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IGF-1 in Brain Growth and Repair Processes

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Handbook of Neurochemistry and Molecular Neurobiology

Abstract:

This chapter addresses the role of insulin‐like growth factor 1 (IGF‐1) and the IGF‐1 receptor (IGF1R) in brain development, injury response, and aging. We concentrate mainly on recent information from murine model systems, with consideration of interesting and relevant data from invertebrates and humans. IGF‐1 and its cognate receptor are both highly expressed in the developing brain, supporting both autocrine and paracrine activity for this anabolic peptide. IGF‐1 deletion or inhibition during brain development attenuates brain growth, with reductions in both cell number and cell size. Cell numbers are notably reduced in the olfactory system, the dentate gyrus of the hippocampus, and the striatum. Brain volume is globally decreased due to a loss of neuropil, with significant reductions in neuronal soma volume, dendritic length and complexity, and synapse number. Myelination is reduced in proportion to the decreases in neuron number and nerve processes in the IGF‐1‐null brain. Conversely, transgenic IGF‐1 overexpression results in increased brain size with increases in cell number, cell size, and dendrite growth with proportionate increases in myelination. Metabolic activity as measured by glucose utilization is significantly decreased in the IGF‐1‐null brain and increased in the transgenic IGF‐1‐overexpressing brain. IGF‐1 deletion in humans is associated with mental retardation and sensorineural deafness. IGF‐1 deletion is also associated with deafness in mice, but no other obvious neurological or behavioral phenotypes have been identified.

IGF‐1 prevents neuronal death in response to a variety of insults in vitro, but cell death appears to be a minor effect in the IGF‐1‐null brain. IGF‐1's physiological effects in brain depend on when and where the peptide is expressed. For example, IGF‐1 is expressed in an olfactory neuron germinal zone early in development, enhancing proliferation of these neurons, which are correspondingly reduced in number in the IGF‐1‐null mouse. IGF‐1 is expressed in long‐axon projection neurons at a later, postmitotic stage, promoting somatic and dendritic growth for these neurons, which are normal in number but small with hypotrophic dendritic arbors in the IGF‐1‐null brain. Increased circulating or brain IGF‐1 is associated with increased hippocampal neurogenesis in adult rodents, and treatment with exogenous IGF‐1 may protect against neurodegeneration in response to brain injury. IGF‐1's anabolic effects in brain are executed via the IRS2‐PI3K‐Akt signaling system. The multifunctional enzyme glycogen synthase kinase 3 (GSK3) is a major target of this pathway. Inhibitory phosphorylation of GSK3 by IGF‐1 enhances glucose utilization and protein synthesis, promoting somatic growth and dendritogenesis in IGF‐1‐expressing projection neurons. Brain IGF‐1 also inhibits the phosphorylation of tau, a microtubule‐associated protein, via the PI3K‐Akt‐GSK3 pathway. This neurofibrillary tangle (NFT) protein is hyperphosphorylated in both IGF‐1‐ and IRS2‐null brains. IGF‐1's role in brain aging is unclear at present. Data obtained from worms to primates suggest that suppression of the IGF system slows the aging process, but it is not yet known if brain aging is altered in IGF‐1‐null or ‐deficient mice.

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Abbreviations

AD:

Alzheimer's disease

Akt:

serine/threonine protein kinase

BAD:

bcl‐associated death promoter

BBB:

blood–brain barrier

BRDU:

bromodeoxyuridine

CNPase:

2′,3′‐cyclic nucleotide, 3′‐phosphodiesterase

EGF:

epidermal growth factor

eIF2B:

eukaryotic initiation factor 2B

FOXO:

forkhead transcription factors

GH:

growth hormone

GLUT:

glucose transporter

GSK3:

glycogen synthase kinase 3

IGF:

insulin‐like growth factor

IGFBP:

IGF‐binding protein

IGF1R:

IGF‐1 receptor

IRS:

insulin receptor substrate

MAG:

myelin‐associated protein

MAPK:

mitogen‐activated protein kinase

MBP:

myelin basic protein

mTOR:

mammalian target of rapamycin

NF‐κB:

nuclear factor kappa B

NFT:

neurofibrillary tangle

NO:

nitric oxide

PCR:

polymerase chain reaction

PDK1:

2, 3‐phosphoinositide‐dependent protein kinase 1, 2

PI3K:

phosphoinositide‐3 kinase

PIP3:

phosphatidylinositol‐3,4,5‐trisphosphate

PLP:

myelin proteolipid protein

PTEN:

phosphatase and tensin homolog

S6K:

ribosomal protein S6 kinase

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  1. C. Bondy
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  2. C. Cheng
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  3. J. Zhong
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  4. W.‐H. Lee
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Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, 10962, Orangeburg, Newyork, USA

    Abel Lajtha (Director) (Director)

  2. Department of Neurology (Division of Neurochemistry and Neurobiology), University of Iowa College of Medicine and Veterans Administration Medical Center, 52242, lowa, lowa, USA

    Ramon Lim

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Bondy, C., Cheng, C., Zhong, J., Lee, W. (2006). IGF-1 in Brain Growth and Repair Processes. In: Lajtha, A., Lim, R. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30381-9_7

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