Activation barriers to structural transition determine deposition rates of Alzheimer's disease Aβ amyloid

William P. Esler, Arthur M. Felix, Evelyn R. Stimson, Marcel J. Lachenmann, Joseph R. Ghilardi, Yi An Lu, Harry V. Vinters, Patrick W. Mantyh, Jonathan P. Lee, John E. Maggio

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Brain amyloid composed of the ≃40-amino-acid human β-amyloid peptide Aβ is integral to Alzheimer's disease pathology. To probe the importance of a conformational transition in Aβ during amyloid growth, we synthesized and examined the solution conformation and amyloid deposition activity of Aβ congeners designed to have similar solution structures but to vary substantially in their barriers to conformational transition. Although all these peptides adopt similar solution conformations, a covalently restricted Aβ congener designed to have a very high barrier to conformational rearrangement was inactive, while a peptide designed to have a reduced barrier to conformational transition displayed an enhanced deposition rate relative to wild-type Aβ. The hyperactive peptide, which is linked to a heritable Aβ amyloidosis characterized by massire amyloid deposition at an early age, displayed a reduced activation barrier to deposition consistent with a larger difference in activation entropy than in activation enthalpy relative to wild-type Aβ. These results suggest that in Alzheimer's disease, as in the prion diseases, a conformational transition in the depositing peptide is essential for the conversion of soluble monomer to insoluble amyloid, and alterations in the activation barrier to this transition affect amyloidogenicity and directly contribute to human disease. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)174-183
Number of pages10
JournalJournal of Structural Biology
Issue number2-3
StatePublished - 2000


  • Alzheimer's disease
  • Amyloid
  • Deposition
  • Peptide conformation

ASJC Scopus subject areas

  • Structural Biology


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