The N‐terminal copper‐binding domain of the amyloid precursor protein protects against Cu 2+ neurotoxicity in vivo

The amyloid precursor protein (APP) contains a Cu binding domain (CuBD) localized between amino acids 135 and 156 (APP 135‐156 ), which can reduce Cu 2+ to Cu 1+ in vitro. The physiological function of this APP domain has not yet being established; nevertheless several studies support the notion that the CuBD of APP is involved in Cu homeostasis. We used APP synthetic peptides to evaluate their protective properties against Cu 2+ neurotoxicity in a bilateral intra‐hippocampal injection model. We found that human APP 135‐156 protects against Cu 2+ ‐induced neurotoxic effects, such as, impairment of spatial memory, neuronal cell loss, and astrogliosis. APP 135‐156 lacking two histidine residues showed protection against Cu 2+ ; however, APP 135‐156 mutated in cysteine 144, a key residue in the reduction of Cu 2+ to Cu 1+ , did not protect against Cu 2+ neurotoxicity. In accordance with recent reports, the CuBD of the Caenorhabditis elegans , APL‐1, protected against Cu 2+ neurotoxicity in vivo. We also found that Cu 2+ neurotoxicity is associated with an increase in nitrotyrosine immunofluorescence as well as with a decrease in Cu 2+ uptake. The CuBD of APP therefore may play a role in the detoxification of brain Cu.