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

J Neurosci. 2001 Mar 15;21(6):1902-10. doi: 10.1523/JNEUROSCI.21-06-01902.2001.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Amyloid beta-Protein Precursor / pharmacology
  • Animals
  • Antibodies / pharmacology
  • Apoptosis / drug effects*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism
  • Insulin-Like Growth Factor Binding Protein 3 / pharmacology
  • Insulin-Like Growth Factor I / antagonists & inhibitors
  • Insulin-Like Growth Factor I / metabolism*
  • Insulin-Like Growth Factor I / pharmacology
  • Mice
  • Mutagenesis, Site-Directed
  • Peptide Fragments / pharmacology
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism
  • Transfection


  • Amyloid beta-Protein Precursor
  • Antibodies
  • Insulin-Like Growth Factor Binding Protein 3
  • Peptide Fragments
  • RNA, Messenger
  • insulin-like growth factor 1, des-(1-3)-
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1