Discussion
Cut and pasted from the Introduction. The following should
be compared and contrasted with the results we produced: The Wetzel
group performed scanning proline and alanine mutagenesis studies of Aβ40
24, 25. Residues whose substitution with proline changed peptide
assembly, residues 15-21, 24-28, and 31-36, were determined to be
regions that form β-sheets. The remaining residues, for which
substitution had no effect, were found to be in disordered, loop, or
turn regions in Aβ40 24. Alanine substitutions between 15-36 led to
slower fibril elongation compared to wild-type Aβ40. The authors
speculated that these changes in assembly kinetics resulted from
differences in hydrophobic packing 25. Other studies have shown that the
Aβ N-terminus is particularly important in controlling aggregation
kinetics of Aβ40, whereas the C-terminus is most important in
controlling Aβ42 aggregation kinetics 26-28. The central hydrophobic
cluster (CHC), Aβ(17-21), appears to play an important role in
maintaining the ability of Aβ to form plaques and in regulating
aggregation propensity 29. The Aβ(21-30) turn region has been reported
to nucleate monomer folding, a key step in the Aβ assembly process 27.
The metastable and heterogeneous nature of Aβ oligomers
38 has made it difficult to obtain detailed
structural and functional characterization of Aβ40 and Aβ42 oligomers
39 . However, to develop knowledge-based drug
therapies for AD, the structure and function of Aβ must be well
understood. This study focused on understanding the mechanisms behind Aβ
monomer folding and assembly by identifying individual amino acids that
affect Aβ folding and assembly dynamics.