Amyloid Fibrils and Prefibrillar Aggregates (eBook)

Daniel Otzen is professor of nanobiotechnology at the Interdisciplinary Nanoscience Center (iNANO) at Aarhus University, Denmark. He obtained his PhD at Aarhus University in 1995 after studies at the lab of Sir Alan Fersht, University of Cambridge, using protein engineering to dissect the folding pathways of model proteins. He has also worked as a staff scientist at Novozymes A/S within the field of stability and folding of industrial enzymes. In 2000 he established his own research group. His interests include pathological and functional amyloid formation, the structures and properties of pre-fibrillar species, approaches to prevent aggregation and oligomer formation and also the folding and stability of membrane proteins. He is a member of the Danish Royal Society of Sciences and Letters.

PREFACE

THE AMYLOID PHENOMENON AND ITS SIGNIFICANCE
Introduction
The Nature of the Amyloid State of Proteins
The Structure and Properties of Amyloid Species
The Kinetics and Mechanism of Amyloid Formation
The Link between Amyloid Formation and Disease
Strategies for Therapeutic Intervention
Looking to the Future
Summary

AMYLOID STRUCTURES AT THE ATOMIC LEVEL: INSIGHTS FROM CRYSTALLOGRAPHY
Atomic Structures of Segments of Amyloid-Forming Proteins
Stability of Amyloid Fibers
Which Proteins Enter the Amyloid State?
Molecular Basis of Amyloid Polymorphism and Prion Strains
Atomic Structures of Steric Zippers Suggest Models for Amyloid Fibers of Parent Proteins
Atomic Structures of Steric Zippers Offer Approaches for Chemical Interventions against Amyloid Formation
Summary

WHAT DOES SOLID-STATE NMR TELL US ABOUT AMYLOID STRUCTURES?
Introduction
Principles of Solid-State NMR Spectroscopy and Experiments for Structural Constraints
Amyloid Fibrils Investigated by Solid-State NMR Spectroscopy
Summary

FROM MOLECULAR TO SUPRAMOLECULAR AMYLOID STRUCTURES: CONTRIBUTIONS FROM FIBER DIFFRACTION AND ELECTRON MICROSCOPY
Introduction
History
Methodology
Recent Advances in Amyloid Structure Determination
Summary

STRUCTURES OF AGGREGATING SPECIES BY SMALL-ANGLE X-RAY SCATTERING
Introduction
Theoretical and Experimental Aspects
Data Analysis and Modeling Methods
Studying Protein Aggregation and Fibrillation Using SAXS
General Strategies for Modeling SAXS Data from Protein Complexes
Summary and Final Remarks

STRUCTURAL AND COMPOSITIONAL INFORMATION ABOUT PRE-AMYLOID OLIGOMERS
General Introduction
Biophysical Techniques to Study Amyloid Oligomers
The Structure and Composition of Amyloid Oligomers
Concluding Remarks

THE OLIGOMER SPECIES: MECHANISTICS AND BIOCHEMISTRY
Introduction
The Structure - Toxicity Relation of Early Amyloids
The Oligomer - Membrane Complex
Biochemical Modifications Underlying Amyloid Toxicity
Summary

PATHWAYS OF AMYLOID FORMATION
Introduction
Nomenclature of the Various Conformational States
Graphical Representations of the Mechanisms Leading to Amyloid
Pathways of Amyloid Fibril Formation
Nucleation Growth versus Nucleated Conformational Conversion
Summary

SEQUENCE-BASED PREDICTION OF PROTEIN BEHAVIOR
Introduction
The Strategy of the Zyggregator Predictions
Aggregation Under Other Conditions
Prediction of the Cellular Toxicity of Protein Aggregates
Relationship to Other Methods of Predicting Protein Aggregation Propensities
Competition between Folding and Aggregation of Proteins
Prediction of Protein Solubility from the Competition between Folding and Aggregation
Sequence-Based Prediction of Protein Interactions with Molecular Chaperones
Summary

THE KINETICS AND MECHANISMS OF AMYLOID FORMATION
Introduction
Classical Theory of Nucleated Polymerization
The Theory of Filamentous Growth with Secondary Pathways
Self-Consistent Solutions for the Complete Reaction Time Course
Summary

FLUORESCENCE SPECTROSCOPY AS A TOOL TO CHARACTERIZE AMYLOID OLIGOMERS AND FIBRILS
Introduction
Fluorescence Spectroscopy for Studies of Amyloid Reactions In vitro
Cysteine-Reactive Fluorescent Probes
Amyloidotropic Probes for Amyloid Fibrils and Oligomeric States
Luminescent Conjugated Poly and Oligothiophenes LCPs and LCOs
Summary

ANIMAL MODELS OF AMYLOID DISEASES
Introduction
Some Big Questions Regarding Amyloid Diseases and Some Answers from Animal Models
Identifying the Toxic Species in the Systemic Amyloidoses
Identifying the Toxic Species in Alzheimer's Disease
Infectious Protein Misfolding
Conclusions

THE ROLE OF AB IN ALZHEIMER'S DISEASE
History of Amyloidosis
Biochemistry of Aß
Amyloid Fibrils
The Soluble Oligomer Theory of AD
Other Factors Involved in Amyloid Plaque Formation in AD
Metal Ions in AD
Other Potential Aß Interactions
Other Neurodegenerative Diseases
Conclusion

EXPERIMENTAL APPROACHES TO INDUCING AMYLOID AGGREGATES
The Need for Reproduc