TY - JOUR
T1 - Secreted Aβ does not mediate neurotoxicity by antibody-stimulated amyloid precursor protein
AU - Sudo, Haruka
AU - Hashimoto, Yuichi
AU - Niikura, Takako
AU - Shao, Zongjun
AU - Yasukawa, Takashi
AU - Ito, Yuko
AU - Yamada, Marina
AU - Hata, Michihiro
AU - Hiraki, Takako
AU - Kawasumi, Masaoki
AU - Kouyama, Keisuke
AU - Nishimoto, Ikuo
N1 - Funding Information:
We especially thank Mark C. Fishman for F11 neurons; Yumi and Yoshiomi Tamai for support; Kazumi Nishihara and Erika Arakawa for technical assistance; and Dovie Wylie for reading of the manuscript. This work was supported by grants from the Japan Medical Association, the Ministry of Education, Science, and Culture of Japan, the Organization for Pharmaceutical Safety and Research (OPSR), KEIO University Grant-in-Aid for Encouragement of Young Medical Scientists (M.K.), KEIO University Medical Science Fund (K.K.), and KEIO University Special Grant-in-Aid for Innovative Collaborative Research Projects (I.N.).
PY - 2001
Y1 - 2001
N2 - Antibodies against APP, a precursor of Aβ deposited in Alzheimer’s disease brain, have been shown to cause neuronal death. Therefore, it is important to determine whether Aβ mediates antibody-induced neurotoxicity. When primary neurons were treated with anti-APP antibodies, Aβ40 and Aβ42 in the cultured media were undetectable by an assay capable of detecting 100 nM Aβ peptides. However, exogenously treated Aβ1.42 or Aβ1-43 required >3 μM to exert neurotoxicity, and 25 μM Aβ1-40 was not neurotoxic. Glutathione-ethyl-ester inhibited neuronal death by anti-APP antibody, but not death by Aβ1-42, whereas serum attenuated toxicity by Aβ1-42, but not by anti-APP antibody. Using immortalized neuronal cells, we specified the domain responsible for toxicity to be cytoplasmic His657-Lys676, but not the Aβ1-42 region, of APP. This indicates that neuronal cell death by anti-APP antibody is not mediated by secreted Aβ.
AB - Antibodies against APP, a precursor of Aβ deposited in Alzheimer’s disease brain, have been shown to cause neuronal death. Therefore, it is important to determine whether Aβ mediates antibody-induced neurotoxicity. When primary neurons were treated with anti-APP antibodies, Aβ40 and Aβ42 in the cultured media were undetectable by an assay capable of detecting 100 nM Aβ peptides. However, exogenously treated Aβ1.42 or Aβ1-43 required >3 μM to exert neurotoxicity, and 25 μM Aβ1-40 was not neurotoxic. Glutathione-ethyl-ester inhibited neuronal death by anti-APP antibody, but not death by Aβ1-42, whereas serum attenuated toxicity by Aβ1-42, but not by anti-APP antibody. Using immortalized neuronal cells, we specified the domain responsible for toxicity to be cytoplasmic His657-Lys676, but not the Aβ1-42 region, of APP. This indicates that neuronal cell death by anti-APP antibody is not mediated by secreted Aβ.
KW - Alzheimer’s disease
KW - Amyloid precursor protein
KW - Antibody-induced neuronal death
KW - Aβ polypeptide
KW - Cytoplasmic domain
KW - Glutathione
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U2 - 10.1006/bbrc.2001.4604
DO - 10.1006/bbrc.2001.4604
M3 - Article
C2 - 11401495
AN - SCOPUS:0034741266
VL - 282
SP - 548
EP - 556
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -