Peroxidase activity of cyclooxygenase-2 (COX-2) cross-links beta-amyloid (Abeta) and generates Abeta-COX-2 hetero-oligomers that are increased in Alzheimer's disease.
Oxidative stress is associated with the neuropathology of Alzheimer's disease. We have previously shown that human Abeta has the ability to reduce Fe(III) and Cu(II) and produce hydrogen peroxide coupled with these metals, which is correlated with toxicity against primary neuronal cells. Cyclooxygenase (COX)-2 expression is linked to the progression and severity of pathology in AD. COX is a heme-containing enzyme that produces prostaglandins, and the enzyme also possesses peroxidase activity. Here we investigated the possibility of direct interaction between human Abeta and COX-2 being mediated by the peroxidase activity. Human Abeta formed dimers when it was reacted with COX-2 and hydrogen peroxide. Moreover, the peptide formed a cross-linked complex directly with COX-2. Such cross-linking was not observed with rat Abeta, and the sole tyrosine residue specific for human Abeta might therefore be the site of cross-linking. Similar complexes of Abeta and COX-2 were detected in post-mortem brain samples in greater amounts in AD tissue than in age-matched controls. COX-2-mediated cross-linking may inhibit Abeta catabolism and possibly generate toxic intracellular forms of oligomeric Abeta.
Nagano
Seiichi
S
Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. bush@helix.mgh.harvard.edu
Huang
Xudong
X
Moir
Robert D
RD
Payton
Sandra M
SM
Tanzi
Rudolph E
RE
Bush
Ashley I
AI
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000737:chemistry; D051546:Cyclooxygenase 2; D019281:Dimerization; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000494:pharmacology; D015151:Immunoblotting; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D008956:Models, Chemical; D018384:Oxidative Stress; D010455:Peptides / Q000737:chemistry; D011233:Precipitin Tests; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D014443:Tyrosine / Q000737:chemistry
D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D007527:Isoenzymes; D008565:Membrane Proteins; D010455:Peptides; D014443:Tyrosine; D006861:Hydrogen Peroxide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases