Secreted Aβ does not mediate neurotoxicity by antibody-stimulated amyloid precursor protein

Antibodies against APP, a precursor of A beta deposited in Alzheimer's disease brain, have been shown to cause neuronal death. Therefore, it is important to determine whether A beta mediates antibody-induced neurotoxicity. When primary neurons were treated with anti-APP antibodies, A beta 40 and A beta 42 in the cultured media were undetectable by an assay capable of detecting 100 nM A beta peptides. However, exogenously treated A beta1-42 or A beta1-43 required >3 muM to exert neurotoxicity, and 25 muM A beta1-40 was not neurotoxic. Glutathione-ethyl-ester inhibited neuronal death by anti-APP antibody, but not death by A beta1-42, whereas serum attenuated toxicity by A beta1-42, but not by anti-APP antibody. Using immortalized neuronal cells, we specified the domain responsible for toxicity to be cytoplasmic His(657)-Lys(676), but not the A beta1-42 region, of APP. This indicates that neuronal cell death by anti-APP antibody is not mediated by secreted A beta. (C) 2001 Academic Press.