Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity

Kenji Usui, John D. Hulleman, Johan F. Paulsson, Sarah J. Siegel, Evan T. Powers, Jeffery W. Kelly

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

Accumulation of amyloid β-peptide (Aβ) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between Aβ and the aldehyde-bearing cholesterol oxidation product 3-β-hydroxy-5-oxo-5,6- secocholestan-6-al is known to increase Aβ amyloidogenicity. Here, we synthesized Aβ variants site-specifically modified with the cholesterol aldehyde at Asp-1, Lys-16, or Lys-28, rather than studying mixtures. These distinct modifications have a similar effect on the thermodynamic propensity for aggregation, enabling aggregation at low concentrations. In contrast, the modification site differentially influences the aggregation kinetics; Lys-16-modified Aβ formed amorphous aggregates fastest and at the lowest concentration (within 2 h at a concentration of 20 nM), followed by the Lys-28 and Asp-1 conjugates. Also, the aggregates resulting from Aβ Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified Aβ under identical conditions and at the same concentration. Our results show that Aβ modification by cholesterol derivatives, especially at Lys-16, renders it kinetically and thermodynamically competent to form neurotoxic aggregates at concentrations approaching the physiologic concentration of Aβ.

Original languageEnglish (US)
Pages (from-to)18563-18568
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number44
DOIs
StatePublished - Nov 3 2009

Keywords

  • Amyloid
  • Oxidative stress
  • Oxidized metabolite
  • Protein misfolding

ASJC Scopus subject areas

  • General

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