P3-206: The effects of ApoE4 on brain inflammation following acute and chronic stimulation with LPS

Abstract

ApoE4, the most prevalent genetic risk factor of Alzheimer's disease (AD), is associated with increased levels of brain inflammation. This may be a secondary consequence to the increased neurodegeneration and amyloidogenesis which are associated with apoE4. Alternatively, this effect may be due to direct stimulation of the brain inflammatory system by apoE4. In the present study, we investigated the effects of apoE4 on brain inflammation by studying the effects of acute and chronic i.c.v. injection of LPS on apoE3 and apoE4 transgenic mice. Immunohistochemical assessment of the brains following a single i.c.v. injection of LPS revealed that the extent of microglial activation and the levels of expression of NF–kB and IL–1β were more pronounced in apoE4 than in apoE3 mice. Furthermore, gene expression studies revealed that the expression of inflammation–related genes, and particularly of NF–kB regulated genes, was significantly higher and more pronounced in apoE4 than in apoE3 mice. These findings suggest that apoE4 enhances acute brain inflammation by modulation of NF–kB signaling. Chronic brain inflammation was induced by continuous i.c.v. injection of LPS for up to one month, utilizing Alzet mini osmotic pumps. This resulted in marked microglial and astrocytic activation accompanied with IL–1β release which, in wild type mice, maintained steady state levels for at least two weeks. The extent to which the sustained inflammatory response is affected by the apoE genotype will be discussed. These animal model findings suggest that the pathological effects of apoE4 can be mediated, at least in part, by its direct effects on brain inflammation, and that similar mechanisms may also play a role in Alzheimer's disease.