Elsevier

Neuroscience

Volume 88, Issue 1, January 1999, Pages 269-279
Neuroscience

Alterations in insulin-like growth factor-1 gene and protein expression and type 1 insulin-like growth factor receptors in the brains of ageing rats

https://doi.org/10.1016/S0306-4522(98)00192-4Get rights and content

Abstract

Ageing in mammals is characterized by a decline in plasma levels of insulin-like growth factor-1 that appears to contribute to both structural and functional changes in a number of tissues. Although insulin-like growth factor-1 has been shown to provide trophic support for neurons and administration of insulin-like growth factor-1 to ageing animals reverses some aspects of brain ageing, age-related changes in insulin-like growth factor-1 or type 1 insulin-like growth factor receptors in brain have not been well documented. In this series of studies, insulin-like growth factor-1 messenger RNA and protein concentrations, and type 1 insulin-like growth factor receptor levels were analysed in young (three to four- and 10–12-month-old), middle-aged (19–20-month-old) and old (29–32-month-old) Fisher 344× Brown Norway rats. Localization of insulin-like growth factor-1 messenger RNA throughout the lifespan revealed that expression was greatest in arteries, arterioles, and arteriolar anastomoses with greater than 80% of these vessels producing insulin-like growth factor-1 messenger RNA. High levels of expression were also noted in the meninges. No age-related changes were detected by either in situ hybridization or quantitative dot blot analysis of cortical tissue. However, analysis of insulin-like growth factor-1 protein levels in cortex analysed after saline perfusion indicated a 36.5% decrease between 11 and 32 months-of-age (P<0.05). Similarly, analysis of type 1 insulin-like growth factor receptor messenger RNA revealed no changes with age but levels of type 1 insulin-like growth factor receptors indicated a substantial decrease with age (31% in hippocampus and 20.8 and 27.3% in cortical layers II/III and V/VI, respectively).

Our results indicate that (i) vasculature and meninges are an important source of insulin-like growth factor-1 for the brain and that expression continues throughout life, (ii) there are no changes in insulin-like growth factor-1 gene expression with age but insulin-like growth factor-1 protein levels decrease suggesting that translational deficiencies or deficits in the transport of insulin-like growth factor-1 through the blood–brain barrier contribute to the decline in brain insulin-like growth factor-1 with age, and (iii) type 1 insulin-like growth factor receptor messenger RNA is unchanged with age but type 1 insulin-like growth factor receptors decrease in several brain regions. We conclude that significant perturbations occur in the insulin-like growth factor-1 axis with age. Since other studies suggest that i.c.v. administration of insulin-like growth factor-1 reverses functional and cognitive deficiencies with age, alterations within the insulin-like growth factor-1 axis may be an important contributing factor in brain ageing.

Section snippets

Animals

Young (three to four and 10–12 months), middle-aged (19–20 months), and old (29–32 months) male Fisher 344× Brown Norway rats (F1) were obtained from the National Institute of Ageing Colony at Harlan Industries (Indianapolis, IN) and housed in an specific pathogen-free facility on a 12:12 h light:dark cycle in a temperature-controlled room. Food (Prolab Rat/Mouse/Hamster 3000 Formula, PMI Feed, St Louis, MO) and water were available ad libitum. Animals were maintained in this facility for three

Insulin-like growth factor-1 gene expression in the meninges and cortical microvasculature

High levels of IGF-1 gene expression were observed in meninges across all age-groups. Although gene expression in this area was not specifically quantified, no differences were apparent between the three age-groups. Prominent IGF-1 gene expression was also observed in the arteries and arterioles of the somatosensory and frontal cortex, and expression was greater than that observed in cortical neurons. Fig. 1 and Fig. 2 show examples of localization of IGF-1 mRNA in cortical microvasculature by

Insulin-like growth factor-1, cerebrovasculature and brain ageing

Previous studies clearly demonstrate that IGF-1 has a trophic action on neurons. IGF-1 administration to cultured neurons has been shown to stimulate cell proliferation, survival, and neurite outgrowth52, 53, 68while, in vivo, IGF-1 has been reported to regulate synaptogenesis and myelin synthesis as well as neurotransmitter release.43, 44, 49, 58, 61, 70Although many of the actions of IGF-1 on neurons and glia are well-established, the source of IGF-1 that contributes to trophic support of

Conclusions

We have found that vascular endothelial cells within the CNS express IGF-1 mRNA and although expression is unchanged, the levels of IGF-1 protein decrease substantially with age. These changes occur concurrently with alterations in type 1 IGF receptor density providing strong evidence for withdrawal of IGF-1-related trophic support in the ageing brain. Since administration of IGF-1 has been shown to reverse several aspects of brain ageing, including cognitive deficits, we propose that

Acknowledgements

This research was supported by grant PO1 AG11370 from the National Institute on Ageing. Materials for the analysis of IGF-1 were the generous gift of the National Hormone and Pituitary Program and NIDDKD.

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