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Metabolite-initiated protein misfolding may trigger Alzheimer's disease

Academic Article
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Overview

related to degree

  • Pelletier, Mary Elizabeth Huff, Ph.D. in Chemistry, Scripps Research 1998 - 2003

authors

  • Zhang, Qinghai
  • Powers, Evan
  • Nieva, Jorge Javier
  • Pelletier, Mary Elizabeth Huff
  • Dendle, M. A.
  • Bieschke, J.
  • Glabe, C. G.
  • Eschenmoser, A.
  • Wentworth Jr., Paul
  • Lerner, Richard
  • Kelly, Jeffery

publication date

  • April 2004

journal

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

abstract

  • Anfinsen showed that a protein's fold is specified by its sequence. Although it is clear why mutant proteins form amyloid, it is harder to rationalize why a wild-type protein adopts a native conformation in most individuals, but it misfolds in a minority of others, in what should be a common extracellular environment. This discrepancy suggests that another event likely triggers misfolding in sporadic amyloid disease. One possibility is that an abnormal metabolite, generated only in some individuals, covalently modifies the protein or peptide and causes it to misfold, but evidence for this is sparse. Candidate metabolites are suggested by the recently appreciated links between Alzheimer's disease (AD) and atherosclerosis, known chronic inflammatory metabolites, and the newly discovered generation of ozone during inflammation. Here we report detection of cholesterol ozonolysis products in human brains. These products and a related, lipid-derived aldehyde covalently modify Abeta, dramatically accelerating its amyloidogenesis in vitro, providing a possible chemical link between hypercholesterolemia, inflammation, atherosclerosis, and sporadic AD.

subject areas

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Chromatography, High Pressure Liquid
  • Humans
  • Microscopy, Atomic Force
  • Protein Folding
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Identity

PubMed Central ID

  • PMC387320

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0400924101

PubMed ID

  • 15034169
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Additional Document Info

start page

  • 4752

end page

  • 4757

volume

  • 101

issue

  • 14

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