Up-Regulation of Insulin-Like Growth Factor-II Receptor in Reactive Astrocytes in the Spinal Cord of Amyotrophic Lateral Sclerosis Transgenic Rats

Up-Regulation of Insulin-Like Growth Factor-II Receptor in Reactive Astrocytes in the Spinal Cord of Amyotrophic Lateral Sclerosis Transgenic Rats

BYAMBASUREN DAGVAJANTSAN,¹ MASASHI AOKI,¹ HITOSHI WARITA,¹ NAOKI SUZUKI¹ and YASUTO ITOYAMA¹

¹Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by selective motor neuron death. We developed a rat model of ALS expressing a human cytosolic copper-zinc superoxide dismutase (SOD1) transgene with two ALS-associated mutations: glycine to alanine at position 93 (G93A) and histidine to arginine at position 46 (H46R). Although the mechanism of ALS is still unclear, there are many hypotheses concerning its cause, including loss of neurotrophic support to motor neurons. Recent evidence suggests that insulin-like growth factors (IGFs) act as neurotrophic factors, and promote the survival and differentiation of neuronal cells including motor neurons. Their ability to enhance the outgrowth of spinal motor neurons suggests their potential as a therapeutic agent for the patients with ALS. In this study, we investigated IGF-II receptor immunoreactivity in the anterior horns of the lumbar level of the spinal cord in SOD1 transgenic rats with the H46R mutation of different ages as well as in normal littermates. The double-immunostaining for IGF-II receptor and glial fibrillary acidic protein (GFAP) demonstrated co-localization on reactive astrocytes (^**p < 0.001) in the end-stage transgenic rats, whereas it was not evident at the pre-symptomatic stage or at the onset of the disease. Our results demonstrated the IGF-II receptor up-regulation in reactive astrocytes in the spinal cord of transgenic rats, which may reflect a protective response against the loss of IGF-related trophic factors. We suggest that IGF receptors may play a key role in the pathogenesis, and may have therapeutic implications in ALS.

keywords —— amyotrophic lateral sclerosis; insulin-like growth factor; transgenic rat; IGF receptor; SOD1

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Tohoku J. Exp. Med., 2008, 214, 303-310

Correspondence: Masashi Aoki, M.D., Ph.D., Department of Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.

e-mail: aokim@mail.tains.tohoku.ac.jp