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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, particularly Aβ40 and Aβ42, are key players in the disease's progression, as they 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 greater 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 over time. 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. The strings are unique from the classical Aβ fibril structures. The significance of our work lies in elucidating molecular behavior of a novel non-fibrillar form of Aβ42 aggregate.
Insights
Researchers studied amyloid beta (Aβ) oligomers, key in Alzheimer's disease (AD). They found that a specific Aβ42 oligomer forms unique string-like assemblies, not fibrils, offering new insights into AD pathology.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Protein misfolding and aggregation are hallmarks of neurodegenerative diseases like Alzheimer's disease (AD).
- Amyloid beta (Aβ) peptides, specifically Aβ40 and Aβ42, are implicated in AD pathogenesis, forming aggregates that cause neuronal toxicity.
- Recent studies highlight Aβ oligomers as potentially more toxic than fibrils, driving interest in their structure-activity relationship.
Purpose of the Study:
- To investigate the aggregation pathway and structural characteristics of a 150 kDa Aβ42 oligomer.
- To determine if this specific 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 did not form fibrils over the study period.
- Over time, these oligomers self-assembled into unique, higher-order string-like structures.
- These novel string assemblies differ structurally from canonical Aβ fibrils.
Conclusions:
- Aβ42 can form non-fibrillar, string-like aggregates distinct from amyloid plaques.
- Understanding these novel aggregate structures is crucial for deciphering their role in Alzheimer's disease toxicity.
- This research provides molecular insights into a previously uncharacterized form of Aβ42 aggregation.
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