Hippocampal gene expression in the GFAP-R237H rat model of Alexander disease at early and late stages of disease

Alexander disease is a rare neurodegenerative disorder caused by mutations in the gene for glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes in the central nervous system. GFAP mutation causes a toxic gain-of-function and protein aggregation, ultimately leading to gliosis, astrocyte dysfunction, and neurodegeneration. To better understand the disease process, a rat model has been generated to mimic the common R239H mutation observed in the human disease (R237H in the rat). This study focuses on hippocampus, a brain region with a heavy burden of pathology, to determine the impact of GFAP mutation at presymptomatic (3 weeks of age) and severe stages ( 8 weeks of age) of disease. Transcription profiling shows progressive neuroinflammation and neurodegeneration. Hippocampi were collected from male and female Gfap+/R237H rats and wild type (Gfap+/+) littermates at P21 and P56 (N = 4 per group, with the exception of P21 females, N = 3 wild type, N = 5 R237H rats).