Alzheimer disease beta-amyloid activity mimics cholesterol oxidase

J Clin Invest. 2005 Sep;115(9):2556-63. doi: 10.1172/JCI23610. Epub 2005 Aug 25.


The abnormal accumulation of amyloid beta-peptide (Abeta) in the form of senile (or amyloid) plaques is one of the main characteristics of Alzheimer disease (AD). Both cholesterol and Cu2+ have been implicated in AD pathogenesis and plaque formation. Abeta binds Cu2+ with very high affinity, forming a redox-active complex that catalyzes H2O2 production from O2 and cholesterol. Here we show that Abeta:Cu2+ complexes oxidize cholesterol selectively at the C-3 hydroxyl group, catalytically producing 4-cholesten-3-one and therefore mimicking the activity of cholesterol oxidase, which is implicated in cardiovascular disease. Abeta toxicity in neuronal cultures correlated with this activity, which was inhibited by Cu2+ chelators including clioquinol. Cell death induced by staurosporine or H2O2 did not elevate 4-cholesten-3-one levels. Brain tissue from AD subjects had 98% more 4-cholesten-3-one than tissue from age-matched control subjects. We observed a similar increase in the brains of Tg2576 transgenic mice compared with nontransgenic littermates; the increase was inhibited by in vivo treatment with clioquinol, which suggests that brain Abeta accumulation elevates 4-cholesten-3-one levels in AD. Cu2+-mediated oxidation of cholesterol may be a pathogenic mechanism common to atherosclerosis and AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / cytology
  • Brain / metabolism
  • Cells, Cultured
  • Chelating Agents / metabolism
  • Cholestenones / chemistry
  • Cholestenones / metabolism
  • Cholesterol / chemistry
  • Cholesterol / metabolism
  • Cholesterol Oxidase / metabolism*
  • Clioquinol / metabolism
  • Copper / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Structure
  • Neurons / cytology
  • Neurons / metabolism
  • Oxidation-Reduction


  • Amyloid beta-Peptides
  • Chelating Agents
  • Cholestenones
  • cholest-4-en-3-one
  • Copper
  • Clioquinol
  • Cholesterol
  • Cholesterol Oxidase