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

Academic Article
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Overview

related to degree

  • Siegel, Sarah, Ph.D. in Chemistry, Scripps Research 2003 - 2008

authors

  • Usui, K.
  • Hulleman, J. D.
  • Paulsson, J. F.
  • Siegel, Sarah
  • Powers, Evan
  • Kelly, Jeffery

publication date

  • 2009

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Accumulation of amyloid beta-peptide (Abeta) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between Abeta and the aldehyde-bearing cholesterol oxidation product 3-beta-hydroxy-5-oxo-5,6-secocholestan-6-al is known to increase Abeta amyloidogenicity. Here, we synthesized Abeta 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 Abeta 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 Abeta Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified Abeta under identical conditions and at the same concentration. Our results show that Abeta 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 Abeta.

subject areas

  • Alzheimer Disease
  • Amino Acid Sequence
  • Amyloid beta-Peptides
  • Animals
  • Cells, Cultured
  • Cholesterol
  • Fluorescence
  • Kinetics
  • Light
  • Microscopy, Immunoelectron
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Neurons
  • Oxidation-Reduction
  • Peptides
  • Protein Structure, Quaternary
  • Rats
  • Scattering, Radiation
  • Thiazoles
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Research

keywords

  • A beta
  • amyloid
  • oxidative stress
  • oxidized metabolite
  • protein misfolding
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Identity

PubMed Central ID

  • PMC2774025

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0804758106

PubMed ID

  • 19841277
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Additional Document Info

start page

  • 18563

end page

  • 18568

volume

  • 106

issue

  • 44

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