Stereochemical specificity of Alzheimer's disease β-peptide assembly

William P. Esler, Evelyn R. Stimson, Jordan B. Fishman, Joseph R. Ghilardi, Harry V. Vinters, Patrick W. Mantyh, John E. Maggio

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The formation and growth of insoluble amyloid deposits composed primarily of the human β-amyloid peptide (Aβ) in brain is an essentially invariant feature of Alzheimer's disease (AD) and is widely believed to contribute to the progressive neurodegeneration of the disorder. To probe the specificity of amyloid formation and growth, we synthesized and examined the self-assembly of D- and L-stereoisomers of Aβ in vitro. While both enantiomers formed insoluble aggregates at similar rates with amyloid-like fibrillar morphology, deposition of soluble Aβ peptide onto preexisting Aβ aggregates was stereospecific. Although the L-peptide deposited readily onto immobilized L-Aβ aggregates with first-order kinetic dependence on soluble peptide concentration, essentially no association between the D-peptide and L-template was observed. Similarly, the D-peptide deposited with first-order kinetics onto a D-Aβ aggregate template but did not deposit onto a similar template composed of aggregates of the L-enantiomer. Furthermore, although the L-Aβ isomer deposited onto authentic AD amyloid in preparations of unfixed AD brain, no focal association between the D-peptide and brain amyloid was detected. These results establish that deposition of soluble Aβ onto preexisting amyloid template is stereospecific, likely involving direct docking interactions between peptide backbone and/or side chains rather than simple hydrophobic association.

Original languageEnglish (US)
Pages (from-to)505-514
Number of pages10
JournalBiopolymers
Volume49
Issue number6
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Aβ aggregation
  • Aβ deposition
  • Enantiomeric peptides
  • Stereoisomers

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Biomaterials
  • Organic Chemistry

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