; Schultz, Stephanie A. ... & Jucker, Mathias
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Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease. Nature, 612(7938), 123-131.
Wagner, Jessica; Degenhardt, Karoline; Veit, Marleen; Louros, Nikolaos; Konstantoulea, Katerina; Skodras, Angelos; Wild, Katleen; Liu, Ping; Obermüller, Ulrike; Bansal, Vikas; Dalmia, Anupriya; Häsler, Lisa M.; Lambert, Marius; De Vleeschouwer, Matthias; Davies, Hannah A.; Madine, Jillian; Kronenberg-Versteeg, Deborah; Feederle, Regina; Del Turco, Domenico ... & Neher, Jonas J.
