The Insulinlike Growth Factor 1 Igfi A Key Modulator Of Neurogenesis And Cognitive Functions

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Activity of insulin-like proteins was discovered in 1957. The precise action of insulin-like growth factor I (IGF-I) remained poorly understood until the production in the 1980s of recombinant human IGF-I. This trophic factor has been well characterized as a factor mediating growth hormone action (Jones & Clemmons, 1995; Isaksson, Ohlsson, Nils-son, Isgaard, & Lindahl, 1991). IGF-I is found in high levels in the blood and is believed to originate mainly from the liver (Pankov, 1999). The detection of the IGF-I gene using molecular techniques showed its presence in several organs, including the brain (Rotwein, Burgess, Milbrandt, & Krause, 1988). Substantial evidence supports the importance of IGF-I and insulin in normal development and maintenance of adequate neuronal functions throughout the entire lifespan. The structure of IGF-I is quite similar to insulin (Isaksson et al., 1991). Interestingly, researchers have suggested that the level of insulin in the brain is quite low and that, in fact, IGF-I could act as insulin in the central nervous system. IGF-I has the capacity to bind to the entire IGF receptor family, including the insulin receptor. High densities of binding sites for IGF-I and insulin are discretely and differentially distributed throughout the brain, with prominent levels localized to the hippocampus. IGF receptors are produced by numerous neuronal and nonneuronal cell types. IGF-I is a well-established stimulant of cell growth, proliferation, and differentiation, and can stimulate glucose transport and prevent cell death (Doré et al., 1997b). These later effects are crucial for survival of postmitotic neurons.

The authors have previously demonstrated that IGF and insulin receptors are tightly regulated and subject to rapid and chronic changes after a multitude of surgical and pharmacological lesions (Doré et al., 1997c; Doré et al., 1996; Kar et al., 1997a). Both the IGF-I and insulin receptors possess similar tyrosine kinase activities, and binding of the ligand to the a-subunit of the receptor induces the au-tophosphorylation of the p-subunits. One of the key phos-phoproteins is the insulin receptor substrate (IRS), which interacts directly with other intracellular signaling substrates, including the phosphatidylinositol 3-kinase/AKT kinase pathway and various other downstream transcription factors (Zheng et al., 2002). Activation of these pathways has been shown to be protective in several chronic and acute neurodegenerative conditions (for example, using models of Huntington and hypoxia (Humbert et al., 2002; Scott et al., 2002)).

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