Murine model of Alexander disease: Analysis of GFAP aggregate formation and its pathological significance

摘要: Alexander disease is caused by a coding mutation in the glial fibrillary acidic protein (GFAP) gene. The pathological hallmark formation of cytoplasmic inclusions within astrocytes known as Rosenthal fibers (RFs), which primarily consist GFAP and several heat shock proteins. presence mutant would appear to be involved RF formation; however, overproduction wild type human mouse brain also results formation. Here, we investigated vivo conditions leading RF-like aggregates. We used transgenic mice (mouse promoter-human cDNA with R239H mutation) dosage transgene could manipulated same genetic locus. found that per se was insufficient for aggregate Instead, 30% increase content over required. aggregates upregulated endogenous nestin gene expression, intermediate filament structure revealed immunostaining fragmented under these conditions. However, overall morphology astrocytes, including their fine processes, unaffected. In this animal model, did not show megalencephaly, leukodystrophy, or seizure characteristic mutation. Nevertheless, mortality after kainate challenge dramatically increased, whereas lacking exhibited similar mice. These indicate containing sufficient induce major phenotype disease, even though it causes some abnormalities mouse.