Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Amyloid beta-Protein Precursor / pharmacology
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Animals
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Antibodies / pharmacology
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Apoptosis / drug effects*
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Cell Line
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Dose-Response Relationship, Drug
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Humans
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Insulin-Like Growth Factor Binding Protein 3 / metabolism
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Insulin-Like Growth Factor Binding Protein 3 / pharmacology
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Insulin-Like Growth Factor I / antagonists & inhibitors
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Insulin-Like Growth Factor I / metabolism*
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Insulin-Like Growth Factor I / pharmacology
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Mice
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Mutagenesis, Site-Directed
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Peptide Fragments / pharmacology
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Protein Binding / drug effects
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Protein Binding / physiology
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RNA, Messenger / metabolism
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes / cytology
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T-Lymphocytes / metabolism
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Transfection
Substances
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Amyloid beta-Protein Precursor
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Antibodies
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Insulin-Like Growth Factor Binding Protein 3
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Peptide Fragments
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RNA, Messenger
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insulin-like growth factor 1, des-(1-3)-
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Insulin-Like Growth Factor I
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Receptor, IGF Type 1