Insulin-like growth factor I (IGF-I) protects cells from apoptosis by Alzheimer's V642I mutant amyloid precursor protein through IGF-I receptor in an IGF-binding protein-sensitive manner.
It has been found that insulin-like growth factor I (IGF-I) exerts cytoprotection against Abeta amyloid-induced neuronal cell death. Deposits of Abeta amyloid are one of the pathological hallmarks of Alzheimer's disease (AD). Here, we examined whether IGF-I exerts protective activity against cell death induced by a familial AD (FAD)-linked mutant of amyloid precursor protein (APP), and we found that IGF-I protected cells from toxicity of FAD-associated V642I mutant of APP in multiple cell systems. IGFBP-3 blocked this action of IGF-I, but not of des(1-3)IGF-I, which was as active as IGF-I in the presence of IGFBP-3. The data also demonstrated that the IGF-I receptor (IGF-IR) mediates the protective activity of IGF-I. The antagonizing function of the IGF-I/IGF-IR system against V642I-APP, which is further antagonized by IGFBP-3, provides a molecular clue to the understanding of AD pathophysiology and to the establishment of potential therapy for AD.
Department of Pharmacology and Neurosciences, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
T
T
Niikura
Y
Y
Hashimoto
T
T
Okamoto
Y
Y
Abe
T
T
Yasukawa
M
M
Kawasumi
T
T
Hiraki
Y
Y
Kita
K
K
Terashita
K
K
Kouyama
I
I
Nishimoto
D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D018972:Insulin-Like Growth Factor Binding Protein 3; D010446:Peptide Fragments; D012333:RNA, Messenger; C058957:insulin-like growth factor 1, des-(1-3)-; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1