Abstract [DO THIS LAST.]
Neurotoxic amyloid β-protein (Aβ) oligomers are thought to be key etiologic agents of Alzheimer’s disease (AD). If this hypothesis is true, then elucidation of structural features mediating the oligomerization process could provide targets for therapeutic drug development. We present here structure-activity relationships determined for Aβ40 and Aβ42 using a scanning D-amino acid substitution strategy. This strategy involved: (1) chemical synthesis of Aβ containing dipeptides comprising D-amino acids; (2) monitoring effects of these substitutions on peptide secondary structure, oligomerization, fibril formation, and fibril morphology; (3) synthesis of Aβ containing single D-amino acid substitutions at sites found in the prior step to affect peptide conformation or assembly; and (4) monitoring the effects of the single D-amino acid substitutions. The results reveal distinct groups of D-amino acid substitutions that substantially altered the oligomerization process of Aβ40 and that of Aβ42. These were substitutions at L17 and N27 in Aβ40 and H14, F20, A21, and M35 in Aβ42 [now summarize the key findings, without getting into excessive and mind-numbing detail].