Alzheimer’s disease – Role of Serum insulin-like growth factor I (IGF-I ) in brain function

IGF-I is an important signal during development, including brain growth. Impaired IGF-I signalling at the blood-brain-barrier by aging, inappropriate diet, sedentary life, stress, inflammatory mediators associated to illnesses and inheritance may underlie the influence of all these factors in development of Alzheimer’s disease.

Authors: Eva Carro and Ignacio Torres-Aleman
Cajal Institute, CSIC, Madrid, Spain

The insulin-like growth factors (IGFs) appeared early in phylogeny (around 600 million years ago) and expanded through gene duplication to include over 30 different molecules in invertebrate species to around 10 in vertebrates (man). In simple organisms IGFs are circumscribed to neural tissues, where they control the feeding behaviour, energy balance, and cell growth and are also probably involved in longetivity determination.

In mammals, although a lower number of IGFs have so far been characterised, their biological role has expanded. Firstly, mammals produce IGFs not only in the brain but in all tissues and while neural control of energy balance and feeding behaviour is still performed though brain insulin parthways, the IGFs participate not only in regulation of body size but in many other physiological processes, including life-span control, that are slowly been unveiled.

Apart from insulin and due to its importance in endocrine loops, the biological role of IGF-I is probably best studied.

Insulin-like growth factor I (IGF-I) is present at high concentrations in the circulation. Tissue-specific genetic ablation has shown that the majority of serum IGF-I is secreted by liver cells, although all major organs synthesize it.

IGF-I is an important signal during development, including brain growth. Although the biological role of IGF-I in organs such as muscle or ovary is reasonably well established, its biological significance in the adult brain is far from clear. In this regard, while local IGF-I synthesis decreases during brain development, protein levels remain relatively constant throughout life until old age, where a decline is found, not only in the brain but also in the bloodstream.

This mismatch between declining local synthesis early after birth and steady protein levels may be explained by the ability of serum IGF-I to access the brain across the blood-brain-barrier. This peripheral IGF-I input to the brain is a physiologically meaningful process of potential impact in brain diseases. Numerous brain mechanisms are regulated by serum IGF-I.

Many of these, such as cell energy modulation or growth and survival are common to other IGF-I target tissues but there are also a number of brain-specific mechanisms regulated by IGF-I which likely underlie the ability of serum IGF-I to modulate the major function of the brain: cognition. We propose that serum IGF-I forms part of the mechanisms involved in the ‘‘cognitive reserve’’ concept of brain responses to homeostasis breakdown.

Based on IGF-I pleiotropy not only in brain but elsewhere, we consider that loss of IGF-I function is an important step towards disease.

Published: 06 Jul 2006

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Keio Journal of Medicine (Keio J Med 55 (2): 59–63, June 2006)

Circulation

Medicine