Insulin-Like Growth Factors and the Brain

The IGFs have interested biologists and physicians for many decades; starting with the somatomedin hypothesis as presented by Daughaday and Salmon in 1957 (1). It was initially thought that somatomedin C (IGF-I) was the liver-derived, circulating form of IGF and controlled postnatal growth in response to GH. After the advent of molecular endocrinology, it was shown that many if not all tissues expressed IGF-I, including the brain. These findings suggested that IGFs may be important as local tissue factors. Today there is evidence that both the endocrine, circulating and the tissue, paracrine/autocrine modes of action are important for normal tissue development and function (2). In this mini-series, we have compiled a group of mini-reviewsontherolesof theIGFsinthecentralnervoussystem. In the review by D’Ercole and Ye (3), the important role of IGF-I in brain development is discussed. IGF-I and the IGF-I receptor (IGF-IR) are widely expressed in the central nervous system, whereas IGF-II is expressed in a more restricted pattern. IGF-binding proteins are similarly expressed during varying phases of development. IGF-I regulates both neuronal and glial cell proliferation and differentiation, apparently by an initial increase in neural progenitor proliferation. Deficits in mouse brain IGF-I or the IGF-IR result in brain retardation, and overexpression leads to brain overgrowth. A few cases of IGF-I or IGF-IR mutations have been described in humans resulting in some form of mental retardation and even microcephaly. Interestingly, when circulating IGF-I levels are elevated later in development and brain levels are reduced, circulating IGF-I can cross the blood-brain barrier and influence brain biology, possibly by preventing neuronal apoptosis. Thus, although the brain IGF system is critical for normal development, circulating IGFs may be important for maintenance of normal central nervous system function. This is borne out to some degree in the second mini-review. Torres-Aleman (4) reviews the relationship of the insulin and IGF system and Alzheimer’s dementia.Thereis increasingevidenceofarelationshipbetweentype 2 diabetes with insulin resistance and an increased risk for dementia. Indeed, a number of animal models that have mutated insulin receptors in the central nervous system or IRS-2 knockout mice demonstrate alterations in tau phosphorylation that affect -amyloid accumulation. In his own studies, Torres-Aleman (4), using mouse models of Alzheimer’s disease, has determined that a deficiency of circulating IGF-I leads to increased -amyloid deposits in the brain, probably due to reduced removal; replacing IGF-I can reverse this effect to some degree, and this suggests a pathogenetic mechanism as well as a therapeutic possibility. Like the brain, the IGF system is fully represented in the complex array of cells making up the peripheral nervous system, where it functions during development and acts later as a survival factor. During development, IGFs affect neurite outgrowth, signaling through their cognate IGF-IR, the signaling pathways having been described in elegant studies by the Feldman laboratory (5). When nerves are damaged, there is a compensatory response with increased expression of this system of growth factors (among others) that affect regeneration. Nervous systemdamagemayoccur indiabetes, forexample,andIGF-Imay affect recovery, at least in rodent models. Circulating IGF-I is also important in these functions on the peripheral nervous system, supporting the hypothesis that both endocrine and paracrine/ autocrine IGF-I regulates complex tissues (6). From the therapeutic aspect, IGF-I was demonstrated to affect both nerve and muscle in animal models and was therefore tested in patients with amyotrophic lateral sclerosis. Unfortunately, to date, the results of these clinical trials have revealed mixed results, and the potential use of recombinant human IGF-I in head trauma, amyotrophic lateral sclerosis, and peripheral nerve damage in humans, despite the promising results in animals, remains to be established. Our readers are indeed fortunate to have the opportunity to digest, in three reviews by leaders in the field, critical summaries of a large body of research in such an important and interesting, and still developing area.