Alexander disease is a fatal neurodegenerative disorder resulting from missense mutations of the intermediate filament protein, GFAP. The pathological hallmark of this disease is the formation of cytoplasmic protein aggregates within astrocytes known as Rosenthal fibers. Transgenic mice engineered to over-express wild-type human GFAP develop an encephalopathy with identical aggregates, suggesting that elevated levels of GFAP in addition to mutant protein contribute to the pathogenesis of this disorder. To study further the effects of elevated GFAP and Rosenthal fibers per se, independent of mutations, we performed gene expression analysis on olfactory bulbs of transgenic mice at two different ages to follow the progression of pathology. The expression profiles reveal a stress response that includes genes involved in glutathione metabolism, peroxide detoxification and iron homeostasis. Many of these genes are regulated by the transcription factor Nfe2l2, which is also increased in expression at 3 weeks. An immune-related response occurs with activation of cytokine and cytokine receptor genes, complement components and acute phase response genes. These transcripts are further elevated with age, with additional induction of macrophage-specific markers such as Mac1 and CD68, suggesting activation of microglia. At 4 months, decreased expression of genes for microtubule-associated proteins, vesicular trafficking proteins and neurotransmitter receptors becomes apparent. Interneuron-specific transcription factors including Dlx family members and Pax6 are downregulated as well as Gad1 and Gad2, suggesting impairment of GABAergic granule cells. Together, these data implicate an initial stress response by astrocytes, which results in the activation of microglia and compromised neuronal function.