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 i n SOD1 transgeni c 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 endstage transgenic rats, whereas it was not evident at t he pre-symptomatic stage or at t he 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. amyotrophic lateral sclerosis; insulin-like growth factor; transgenic rat; IGF receptor; SOD1Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease cause d by selective motor neuron death. Approximately 10% of cases of ALS are inherited, usually as an autosomal dominant trait. In ~25% of familial cases, the disease is caused by mutations in the gene encoding cytosolic copper-zinc superoxide dismutase (SOD1)(Aoki et al. 1993; Rosen 1993). The overexpression of mutant human SOD1 in mice is used as model for ALS, however, some experimental manipulations are difficult in transgenic (Tg) mice because of size limitations. Thus, we developed a rat model of ALS expressing a human SOD1 transgene with two ALS-associated mutations: glycine to alanine atposition 93 (G93A) and histidine to arginine at position 46 (H46R) (Nagai et al. 2001). Similar to its murine counter pa rt, the transgenic rats that express human SO D1 transgene ALS-a ssociated mutations develop striking motor neuron degeneration and paralysis. Although the m echan ism of AL S is still unclear, there are many hypotheses concerning its cause of ALS, including loss of neurotrophic support to motor neurons (Rowland and Shneider 2001). The insulin-like growth factors (IGF-I and IGF-II) areneurotrophic factors expressed in the central nervous system that promote the survival and differentiation of neuronal cells includingmotor neurons. They could be of therapeutic value in human neurodegenerative disorders, including ALS (Adem et al. 1994; Hawkes and Kar2003; Narai et al. 2005). Evidence that IGF-I rescues mo to r neurons in vitro and in animals. (Kaspar et al. 2003) has led to therapeutic trials of human recombinant IGF-I in patients with ALS The biological actions of the IGFs are mediated through specific cell membrane receptors design ated as th e IGF-I and I GFII receptors(Sepp-Lorenzino 1998; Hawkes and Kar 2003; Kim et al. 2004). Alterations of the IGF-I and IGF-II binding sites in the spinal cord of the patients with ALS would support their involvement in the pathology of ALS (Dore et al. 1996; Chung et al. 2003; Kar et al. 2006). (H46R) mutant Tg rat as an in vivo model of ALS and performedimmunohistochemical studies to investigate the changes of the IGF-II receptor in the spinal cord.