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

Abstract

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 colocalization 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 IGFrelated 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; SOD1 Tohoku

Increased levels and activity of cathepsins B and D in kainate-induced toxicity

“…The microglia, on the other hand, did not express IGF-II/M6P receptors either in control or in kainic acid-treated rats. This observation is consistent with some earlier results which showed a disparity in the localization of the lysosomal enzymes and the receptor in glial cells following injury or pathological conditions (German et al, 2002;Nakanishi, 2003;Hawkes et al, 2006;Dagvajantsan et al, 2008;Amritraj et al, 2009). Since lysosomal enzymes can partly be transported by cation-dependent-M6P as well as sortilin receptors (Hawkes and Kar, 2004;Braulke and Bonifacino, 2009), it is possible that trafficking of cathepsins in reactive microglia may be mediated by these receptors rather than the IGF-II/M6P receptor.…”

Proteomic CNS Profile of Delayed Cognitive Impairment in Mice Exposed to Gulf War Agents

“…It is possible that we were unable to capture microgliosis if it occurred at an intermediate timepoint between those examined in our study. While astrogliosis has been associated with various neurocognitive disorders (De Keyser et al 2008), a number of studies show a possible protective role of reactive astroglia in CNS injuries (Myer et al 2006;Faulkner et al 2004;Dagvajantsan et al 2008). Our observation of astrogliosis only suggests an association between GW agent-induced astrogliosis and behavioral changes.…”

Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice

“…This observation is consistent with some earlier results that showed a disparity in the localization of the lysosomal enzymes and the receptor in glial cells after injury or pathological condi-tions. 16,33,46,67,68 Because certain lysosomal enzymes can be transported via a cation-dependent M6P receptor in selected cells, 22,69 it is possible that cathepsins in reactive microglia may be transported by a cation-dependent M6P receptor rather than the IGF-II/M6P receptor. Earlier studies using cultured cells have shown that U18666A treatment or siRNA-mediated NPC1 depletion, can redistribute IGF-II/M6P receptors to cholesterolladen endosomes and impair receptor recycling from late endosomes to the trans-Golgi network.…”