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

Antibodies against APP, a precursor of A beta deposited in Alzheimer's dise ase brain, have been shown to cause neuronal death. Therefore, it is import ant to determine whether A beta mediates antibody-induced neurotoxicity. Wh en primary neurons were treated with anti-APP antibodies, A beta 40 and A b eta 42 in the cultured media were undetectable by an assay capable of detec ting 100 nM A beta peptides. However, exogenously treated A beta1-42 or A b eta1-43 required >3 muM to exert neurotoxicity, and 25 muM A beta1-40 was n ot neurotoxic. Glutathione-ethyl-ester inhibited neuronal death by anti-APP antibody, but not death by A beta1-42, whereas serum attenuated toxicity b y A beta1-42, but not by anti-APP antibody. Using immortalized neuronal cel ls, 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 n euronal cell death by anti-APP antibody is not mediated by secreted A beta. (C) 2001 Academic Press.