Biophysics And Biochemistry Of Protein Aggregation: Experimental And Theoretical Studies On Folding, Misfolding, And Self-assembly Of Amyloidogenic Peptides

Experimental and Theoretical Studies on Folding, Misfolding, and Self-Assembly of Amyloidogenic Peptides

Jian-Min Yuan, Huan-Xiang Zhou;;;

• Editorial: WSPC
• Año: 2017
• ISBN:
  9789813202399
• Categoría: Biological Sciences
• Categoría: Biochemistry

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This book reviews current research on the important processes involved in neurodegenerative diseases (e.g. Alzheimer's disease) and the peptides and proteins involved in the amyloidogenic processes. It covers the design and developments of anti-amyloid inhibitors, and gives readers a fundamental understanding of the underlying oligomerization and aggregation processes of these diseases from both computational and experimental points of view.

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Contents:

• Preface
• Perplexity of Amyloid β-Protein Oligomer Formation: Relevance to Alzheimer's Disease (Brigita Urbanc)
• Exploring the Aggregation Mechanism of Intrinsically Disordered Tau Protein (Ruxi Qi, Guanghong Wei, Ruth Nussinov and Buyang Ma)
• Design and Application of Anti-Amyloid Peptide-Based Inhibitors as a Therapeutic Strategy of Alzheimer's Disease (Rita P-Y Chen)
• Statistical Mechanics and Kinetics of Amyloid Fibrillation (Liu Hong, Chiu Fan Lee and Ya Jing Huang)
• Kinetic Studies of Protein Aggregation With and Without the Presence of Crowders (John S Schreck, John Bridstrup and Jian-Min Yuan)
• Thermodynamics and Kinetics of Protein Folding and Aggregation (Min-Yeh Tsai, Jian-Min Yuan and Sheng Hsien Lin)
• Folding and Misfolding of Amyloid-β40 and 42 in Alzheimer's Disease (Yu-Jen Chang and Yun-Ru Chen)
• Single-Molecule Fluorescence Resonance Energy Transfer Studies of β-Amyloid Clusters in Physiological Solutions (Jun Han, Erwen Mei, Mei-Ping Kung, Hank F Kung, Jian-Min Yuan and Hai-Lung Dai)

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Readership: Graduate students and researchers studying the field of neurodegnerative diseases and interested in the chemical processes that occur.
-->Amyloid Peptide/Protein;Neurodegenerative Diseases;Alzheimer's Disease;Protein Aggregation;Protein Misfolding;Anti-Amyloid Inhibitors Key Features:

• Written by practicing experts in the field
• Provides the most up-to-date information of research in the field
• Both experimental and computational perspectives are covered

Perplexity of Amyloid β-Protein Oligomer Formation: Relevance to Alzheimer’s Disease

1

Brigita Urbanc

Department of Physics, Drexel University,
Philadelphia, PA 19104, USA
Faculty of Mathematics and Physics,
University of Ljubljana,
1000 Ljubljana, Slovenia

Aberrant aggregation into oligomers and amyloid fibrils is a universal process shared across many proteins associated with human diseases. Alzheimer’s disease (AD) is characterized by extracellular amyloid deposits, rich in amyloid β-protein (Aβ), intracellular neurofibrillary tangles, made of tau protein aggregates, and massive neuronal loss. Aβ is hypothesized to be the key protein that initiates AD pathology by forming soluble oligomers, which are posited to start the cascade of events leading to neurodegeneration. Aβ is generated from the amyloid precursor protein (APP) by sequential cleavages of β- (or α-) and γ-secretases. Although sporadic AD is the dominant form of the disease, a number of naturally occurring mutations in APP lead to early onset familial forms of AD (FAD) by either increasing Aβ production, altering Aβ assembly dynamics, or both. Studies of assembly dynamics of naturally occurring Aβ isoforms offer insights into interactions that drive Aβ assembly dynamics. This chapter highlights the perplexity of Aβ oligomer formation by comparing and contrasting its universal and specific aspects. The current understanding of Aβ oligomer formation and its role in AD is discussed in the light of recent findings that challenge the toxic oligomer paradigm.

1.Introduction

1.1.Universality of protein aggregation

Protein aggregation is ubiquitous in nature. Numerous in vitro studies have shown that under aggregation-promoting external conditions, such as high temperature or acidic pH, any protein can aggregate, suggesting a universal mechanism of protein self-assembly.¹ The process of protein aggregation is reminiscent of self-assembly of colloid materials, which display intriguing transitions between gas, liquid, solid, and liquid-crystalline phases.^2,3 Protein aggregation into amyloid fibrils and their subsequent deposition into extra or intracellular inclusions in the brain represents a hallmark of several neurodegenerative diseases. For amyloid β-protein (Aβ) and microtubule-associated protein tau in Alzheimer’s disease (AD), α-synuclein in Parkinson’s disease, amylin in diabetes II mellitus, prions, and many other proteins associated with human disorders, the process of aggregation involves a transition from a disordered statistical coil-like monomeric state to a highly structured amyloid fibril. While the aggregation process may not be fully understood, the macromolecular structure of amyloid fibrils is universal across different proteins and characterized by cross-β motif, comprising long, stacked β-sheets, stabilized by intermolecular hydrogen bonding that is parallel to the fibrillar axis.⁴ Despite the common cross-β macromolecular structure, atomistic details and the molecular arrangement of individual peptides into a fibril depend on the amino acid sequence.⁵ Moreover, the amino acid sequence does not uniquely determine the amyloid fibrillar structure. Under different fibril growth conditions, the same protein aggregates into fibrils with distinct molecular-level structures.⁶ This molecular-level polymorphism of amyloid fibrillar structure was proposed to contribute to disease variations in vivo.⁷

