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

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.