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Updated: May 28, 2025
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Published on: March 21, 2025
Kinetics of Amyloid Oligomer Formation
Jiapeng Wei1, Georg Meisl1, Alexander J Dear2,3
1Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; email: jw2219@cam.ac.uk, gm373@cam.ac.uk, tpjk2@cm.ac.uk.
Abstract:
Low-molecular-weight oligomers formed from amyloidogenic peptides and proteins have been identified as key cytotoxins across a range of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Developing therapeutic strategies that target oligomers is therefore emerging as a promising approach for combating protein misfolding diseases. As such, there is a great need to understand the fundamental properties, dynamics, and mechanisms associated with oligomer formation. In this review, we discuss how chemical kinetics provides a powerful tool for studying these systems. We review the chemical kinetics approach to determining the underlying molecular pathways of protein aggregation and discuss its applications to oligomer formation and dynamics. We discuss how this approach can reveal detailed mechanisms of primary and secondary oligomer formation, including the role of interfaces in these processes. We further use this framework to describe the processes of oligomer conversion and dissociation, and highlight the distinction between on-pathway and off-pathway oligomers. Furthermore, we showcase on the basis of experimental data the diversity of pathways leading to oligomer formation in various in vitro and in silico systems. Finally, using the lens of the chemical kinetics framework, we look at the current oligomer inhibitor strategies both in vitro and in vivo.
Insights
Chemical kinetics offers a powerful method to study toxic oligomer formation in neurodegenerative diseases like Alzheimer's and Parkinson's. Understanding these protein aggregation pathways is key to developing new therapeutic strategies.
Area of Science:
- Biochemistry
- Chemical Kinetics
- Neuroscience
Background:
- Low-molecular-weight oligomers of amyloidogenic peptides/proteins are cytotoxins in neurodegenerative disorders (e.g., Alzheimer's, Parkinson's).
- Targeting these toxic oligomers is a promising therapeutic strategy for protein misfolding diseases.
- Understanding oligomer formation mechanisms, dynamics, and properties is crucial.
Purpose of the Study:
- To review the application of chemical kinetics for studying protein aggregation and oligomer formation.
- To elucidate the molecular pathways, dynamics, and mechanisms of oligomer formation, conversion, and dissociation.
- To highlight the role of interfaces and distinguish between on-pathway and off-pathway oligomers.
Main Methods:
- Review of chemical kinetics principles applied to protein aggregation systems.
- Analysis of experimental and in silico data to showcase diverse oligomer formation pathways.
- Examination of oligomer inhibitor strategies through the lens of chemical kinetics.
Main Results:
- Chemical kinetics provides detailed insights into primary and secondary oligomer formation mechanisms.
- The framework reveals processes of oligomer conversion, dissociation, and the nature of on/off-pathway oligomers.
- Diverse in vitro and in silico systems demonstrate varied oligomerization pathways.
Conclusions:
- Chemical kinetics is a powerful tool for dissecting the complex mechanisms of toxic oligomer formation.
- This understanding is essential for designing effective therapeutic interventions against neurodegenerative diseases.
- The review provides a framework for evaluating current and future oligomer-targeting strategies.