1.2.Intrinsically disordered proteins

The process of aggregation from a monomeric statistical coil-like state into an ordered amyloid fibril is further complicated by the fact that many proteins associated with human diseases, including Aβ and tau, belong to a class of intrinsically disordered proteins (IDPs),^a which makes their characterization difficult on all levels. IDPs challenge the classical concept of protein function arising from a rigid three-dimensional (3D) structure.⁸ Uversky et al. reported that IDPs differ from globular proteins by possessing a large net charge and low hydrophobicity,⁹ resulting in hydrodynamic properties resembling a statistical coil in a poor solvent.¹⁰ Intrinsic disorder is widespread among proteins as more than 30% of gene sequences in eukaryotic genomes encode proteins or protein regions that lack a well-defined 3D structure.^11,12 Their disordered and thus flexible nature allows them to easily adopt various conformations in the presence of natural ligands, which was proposed to be essential to their physiological function.¹³

1.3.What role do Aβ oligomers play in AD?

AD is the leading cause of dementia among elderly and despite an effort that spans more than a century, the puzzle of AD is still unsolved, causing increasing emotional and financial damages to humankind across the globe. This chapter summarizes several aspects of early events in self-assembly of Aβ, the principal protein that is posited to play the key role in triggering AD. Strong evidence suggests that amyloid fibril formation from monomeric states proceeds through formation of soluble, low-molecular-weight (LMW) assemblies, called oligomers, which are postulated to be the principal pathogenic species triggering the disease.^14,15 Although the noun “oligomer” is derived from the Greek word oligos, meaning “few”, the usage of this noun in the current literature does not discriminate between LMW and other nonfibrillar or even fibrillar assemblies. A wealth of scientific findings supports their seminal role in AD and yet the term oligomer remains ill-defined.

The perplexity of Aβ oligomer formation dynamics stems from what appears to be a contradiction between its universality and specificity. Universality is evident considering that Aβ akin to numerous other proteins forms not only amyloid fibrils but also oligomers, which appear to share a common structural motif and perhaps also a common mechanism of toxicity.¹⁶ Specificity manifests itself in the multitude of naturally occurring Aβ variants, which stem in part from genetic polymorphism and which produce a variety of distinct AD-related pathologies. An important lesson learned from numerous in vitro, in silico, and animal model studies of these mutations is that a single amino acid substitution can significantly alter assembly dynamics, assembly structure, and can strongly modify human pathology. Perhaps one of the major challenges is to figure out how to bridge a gap among in vivo, in vitro, and in silico findings, which sometimes appear contradictory. These difficulties originate in part in the intrinsically disordered nature of Aβ, which adopts a wide range of monomer conformations with structural characteristics that are strongly sensitive to external conditions.^17–19

Despite a wealth of knowledge accumulated over past decades, there is no consensus on which of the many reported oligomeric species is the proximate neurotoxic species in AD, which structural aspects of Aβ oligomers might be mediating toxicity, and how to prevent or reverse the damage caused by these presumably toxic Aβ oligomers. Aβ oligomers are the central topic of this chapter. Aβ oligomer formation, their structural characteristics, and their role in AD are discussed from the experimentally driven computational biophysics perspective.

2.Aβ and AD: Cause and Effect?

Since the discovery of abnormal inclusions in the brain of the first AD patien...

Índice

• Cover
• Halftitle
• World Scientific Lecture and Course Notes in Chemistry
• Title
• Copyright
• Preface
• Contents
• Chapter 1. Perplexity of Amyloid β-Protein Oligomer Formation: Relevance to Alzheimer’s Disease
• Chapter 2. Exploring the Aggregation Mechanism of Intrinsically Disordered Tau Protein
• Chapter 3. Design and Application of Anti-Amyloid Peptide-Based Inhibitors as a Therapeutic Strategy of Alzheimer’s Disease
• Chapter 4. Statistical Mechanics and Kinetics of Amyloid Fibrillation
• Chapter 5. Kinetic Studies of Protein Aggregation With and Without the Presence of Crowders
• Chapter 6. Thermodynamics and Kinetics of Protein Folding and Aggregation
• Chapter 7. Folding and Misfolding of Amyloid-β40 and 42 in Alzheimer’s Disease
• Chapter 8. Single-Molecule Fluorescence Resonance Energy Transfer Studies of β-Amyloid Clusters in Physiological Solutions
• Index