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Heme binding induces dimerization and nitration of truncated β-amyloid peptide Aβ16 under oxidative stress.

Several observations suggest a link between (ferric) heme and Alzheimer s disease (AD), for example, an increase in heme oxygenase 1, 2] a loss of complex IV, and abnormal iron metabolism. These observations suggest that heme metabolism is altered in age-related disorders. As a possible explanation, hemin has been proposed to interact with b-amyloid peptides (Ab), and it is now well established that Ab peptides bind ferric heme. The adducts of hemin–Ab peptides also exhibit increased peroxidase activity with respect to free hemin, but these complexes have not been characterized. Herein we provide thermodynamic and spectroscopic data showing that hemin b can coordinate two Ab16 molecules to form the low-spin, six-coordinated complex [hemin(Ab16)2], and this is in equilibrium with the high-spin [hemin(Ab16)] species, the relative amounts of which strongly depend on peptide concentration and temperature. In the presence of H2O2, hemin-Ab16 complexes produce dimerization of the peptide through dityrosine cross-linking, and in addition the peptide undergoes endogenous nitration at Tyr10 when nitrite is also present in solution. This result is important because both cross-linking and nitration at Tyr10 critically enhance Ab aggregation and plaque formation, thus showing that the binding of heme to Ab can indeed be a factor contributing to neuroinflammation and Ab aggregation. The endogenous peroxidative (H2O2) and nitrative (H2O2/NO2 ) activities exhibited by the hemin–Ab16 peptide add to, and are likely more deleterious than, the oxidation and nitration of external substrates which have been previously reported. Upon adding Ab16 to a 50 mm aqueous phosphate buffer solution of hemin b at pH 7.4 and 300 K, the broad Soret band of the complex near l = 385 nm progressively changes to give a sharp, red-shifted band at l = 414 nm, with additional visible bands at l = 535 and 566 nm (Figure 1C, and see the Supporting Information). The conversion from the high-spin to the low-spin hemin species is complete after addition of 20 equivalents of Ab16, and spectrophotometric data analysis (see the Supporting Information) confirms a 2:1 Ab16/hemin stoichiometry, thus indicating the formation of the [hemin(Ab16)2] complex. The Mçssbauer and H NMR spectra are consistent with a low-spin (S = 1/2) iron(III) center coordinated by two axial imidazole ligands. However, below saturating amounts of Ab16, the Mçssbauer spectrum clearly indicates the presence of a minor high-spin species (Figure 2). Figure 1. UV/vis spectra recorded in 50 mm phosphate buffer solution at pH 7.4. A) Hemin b (1.2 10 5 m). B) Hemin b in the presence of an excess (20 equiv) of Ab16 peptide at 319 K. C) The same as (B) but at 300 K, the spectral changes are fully reversible. The D symbol indicates an increase in temperature.