, 2010). The “null hypothesis” in studies of Alzheimer’s disease has been centered on Amyloid-β (Aβ) (Cuajungco et al., 2000). The central tenet of Aβ toxicity is linked with the presence of redox metals, mainly copper and iron. Direct evidence of increased metal concentrations within amyloid plaques is based on physical measurements that proved that there is an increase in the metal concentrations within the amyloid plaques (see above) (Rajendran et al., 2009). Copper is known to bind to Aβ via histidine (His13, His14, His6) and tyrosine (Tyr10) residues (Hung et al., 2010). Besides Cu(II), Aβ also binds Zn(II)
and Fe(III). Cu(II) interaction with Aβ promotes its neurotoxicity which correlates with the metal reduction [Cu(II) → Cu(I)] JQ1 and the generation of hydrogen peroxide which in turn can be catalytically decomposed forming hydroxyl radical. Linsitinib research buy Cu(II) promotes the neurotoxicity of Aβ with the greatest effect for Aβ (1–42) > Aβ (1–40), corresponding to the capacity to reduce Cu(II) to Cu(I), respectively and form hydrogen peroxide (Cuajungco et al., 2000). The copper complex of Aβ(1–42) has a highly positive reduction potential, characteristic of strongly reducing cupro-proteins. EPR spectroscopy has been employed to show, that the
N-terminal residues of His13, His14, His6 and Tyr10 are involved in the complexation of Cu in Aβ ( Cerpa et al., 2004 and Butterfield et al., 2001). It has recently been proposed that N-terminally complexed Cu(II) is reduced by electrons originating from the C-terminal methionine (Met35) residues according to the reaction: equation(10) MetS + Aβ-Cu(II) ↔ MetS+ Phosphatidylinositol diacylglycerol-lyase + Aβ-Cu(I)forming the sulphide radical of Met35 (MetS+ ) and reducing Cu(II). Based on the thermodynamic calculations the
above reaction is rather unfavourable. However, the rate of electron transfer between MetS and Aβ-Cu(II) may be enhanced by the subsequent exergonic reaction of deprotonation of MetS+ , leaving behind the 4-methylbenzyl radical, thus making the reaction (16) viable in vivo ( Valko et al., 2005). The sulphide radical MetS+ may react for example with superoxide anion radical: equation(11) MetS+ + O2− → 2MetOforming Met-sulphoxide (MetO) which has been isolated from AD senile plaques. Amyloid-β has neurotoxic properties and has been proved to stimulate copper-mediated oxidation of ascorbate (Dikalov et al., 2004): equation(12) Aβ-Cu(II) + AscH− ↔ Aβ-Cu(I) + Asc− + H+ equation(13) Aβ-Cu(II) + Asc− ↔ Aβ-Cu(I) + Asc equation(14) Aβ-Cu(I) + H2O2 → Aβ-Cu(II) + OH + OH− (Fenton) equation(15) Aβ-Cu(I) + O2 ↔ Aβ-Cu(II) + O2 Cu(I) may catalyze free radical oxidation of the peptide via the formation of free radicals by the Fenton reaction.