Biochemical and histopathological alterations in TAR DNA‐binding protein‐43 after acute ischemic stroke in rats

J. Neurochem. (2011) 116 , 957–965. Abstract Nuclear factor TAR DNA‐binding protein‐43 (TDP‐43) is considered to play roles in pathogenesis of human neurodegenerative diseases, so‐called TDP‐43 proteinopathy, via its proteolytic cleavage, abnormal phosphorylation, subcellular redistribution, and insolubilization generating TDP‐43‐positive neuronal intracellular inclusions. The purpose of this study was to elucidate biochemical and histopathological alternations in TDP‐43 specific to acute ischemic stroke. Adult male rats were subjected to a 90‐min middle cerebral artery occlusion. We examined the proteolytic cleavage, phosphorylation, subcellular localization, and solubility of TDP‐43 by immunoblottings and histopathological examinations using the ischemic and sham‐operated cortex. The level of full‐length TDP‐43 (43 kDa) decreased and that of the 25‐kDa C‐terminal fragment increased after acute ischemic stroke, which can be explained by proteolytic cleavage of TDP‐43. Cytoplasmic redistribution and altered nuclear distribution of TDP‐43 was observed after acute ischemic stroke, whereas abnormal phosphorylation and insolubilization of TDP‐43 as well as formation of intracellular inclusions were not observed. Ischemic neurons with the cytoplasmic redistribution of TDP‐43 expressed ubiquitin and activated caspase 3 and were terminal deoxynucleotidyl transferase‐mediated uridine 5′‐triphosphate‐biotin nick end labeling‐positive. In conclusion, biochemical and histopathological alterations in TDP‐43 were identified in rats after acute ischemic stroke, although there was very less similarity between TDP‐43 alterations observed in acute ischemic stroke and those observed in TDP‐43 proteinopathy.