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

Abstract

Oxidative stress is associated with the neuropathology of Alzheimer's disease. We have previously shown that human Aβ 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 Aβ and COX-2 being mediated by the peroxidase activity. Human Aβ 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 Aβ, and the sole tyrosine residue specific for human Aβ might therefore be the site of cross-linking. Similar complexes of Aβ 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 Aβ catabolism and possibly generate toxic intracellular forms of oligomeric Aβ. Oxidative stress is associated with the neuropathology of Alzheimer's disease. We have previously shown that human Aβ 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 Aβ and COX-2 being mediated by the peroxidase activity. Human Aβ 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 Aβ, and the sole tyrosine residue specific for human Aβ might therefore be the site of cross-linking. Similar complexes of Aβ 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 Aβ catabolism and possibly generate toxic intracellular forms of oligomeric Aβ. The neocortical accumulation of β-amyloid (Aβ) 1The abbreviations used are: Aβ, β-amyloid; AD, Alzheimer's disease; COX, cyclooxygenase; HRP, horseradish peroxidase; DT, dityrosine; NSAID, nonsteroidal anti-inflammatory drug; PG, prostaglandin; HPLC, high pressure liquid chromatography. may play a central role in Alzheimer's disease (AD) (1Glenner G.G. Wong C.W. Biochem. Biophys. Res. Commun. 1984; 120: 885-890Crossref PubMed Scopus (4244) Google Scholar, 2Masters C.L. Multhaup G. Simms G. Pottgiesser J. 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Chem. 2002; 277: 40302-40308Abstract Full Text Full Text PDF PubMed Scopus (537) Google Scholar), which may be important in designing treatment strategies for AD. Human Aβ is a metalloprotein that binds Zn(II) and Cu(II) in amyloid plaque (9Opazo C. Huang X. Cherny R. Moir R. Roher A. White A. Cappai R. Masters C. Tanzi R. Inestrosa N. Bush A. J. Biol. Chem. 2002; 277: 40302-40308Abstract Full Text Full Text PDF PubMed Scopus (537) Google Scholar, 10Cherny R.A. Legg J.T. McLean C.A. Fairlie D. Huang X. Atwood C.S. Beyreuther K. Tanzi R.E. Masters C.L. Bush A.I. J. Biol. Chem. 1999; 274: 23223-23228Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar, 11Dong J. Atwood C.S. Anderson V.E. Siedlak S.L. Smith M.A. Perry G. Carey P.R. Biochemistry. 2003; 42: 2768-2773Crossref PubMed Scopus (527) Google Scholar). The ability of Aβ to produce H2O2 is mediated by the reduction of Cu(II) and Fe(III) to Cu(I) and Fe(II), respectively (8Huang X. Cuajungco M.P. Atwood C.S. Hartshorn M.A. Tyndall J. Hanson G.R. Stokes K.C. Leopold M. Multhaup G. Goldstein L.E. Scarpa R.C. Saunders A.J. Lim J. Moir R.D. Glabe C. Bowden E.F. Masters C.L. Fairlie D.P. Tanzi R.E. Bush A.I. J. Biol. Chem. 1999; 274: 37111-37116Abstract Full Text Full Text PDF PubMed Scopus (731) Google Scholar, 12Huang X. Atwood C.S. Hartshorn M.A. Multhaup G. Goldstein L.E. Scarpa R.C. Cuajungco M.P. Gray D.N. Lim J. Moir R.D. Tanzi R.E. Bush A.I. Biochemistry. 1999; 38: 7609-7616Crossref PubMed Scopus (1036) Google Scholar). Rat Aβ, substituted at three residues compared with human Aβ (Arg5 → Gly, Tyr10 → Phe, and His13 → Arg), is less redox active, producing less H2O2, and is correspondingly less toxic (8Huang X. Cuajungco M.P. Atwood C.S. Hartshorn M.A. Tyndall J. Hanson G.R. Stokes K.C. Leopold M. Multhaup G. Goldstein L.E. Scarpa R.C. Saunders A.J. Lim J. Moir R.D. Glabe C. Bowden E.F. Masters C.L. Fairlie D.P. Tanzi R.E. Bush A.I. J. Biol. 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Dis. 2001; 8: 792-806Crossref PubMed Scopus (64) Google Scholar). Cyclooxygenases (COX) are members of a heme enzyme family that catalyze the rate-limiting reaction to produce prostaglandins (15Smith W.L. DeWitt D.L. Garavito R.M. Annu. Rev. Biochem. 2000; 69: 145-182Crossref PubMed Scopus (2477) Google Scholar). COX-1 is the widely expressed constitutive form, and COX-2 is the inducible form that is up-regulated by cytokines and mitogens. COX-2 may play an important role in AD. Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), inhibitors of COX, delay the onset of AD (16Rogers J. Kirby L.C. Hempelman S.R. Berry D.L. McGeer P.L. Kaszniak A.W. Zalinski J. Cofield M. Mansukhani L. Willson P. Kogan F. Neurology. 1993; 43: 1609-1611Crossref PubMed Google Scholar, 17Beard C.M. Waring S.C. O'Brien P.C. Kurland L.T. Kokmen E. Mayo. Clin. 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The peroxidase reaction of COX is analogous to that of HRP and can utilize a wide range of hydroperoxides including H2O2, rather than PGG2, as substrates (15Smith W.L. DeWitt D.L. Garavito R.M. Annu. Rev. Biochem. 2000; 69: 145-182Crossref PubMed Scopus (2477) Google Scholar). We suspected that the peroxidase activity of COX-2 might the of Aβ we the of COX-2 Aβ and the of complexes in vitro and in were and by high pressure liquid acid and by the W. of COX-2 and were and were Aβ residues and Aβ residues N. T. J. J. R. R. Masters C.L. Beyreuther K. