Apolipoprotein E expression is elevated by interleukin 1 and other interleukin 1-induced factors

Background: We have previously outlined functional interactions, including feedback cycles, between several of the gene products implicated in the pathogenesis of Alzheimer's disease. A number of Alzheimer-related stressors induce neuronal expression of apolipoprotein E (ApoE), beta-amyloid precursor protein (beta APP), and fragments of the latter such as amyloid beta-peptide (A beta) and secreted APP (sAPP). These stressors include interleukin-1 (IL-1)-mediated neuroinflammation and glutamate-mediated excitotoxicity. Such circumstances are especially powerful when they transpire in the context of an APOE epsilon 4 allele. Methods: Semi-quantitative immunofluorescence imaging was used to analyze rat brains implanted with IL-1 beta slow-release pellets, sham pellets, or no pellets. Primary neuronal or NT2 cell cultures were treated with IL-1 beta, glutamate, A beta, or sAPP; relative levels of ApoE mRNA and protein were measured by RT-PCR, qRT-PCR, and western immunoblot analysis. Cultures were also treated with inhibitors of multi-lineage kinases-in particular MAPK-p38 (SB203580), ERK (U0126), or JNK (SP600125)-prior to exposure of cultures to IL-1 beta, A beta, sAPP, or glutamate. Results: Immunofluorescence of tissue sections from pellet-implanted rats showed that IL-1 beta induces expression of beta APP, IL-1 alpha, and ApoE; the latter was confirmed by western blot analysis. These protein changes were mirrored by increases in their mRNAs, as well as in those encoding IL-1 beta, IL-1 beta-converting enzyme (ICE), and tumor necrosis factor (TNF). IL-1 beta also increased ApoE expression in neuronal cultures. It stimulated release of sAPP and glutamate in these cultures too, and both of these agents-as well as A beta-stimulated ApoE expression themselves, suggesting that they may contribute to the effect of IL-1 beta on ApoE levels. Inhibitors of MAPK-p38, ERK, and JNK inhibited ApoE induction by all these agents except glutamate, which was sensitive only to inhibitors of ERK and JNK. Conclusion: Conditions of glial activation and hyperexcitation can elevate proinflammatory cytokines, ApoE, glutamate, beta APP, and its secreted fragments. Because each of these factors promotes glial activation and neuronal hyperexcitation, these relationships have the potential to sustain self-propagating neurodegenerative cycles that could culminate in a progressive neurodegenerative disorder such as Alzheimer's disease.