Human Aβ1–42 reduces iron‐induced toxicity in rat cerebral cortex

Abstract

Senile plaques, the major neuropathological lesions of Alzheimer's disease (AD), are composed primarily of amyloid-β (Aβ) peptide and contain high concentrations of iron (1.0 mM). We have previously shown that intracortical injections of 1.0 mM iron to adult rats produce significantly more neuronal loss than control injections of saline vehicle, whereas injections of Aβ do not. Because iron has been shown to increase the in vitro toxicity of Aβ, the present study was undertaken to determine whether iron can make Aβ neurotoxic in vivo. Aβ and 1.0 mM iron (as ferric ammonium citrate) were coinjected into rat cerebral cortex, and the neuronal loss was compared with that produced by pure Aβ or pure iron. The human and rat variants of Aβ_1–42 were compared to determine whether they produce the same amount of neuronal loss when combined with iron. Coinjection of iron with either Aβ variant caused significantly more neuronal loss than Aβ peptide alone, suggesting that iron may contribute to the toxicity associated with senile plaques. Rat Aβ_1–42 combined with iron was as toxic as iron alone, whereas iron combined with human Aβ_1–42 was significantly less toxic. This latter finding indicates that fibrillar human Aβ is able to reduce iron-induced neurotoxicity in vivo and raises the interesting possibility that senile plaques in AD may represent a neuroprotective response to the presence of elevated metal ions.