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].