Brain amyloid composed of the approximate to 40-amino-acid human beta-amylo
id peptide A beta is integral to Alzheimer's disease pathology. To probe th
e importance of a conformational transition in A beta during amyloid growth
, we synthesized and examined the solution conformation and amyloid deposit
ion activity of A beta congeners designed to have similar solution structur
es but to vary substantially in their barriers to conformational transition
. Although all these peptides adopt similar solution conformations, a coval
ently restricted A beta congener designed to have a very high barrier to co
nformational rearrangement was inactive, while a peptide designed to have a
reduced barrier to conformational transition displayed an enhanced deposit
ion rate relative to wild-type A beta. The hyperactive peptide, which is li
nked to a heritable A beta amyloidosis characterized by massive amyloid dep
osition at an early age, displayed a reduced activation barrier to depositi
on consistent with a larger difference in activation entropy than in activa
tion enthalpy relative to wild-type A beta. These results suggest that in A
lzheimer's disease, as in the prion diseases, a conformational transition i
n the depositing peptide is essential for the conversion of soluble monomer
to insoluble amyloid, and alterations in the activation barrier to this tr
ansition affect amyloidogenicity and directly contribute to human disease.
(C) 2000 Academic Press.