Secreted Abeta does not mediate neurotoxicity by antibody-stimulated amyloid precursor protein.
Antibodies against APP, a precursor of Abeta deposited in Alzheimer's disease brain, have been shown to cause neuronal death. Therefore, it is important to determine whether Abeta mediates antibody-induced neurotoxicity. When primary neurons were treated with anti-APP antibodies, Abeta40 and Abeta42 in the cultured media were undetectable by an assay capable of detecting 100 nM Abeta peptides. However, exogenously treated Abeta1-42 or Abeta1-43 required >3 microM to exert neurotoxicity, and 25 microM Abeta1-40 was not neurotoxic. Glutathione-ethyl-ester inhibited neuronal death by anti-APP antibody, but not death by Abeta1-42, whereas serum attenuated toxicity by Abeta1-42, 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 Abeta1-42 region, of APP. This indicates that neuronal cell death by anti-APP antibody is not mediated by secreted Abeta.
Sudo
H
H
Department of Pharmacology and Neurosciences, KEIO University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Hashimoto
Y
Y
Niikura
T
T
Shao
Z
Z
Yasukawa
T
T
Ito
Y
Y
Yamada
M
M
Hata
M
M
Hiraki
T
T
Kawasumi
M
M
Kouyama
K
K
Nishimoto
I
I
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000276:immunology / Q000633:toxicity*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D018076:DNA, Complementary / Q000235:genetics; D004274:DNA, Recombinant / Q000235:genetics; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D000975:Antioxidants; D017077:Culture Media, Conditioned; D018076:DNA, Complementary; D004274:DNA, Recombinant; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C042431:S-ethyl glutathione; D005978:Glutathione