C-terminal turn stability determines assembly differences between Aβ40 and Aβ42.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Amyloid beta-protein (Aβ) oligomerization is central to Alzheimer's disease pathogenesis.
• Aβ42 is significantly more pathogenic than Aβ40, but the structural basis remains unclear.

Purpose of the Study:

• To elucidate the structural differences between Aβ42 and Aβ40 that explain their differential pathogenicity.
• To investigate the role of a specific C-terminal turn in Aβ42 structure and function.

Main Methods:

• Computational modeling to predict protein structures.
• Chemical synthesis of modified amyloid beta peptides.
• Analysis of peptide oligomerization and secondary structure formation.
• Assessment of the toxicity of different Aβ assemblies.

Main Results:

• A C-terminal Val36-Gly37 turn and a stabilizing β-hairpin structure were identified in Aβ42, absent in Aβ40.
• Amino acid substitutions altering this turn modulated Aβ42 oligomerization and toxicity.
• Introducing the Aβ42-like turn into Aβ40 increased its oligomerization, toxicity, and altered its assembly characteristics.

Conclusions:

• The Val36-Gly37 turn is a critical structural determinant of Aβ42 pathogenicity.
• This turn may be the key feature distinguishing Aβ42 from Aβ40.
• The Aβ42 C-terminal turn represents a promising therapeutic target for Alzheimer's disease.