Alzheimer disease beta-amyloid activity mimics cholesterol oxidase.
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.
Puglielli
Luigi
L
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Friedlich
Avi L
AL
Setchell
Kenneth D R
KD
Nagano
Seiichi
S
Opazo
Carlos
C
Cherny
Robert A
RA
Barnham
Kevin J
KJ
Wade
John D
JD
Melov
Simon
S
Kovacs
Dora M
DM
Bush
Ashley I
AI
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
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D002783:Cholestenones; C000475:cholest-4-en-3-one; D003300:Copper; D007464:Clioquinol; D002784:Cholesterol; D002789:Cholesterol Oxidase