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The oxidative stress metabolite 4-hydroxynonenal promotes Alzheimer protofibril formation

Academic Article
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Overview

related to degree

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

authors

  • Siegel, Sarah
  • Bieschke, J.
  • Powers, Evan
  • Kelly, Jeffery

publication date

  • 2007

journal

  • Biochemistry  Journal

abstract

  • 4-Hydroxynonenal (4-HNE), formed as a consequence of oxidative stress, exists at increased concentrations in Alzheimer's disease (AD) patients and is found in amyloid beta peptide (Abeta) plaques associated with AD. Although it remains an open question as to whether oxidative stress is a causative factor or a consequence of AD, we show here that 4-HNE, putatively resulting from the peroxidation of lipids, covalently modifies Abeta, triggering its aggregation. These Abeta modifications result from 1,4 conjugate addition and/or Schiff base formation, they occur at multiple locations on a single Abeta peptide, and they result in covalent cross-linking of Abeta peptides. The consequence of these reactions is that 4-HNE accelerates the formation of Abeta protofibrils while inhibiting the production of straight, mature fibrils. Recent studies implicating Abeta oligomers and protofibrils in the neurotoxic process that ultimately leads to AD suggest that the Abeta aggregates induced by 4-HNE may be important in the pathogenesis of AD. These results provide further incentive to understand the role of oxidative stress and small-molecule Abeta modifications in sporadic AD.

subject areas

  • Aldehydes
  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Chromatography, Gel
  • Humans
  • Oxidative Stress
  • Peptide Fragments
  • Protein Conformation
  • Protein Structure, Quaternary
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Identity

PubMed Central ID

  • PMC2530822

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi061853s

PubMed ID

  • 17279615
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Additional Document Info

start page

  • 1503

end page

  • 1510

volume

  • 46

issue

  • 6

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