2017/08/01 by Tomohiro Ohgomori, Ryo Yamasaki, Hideyuki Takeuchi +3
paper · doi:10.1111/ejn.13650
Abstract Signal transducer and activator of transcription ( STAT ) proteins are activated by phosphorylation in the spinal cord of patients suffering from amyotrophic lateral sclerosis ( ALS ). The major scope of our study is a comprehensive histological characterization of the mechanisms underlying neuronal and glial STAT 3 activation in the pathogenesis of ALS using SOD 1 G93A mice. We calculated the fold changes ( FC s, ratios vs. appropriate controls) of the numerical densities of the following phosphorylated STAT 3‐positive ( pSTAT 3) + cells – choline acetyltransferase (Ch AT ) + α‐motoneurons, ionized calcium‐binding adapter molecule 1 (Iba1) + microglia, and S100β + astrocytes in SOD 1 G93A mice. The FC s of pSTAT 3 + microglia and pSTAT 3 + astrocytes were increased from 9 to 15 weeks of age and then plateaued until 21 weeks. In contrast, the FC s of pSTAT 3 + α‐motoneurons peaked at 9 weeks and then decreased until 21 weeks. The immunoreactivity for nonphosphorylated neurofilament protein ( SMI ‐32), a marker of axonal impairment, was decreased in pSTAT 3 + α‐motoneurons compared with pSTAT 3 − α‐motoneurons at 9 weeks of age. We then compared the following pharmacological models – the chronic administration of 3,3′‐iminodipropionitrile ( IDPN ), which models axonal impairment, and the acute administration of lipopolysaccharide ( LPS ), which is a model of neuroinflammation. The FC s of pSTAT 3 + α‐motoneurons were increased in IDPN ‐treated mice, while those of pSTAT 3 + microglia were increased in LPS ‐treated mice. The FC s of pSTAT 3 + astrocytes were higher in SOD 1 G93A mice at 9 weeks compared with IDPN ‐ and LPS ‐treated mice. Our results indicate that axonopathy and neuroinflammation may trigger the respective activation of neuronal and glial STAT 3, which is observed during ALS pathogenesis.