Aggregation Dynamics of a 150 kDa Aβ42 Oligomer: Insights from Cryo Electron Microscopy and Multimodal Analysis.

Autor:	Kamalaldinezabadi SS; Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA., Watzlawik JO; The Departments on Neuroscience and Pharmacology, Mayo Clinic, Jacksonville, FL 32224, USA., Rosenberry TL; The Departments on Neuroscience and Pharmacology, Mayo Clinic, Jacksonville, FL 32224, USA., Paravastu AK; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA., Stagg SM; Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.; Department of Biological Sciences, Florida State University, Tallahassee, FL 32306, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 30. Date of Electronic Publication: 2024 Jul 30.
DOI:	10.1101/2024.07.30.605873
Abstrakt:	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. Competing Interests: Competing Interests: The authors declare no competing interests.
Databáze:	MEDLINE
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