The allele E4 of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease (AD) and the chronic brain inflammation which is associated with AD is more pronounced in subjects who carry this allele. In the present study, we employed mice transgenic for the human apoE isoforms apoE3 or apoE4 on a null mouse apoE background and intracerebroventricular injection of LPS to investigate the possibility that the regulation of brain inflammation is affected by the apoE genotype. LPS treatment of control mice resulted in activation of brain astrocytes and microglia whose extent decreased with age. LPS treatment of 6-month-old apoE transgenic and control mice resulted in marked activation of brain astrocytes in the control and apoE3 transgenic mice but had no effect on astrogliosis of age-matched apoE-deficient and apoE4 transgenic mice. In contrast, there were no significant differences between the levels of activated microglia of the apoE3 and apoE4 transgenic mice following LPS treatment. Immunoblot assays revealed that the apoE4 and apoE3 transgenic mice had the same levels of brain apoE, which were similarly increased following LPS treatment. These results show that LPS-induced astrogliosis in apoE transgenic mice is regulated isoform-specifically by apoE3 and not by apoE4 and suggest that similar mechanisms may mediate the phenotypic expression of the apoE4 genotype in AD and in other neurodegenerative diseases.