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Aggregation dynamics of a 150 kDa Aβ42 oligomer: Insights from cryo electron microscopy and multimodal analysis
S Shirin Kamalaldinezabadi1, Jens O Watzlawik2, Terrone L Rosenberry2
1Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.
Abstract:
Protein misfolding is a widespread phenomenon that can result in the formation of protein aggregates, which are markers of various disease states, including Alzheimer's disease (AD). In AD, amyloid beta (Aβ) peptides are key players in the disease's progression, particularly the 40- and 42- residue variants, Aβ40 and Aβ42. These peptides aggregate to form amyloid plaques and contribute to neuronal toxicity. Recent research has shifted attention from solely Aβ fibrils to also include Aβ protofibrils and oligomers as potentially critical pathogenic agents. Particularly, oligomers demonstrate more significant toxicity compared to other Aβ specie. Hence, there is an increased interest in studying the correlation between toxicity and their structure and aggregation pathway. The present study investigates the aggregation of a 150 kDa Aβ42 oligomer that does not lead to fibril formation. Using negative stain transmission electron microscopy (TEM), size exclusion chromatography (SEC), dynamic light scattering (DLS), and cryo-electron microscopy (cryo-EM), we demonstrate that 150 kDa Aβ42 oligomers form higher-order string-like assemblies over time. These strings are unique from the classical Aβ fibrils. The significance of our work lies in elucidating molecular behavior of a novel non-fibrillar form of Aβ42 aggregate.
Insights
Researchers studied Alzheimer's disease (AD) by examining amyloid beta 42 (Aβ42) oligomers. They discovered these oligomers form unique string-like assemblies, not typical fibrils, offering new insights into AD pathology.
Area of Science:
- Neuroscience
- Biochemistry
- Structural Biology
Background:
- Protein misfolding and aggregation are hallmarks of neurodegenerative diseases like Alzheimer's disease (AD).
- Amyloid beta (Aβ) peptides, particularly Aβ40 and Aβ42, are central to AD pathogenesis, forming aggregates that cause neuronal toxicity.
- Oligomeric forms of Aβ are increasingly recognized as highly toxic species, prompting research into their structure and aggregation pathways.
Purpose of the Study:
- To investigate the aggregation pathway and structural characteristics of a specific 150 kDa Aβ42 oligomer.
- To determine if this Aβ42 oligomer forms classical amyloid fibrils or alternative structures.
- To elucidate the molecular behavior of novel, non-fibrillar Aβ42 aggregates.
Main Methods:
- Negative stain transmission electron microscopy (TEM) for structural visualization.
- Size exclusion chromatography (SEC) to assess aggregate size and distribution.
- Dynamic light scattering (DLS) for particle size analysis.
- Cryo-electron microscopy (cryo-EM) for high-resolution structural determination.
Main Results:
- The 150 kDa Aβ42 oligomer does not form classical amyloid fibrils.
- Over time, these oligomers self-assemble into unique, higher-order string-like structures.
- Structural analysis revealed these strings differ significantly from established Aβ fibril morphology.
Conclusions:
- A novel, non-fibrillar aggregation pathway exists for Aβ42 oligomers.
- These string-like assemblies represent a distinct form of Aβ aggregate with potential implications for AD.
- Understanding the structure of these non-fibrillar aggregates is crucial for deciphering their toxicity and role in Alzheimer's disease progression.
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