Cu(II) Potentiation of Alzheimer Aβ Neurotoxicity

Abstract

Oxidative stress markers as well as high concentrations of copper are found in the vicinity of A␤ amyloid deposits in Alzheimer's disease. The neurotoxicity of A␤ in cell culture has been linked to H 2 O 2 generation by an unknown mechanism. We now report that Cu(II) markedly potentiates the neurotoxicity exhibited by A␤ in cell culture. The potentiation of toxicity is greatest for A␤1-42 > A␤1-40 > > mouse/rat A␤1-40, corresponding to their relative capacities to reduce Cu(II) to Cu(I), form H 2 O 2 in cell-free assays and to exhibit amyloid pathology. The copper complex of A␤1-42 has a highly positive formal reduction potential (Ϸ؉500 -550 mV versus Ag/AgCl) characteristic of strongly reducing cuproproteins. These findings suggest that certain redox active metal ions may be important in exacerbating and perhaps facilitating A␤-mediated oxidative damage in Alzheimer's disease.Oxidative damage in the neocortex coincides with A␤ accumulation both in Alzheimer's disease (AD) 1 (1) and in A␤ amyloid-bearing transgenic mice (2), but the mechanisms of oxidation are unknown. The possibility that A␤ accumulation causes oxidation, perhaps by radical formation (3), has been explored, but the nature of the chemistry involved in generating A␤-associated oxidation products such as lipid peroxides (4) remains to be elaborated. In culture, A␤-induced neurotoxicity is characterized by elevated cellular H 2 O 2 and is combated by antioxidants such as vitamin E and catalase (5). The origin of the toxic H 2 O 2 is unknown.Recently, we reported that Fe(III) interacts directly with A␤1-42 and A␤1-40 to produce H 2 O 2 and TBARS formation in a cell-free manner in vitro, through reduction of the metal ion (6), suggesting that a source of the H 2 O 2 that mediates toxicity in cell cultures exposed to A␤ is extracellular. Cu(II)and Fe(III) have been found in abnormally high concentrations in amyloid plaques (Ϸ0.4 and Ϸ1 mM, respectively) and AD-affected neuropil (7), and copper-selective chelators have been shown to dissolve A␤ deposits extracted from AD post-mortem brain specimens (8). Therefore, these metal ions may be important cofactors in A␤-associated oxidative damage. Importantly, we have also reported that the generation of both Cu(II) and Fe(III)-mediated TBARS is greatest for A␤1-42 Ͼ A␤1-40 Ͼ Ͼ rat A␤1-40 (6). This rank order is of interest because it mirrors the relative participation of the peptides in amyloid neuropathology, and because the most active one (A␤1-42) is overproduced in familial AD (9). Rats and mice do not develop amyloid (10), even in mice transgenic for familial-AD linked mutant presenilin that overexpress endogenous mouse A␤1-42 (11), probably due to the three amino acid substitutions in their homologue of A␤ (Arg 5 3 Gly, Tyr 10 3 Phe, and His 13 3 Arg) (12).Although Fe(III) mediates and potentiates A␤1-40 toxicity in cell culture (13), it is not clear whether this is due to metal interaction with the peptide or due to a nonspecific increase in reactive oxygen species (ROS) generation within the cell. R...

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