Out-of-Register Parallel β-Sheets and Antiparallel β-Sheets Coexist in 150-kDa Oligomers Formed by Amyloid-β(1-42)

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Alzheimer's disease is linked to amyloid-β peptide (Aβ) aggregation.
• Aβ(1-42) forms oligomeric aggregates with distinct structural features.
• Understanding Aβ(1-42) oligomer structure is crucial for disease mechanism insights.

Purpose of the Study:

• To elucidate the secondary structure and inter-strand organization of Aβ(1-42) oligomers.
• To investigate the structural basis of Aβ(1-42) aggregation.
• To identify novel assembly pathways and factors limiting aggregate growth.

Main Methods:

• Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy.
• Measurements of β-strand secondary structure.
• ¹³C-¹³C dipolar recoupling experiments.

Main Results:

• Identified a second β-strand (residues 11-24) in Aβ(1-42) oligomers.
• Observed a parallel β-sheet organization for residues 11-24, coexisting with an antiparallel β-sheet (residues 30-42).
• Revealed an unusual inter-strand registry shift of three residues in the parallel β-sheet, deviating from typical in-register structures.

Conclusions:

• Aβ(1-42) oligomers exhibit a previously unknown parallel β-sheet organization with registry shifts.
• This unique structure suggests a novel aggregation pathway for Aβ(1-42).
• The findings provide insights into why these aggregates may not grow indefinitely.