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Serum insulin-like growth factor I regulates brain amyloid-β levels

Nature Medicine volume 8, pages 1390–1397 (2002)Cite this article

Abstract

Levels of insulin-like growth factor I (IGF-I), a neuroprotective hormone, decrease in serum during aging, whereas amyloid-β (Aβ), which is involved in the pathogenesis of Alzheimer disease, accumulates in the brain. High brain Aβ levels are found at an early age in mutant mice with low circulating IGF-I, and Aβ burden can be reduced in aging rats by increasing serum IGF-I. This opposing relationship between serum IGF-I and brain Aβ levels reflects the ability of IGF-I to induce clearance of brain Aβ, probably by enhancing transport of Aβ carrier proteins such as albumin and transthyretin into the brain. This effect is antagonized by tumor necrosis factor-α, a pro-inflammatory cytokine putatively involved in dementia and aging. Because IGF-I treatment of mice overexpressing mutant amyloid markedly reduces their brain Aβ burden, we consider that circulating IGF-I is a physiological regulator of brain amyloid levels with therapeutic potential.

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Figure 1: IGF-I modulates brain Aβ levels.
Figure 2: IGF-I decreases brain Aβ burden in a model of AD amyloidosis.
Figure 3: IGF-I modulates the permeability of the brain-CSF barrier to albumin, an Aβ carrier protein.
Figure 4: IGF-I increases brain levels of transthyretin, an Aβ carrier protein.
Figure 5: TNF-α antagonizes the effects of IGF-I.

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Acknowledgements

We thank R.J. Sancho and F. Lozano for expert help; and A. Nuñez for help in measuring culture resistances. This work was supported by grants from FISS (01/1188) and CAM (08.5/0039/2000).

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Authors and Affiliations

  1. Laboratory of Neuroendocrinology, Cajal Institute, CSIC, Madrid, Spain

    E. Carro, J.L. Trejo & I. Torres-Aleman

  2. Clinica Universitaria de Navarra, Universidad de Navarra, Pamplona, Spain

    T. Gomez-Isla

  3. Clinical Endocrinology Branch, National Institutes of Health, Bethesda, Maryland, USA

    D. LeRoith

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Correspondence to I. Torres-Aleman.

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Competing interests

E.C. and I.T.-A. in conjunction with the CSIC and Complutense University of Madrid have applied for a patent, in Spain, which includes a process to use IGF-I in several neurodegenerative conditions. In addition, I.T.-A. is a founder of Policlonal SL which has licensed this patent.

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Carro, E., Trejo, J., Gomez-Isla, T. et al. Serum insulin-like growth factor I regulates brain amyloid-β levels. Nat Med 8, 1390–1397 (2002). https://doi.org/10.1038/nm1202-793

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