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J. Biol. Chem., Vol. 279, Issue 15, 14673-14678, April 9, 2004

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Peroxidase Activity of Cyclooxygenase-2 (COX-2) Cross-links -Amyloid (A) and Generates A-COX-2 Hetero-oligomers That Are Increased in Alzheimer's Disease^*

Seiichi Nagano, Xudong Huang, Robert D. Moir¶, Sandra M. Payton, Rudolph E. Tanzi¶, and Ashley I. Bush||**

From the Laboratory for Oxidation Biology, Genetics and Aging Research Unit, and the Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, the ^¶Genetics and Aging Research Unit and the Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, and the ^||Department of Pathology, University of Melbourne, and Oxidation Disorders Laboratory, Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia

Oxidative stress is associated with the neuropathology of Alzheimer's disease. We have previously shown that human A 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 A and COX-2 being mediated by the peroxidase activity. Human A 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 A, and the sole tyrosine residue specific for human A might therefore be the site of cross-linking. Similar complexes of A 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 A catabolism and possibly generate toxic intracellular forms of oligomeric A.

Received for publication, December 1, 2003 , and in revised form, December 22, 2003.

^* This work was supported by National Institutes of Health Grant R01-1912686, the Alzheimer's Association, and the National Health and Medical Research Council (to A. I. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of Uehara Memorial Foundation Postdoctoral Fellowship.

^** To whom correspondence should be addressed: Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, Bldg. 114, 16th St., Charlestown, MA 02129. Tel.: 617-726-8244; Fax: 617-724-1823; E-mail: bush{at}helix.mgh.harvard.edu.

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