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar) were and were and were The were Brain human post-mortem brain samples affected AD E. 1991; PubMed Scopus Google Scholar), affected AD and were the Brain The of is in were in the or post-mortem between the of and AD used for AD AD AD AD AD AD AD AD AD in a of peptide were in the of the The peptide was a of Aβ were by which we have previously as an for Aβ X. Atwood C.S. Moir R.D. Hartshorn M.A. Tanzi R.E. Bush A.I. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). Aβ was with COX-2 in a of of and at of and were in COX-2 inhibitors were the enzyme was with the for of acids in Aβ, the peptide was with the for at to COX-2 and hydrogen peroxide. The reaction was by for reacted in vitro were with of at and with of for at of Aβ or COX-2 and AD brain samples were by a in of The was by at for and to a protein of with with of to the of proteins, the was with of or COX-2 at and with of for at the were three with and for at with samples in were a and by at for The was to at for The was with for or for for at The was with a primary at by a horseradish for at was detected by Perry The of the was by of of the of COX-2 the of Aβ, we COX-2 with human synthetic Aβ in the of H2O2 for We observed that the synthetic Aβ that the of COX-2 and H2O2 the of an Aβ as as Aβ in the range of of Aβ with COX-2 amounts of the and Aβ the was of H2O2 may have of the reduction and subsequent of B. Biochem. 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The was with compared with at the and were for these and inhibitors of COX-1 and the cross-linking of Aβ mediated by a of a compared with the of COX-2 by at for Aβ cross-linking which the possibility that in heme might the cross-linking of Aβ by Therefore, the is by the enzymatic peroxidase activity of COX-2. and His13 in human are substituted in rat which not in the of COX-2 Therefore, of these three residues may be the site of cross-linking by a to the acid for the we the of for acid M. A. D. J. Biochem. 2001; PubMed Scopus Google Scholar) the cross-linking by an not have an which tyrosine the cross-linking with the of dityrosine a not inhibit the cross-linking rather the of Aβ. may indicate that the residues play a role in or that the is in as a the with is that the are not for Although studies of acid substituted Aβ be to these these not and and that cross-linking be a of the activity of COX-2. We for that COX-2 might with Aβ in is for SDS-resistant Aβ dimers and being in post-mortem brain tissue C.L. Multhaup G. Simms G. Pottgiesser J. Martins R.N. Beyreuther K. EMBO J. 1985; 4: 2757-2763Crossref PubMed Scopus (806) Google Scholar, C. Roher J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). is of H2O2 in brain tissue M.A. Perry G. Richey P.L. Sayre L.M. Anderson V.E. Beal M.F. Kowall N. 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Nature. 1996; 382: 120-121Crossref PubMed Scopus (788) Google Scholar, 6Cuajungco M.P. Goldstein L.E. Nunomura A. Smith M.A. Lim J.T. Atwood C.S. Huang X. Farrag Y.W. Perry G. Bush A.I. J. Biol. Chem. 2000; 275: 19439-19442Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar). to increased H2O2 in AD may also metabolism and H2O2 Aβ or and and as a for COX-2-mediated cross-linking of Aβ. of and or of hydrogen peroxide may therefore be strategies to Aβ by COX-2. Such a mechanism may to the of which hydrogen peroxide by Aβ by to and at site C.W. Bush A.I. A. S. M. L. L. Cherny R.A. A. D. C. M. D. S. Beyreuther K. Tanzi R.E. Masters C.L. Arch. Neurol. 2003; PubMed Scopus Google Scholar). The tyrosine of human Aβ is to the that interact with the peptide T. K. N. Biochemistry. 2000; PubMed Scopus Google Scholar, T. K. 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P. S.A. R. Smith M.P. T. N. Nature. 2001; PubMed Scopus Google Scholar). The of and used in are to in the by S. P. S.A. R. Smith M.P. T. N. Nature. 2001; PubMed Scopus Google Scholar), that the of human The of Aβ cross-linking Aβ and may be a mechanism for the of AD. We detected the complexes of Aβ and COX-2 human brains by with against complexes are increased in AD in affected may be to the increased activity of COX-2 cross-linking of COX-2 and Aβ or to of the complexes in AD. The of COX-2 that we observed has also previously detected in AD brains G.M. Aisen P.S. Neuroscience. 1998; 87: 319-324Crossref PubMed Scopus (412) Google Scholar). is with that reaction with Aβ may to the of COX-2 such a that is to Aβ, to be increased in AD brain The of the complex is not we that Aβ reaction with COX-2 may with COX-2 or we that COX-2 the of Aβ by the generation of such complexes Therefore, the of complexes in human tissue is that these two are in in and that therefore the of Aβ by COX-2 in AD may to the Aβ oligomeric forms that are to the disease the intracellular of Aβ by COX-2 is an in the pathology of AD, may be a treatment to or delay the disease progression at