Quenched hydrogen-deuterium exchange NMR of a disease-relevant Aβ(1-42) amyloid polymorph

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Alzheimer's disease pathogenesis involves amyloid-beta (Aβ) peptide aggregation into fibrils.
• Aβ(1-42) and Aβ(1-40) peptides form amyloid fibrils with diverse structures, known as polymorphs.
• Understanding these polymorph structures is crucial for elucidating disease mechanisms.

Purpose of the Study:

• To compare the secondary structural features of two distinct Aβ(1-42) fibril polymorphs.
• To investigate the structural differences between Aβ(1-42) fibril polymorphs using quenched hydrogen-deuterium exchange.
• To classify the observed Aβ(1-42) fibril polymorphisms based on structural analysis.

Main Methods:

• Solid-state Nuclear Magnetic Resonance (NMR) was used to determine the 3D structure of a disease-relevant Aβ(1-42) fibril.
• Quenched hydrogen-deuterium (H/D) exchange was employed to probe the secondary structure of Aβ(1-42) fibril polymorphs.
• Comparative analysis of H/D exchange data from two different Aβ(1-42) fibril structures.

Main Results:

• The study compared H/D exchange data from a known Aβ(1-42) fibril structure with previously determined data from another polymorph.
• Significant secondary structural differences were identified between the two Aβ(1-42) fibril polymorphs.
• The observed structural variations support the classification of these polymorphisms as segmental.

Conclusions:

• The two studied Aβ(1-42) fibril polymorphs exhibit distinct secondary structures.
• The findings suggest that Aβ(1-42) fibril polymorphism can be characterized as segmental.
• This structural classification provides insights into the heterogeneity of amyloid fibrils in Alzheimer's disease.