Activation barriers to structural transition determine deposition rates ofAlzheimer's disease A beta amyloid

Citation
Wp. Esler et al., Activation barriers to structural transition determine deposition rates ofAlzheimer's disease A beta amyloid, J STRUCT B, 130(2-3), 2000, pp. 174-183
Citations number
41
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF STRUCTURAL BIOLOGY
ISSN journal
1047-8477 → ACNP
Volume
130
Issue
2-3
Year of publication
2000
Pages
174 - 183
Database
ISI
SICI code
1047-8477(200006)130:2-3<174:ABTSTD>2.0.ZU;2-J
Abstract
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.