Free insulin-like growth factor (IGF)-I and IGF binding proteins 2, 5, and 6 in spinal motor neurons in amyotrophic lateral sclerosis

Abstract

Background: Insulin-like growth factor-I (IGF-I) is a potent survival factor for motor neurons and is being investigated as possible therapeutic agent for amyotrophic lateral sclerosis. However, very little information is available on the components of the IGF-I system in this disease. Insulin-like growth factor binding proteins (IGFBPs) play an important part in regulating the bioavailability of IGF-I.

Methods: We investigated the components of the IGF-I system in spinal cord sections of ten patients with amyotrophic lateral sclerosis and in ten controls without neurological disease. IGF-I was studied by western immunoblotting. IGFBPs and IGF-I receptors were investigated by immunohistochemistry and Western immunoblotting.

Findings: Total IGF-I in ventral horn homogenates did not differ between patients and controls. However, free IGF-I was 53% lower in patients than in controls. Compared with controls, immunoreactivity in the spinal motor neurons of patients with amyotrophic lateral sclerosis was 64% higher for IGFBP2, 46% higher for IGFBP5, and 33% higher for IGFBP6, with upregulation of IGF-I receptors. Immunoreactivity for IGFBPs1, 3, and 4 did not differ between patients and controls.

Interpretation: In the ventral horns of patients, free IGF-I is reduced, which could be because of specific increases in IGFBPs 2, 5, and 6 in spinal motor neurons. This abnormality might have an important role in the processes leading to motor neuron death, and should be taken into account when developing treatments aimed to stimulate IGF-I receptors in motor neurons.