Time-Resolved Structure Changes of Amyloid Beta Peptides from Monomer to Fibrillar Aggregates Revealed by Small-Angle X-ray Scatterings

Abstract

Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases that cause dementia and millions of people worldwide is afflicted with AD. The main feature of AD is known as the accumulation of fibrillar aggregates formed by misfolded amyloid beta (Aβ) peptides in brain tissues, but there are still many questions remained on the origin and pathogenesis of AD. Many studies have shown that Aβ40 and Aβ42 peptides with 40 and 42 amino acid residues are the major isoforms of Aβ peptides that form fibrillar aggregates, and Aβ42 peptide has higher toxicity and faster aggregation rate than Aβ40 peptide does.

Recently, it has been suggested that the oligomeric structures of Aβ peptides formed during the aggregation process can be toxic species, not the fibril aggregates. Thus, there have been strong demands for monitoring structural change of Aβ peptides during aggregation process. While various experimental techniques have been used to observe the aggregation process of Aβ peptides, the structural information from these techniques may not represent the innate structure of peptides in solution, as the peptides can be deformed/damaged in the sample preparation step of drying and straining.

Here, small-angle X-ray scattering (SAXS) technique has been chosen to monitor the structural changes of Aβ peptides dispersed in aqueous solution during aggregation process where the peptides remain in solution without additional sample treatment. Through SAXS experiments, we showed that structural changes of Aβ40 and Aβ42 peptides from the hydrated monomer to aggregated fibril structure are very different in aggregation process without X-ray beam damage and demonstrated the observed results are consistent with previous studies using other techniques. Additionally, we provided more detailed information including growth direction, packing density, and chain flexibility of Aβ aggregates. The results were also supported by dynamic light scattering experiment and Thioflavin T spectroscopic assay.