title: Alzheimer disease beta-amyloid activity mimics cholesterol oxidase.
abstract: 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.
authors.affiliation: Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Puglielli
authors.forename: Avi L
authors.initials: AL
authors.lastname: Friedlich
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.forename: Seiichi
authors.initials: S
authors.lastname: Nagano
authors.forename: Carlos
authors.initials: C
authors.lastname: Opazo
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.forename: Simon
authors.initials: S
authors.lastname: Melov
authors.forename: Dora M
authors.initials: DM
authors.lastname: Kovacs
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000378:metabolism; D002783:Cholestenones / Q000737:chemistry / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D002789:Cholesterol Oxidase / Q000378:metabolism*; D007464:Clioquinol / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D002783:Cholestenones; C000475:cholest-4-en-3-one; D003300:Copper; D007464:Clioquinol; D002784:Cholesterol; D002789:Cholesterol Oxidase