APOE Genotype and an ApoE-mimetic Peptide Modify the Systemic and Central Nervous System Inflammatory Response

Abstract

Human apolipoprotein E is the major apolipoprotein expressed in the brain and exists as three isoforms, designated E2, E3, and E4. Although evidence suggests that apolipoprotein E plays an important role in modifying systemic and brain inflammatory responses, there is little data investigating apoE isoform-specific effects in vivo. In this study, we compared the inflammatory responses of targeted-replacement mice expressing the human APOE3 and APOE4 genes after intravenous administration of lipopolysaccharide. Animals expressing the E4 allele had significantly greater systemic and brain elevations of the pro-inflammatory cytokines TNFalpha and IL-6 as compared with their APOE3 counterparts, suggesting an isoform-specific effect of the immunomodulatory properties of apoE. Furthermore, intravenous administration of a small apoE-mimetic peptide derived from the receptor-binding region of the apoE holoprotein (apoE-(133-149)) similarly suppressed both systemic and brain inflammatory responses in mice after lipopolysaccharide administration. These results suggest that apoE plays an isoform-specific role in mediating the systemic and brain inflammatory responses. Moreover, because exogenous administration of this apoE mimetic peptide is effective at suppressing both systemic and brain inflammation, it may represent a novel therapeutic strategy for diseases characterized by systemic or central nervous system inflammation, such as septic shock, multiple sclerosis, and traumatic brain injury.

Apolipoprotein E mimetic peptide, CN‐105, improves outcomes in ischemic stroke

“…We have previously demonstrated that larger peptides derived from the apoE receptor‐binding region (apoE133‐149) retain the neuroprotective and anti‐inflammatory properties8, 17, 30, 52, 53 of the apoE holoprotein. However, these peptides were limited by their relatively larger size, resulting in lower CNS penetration and higher cost of production.…”

Genetics of primary progressive multiple sclerosis

“…CREE inflammation and influences repair following injury with allele-specific effects. The APOE E4 allele is associated with less effective downregulation of inflammatory cytokines in the brain than the APOE E3 allele and contributes to an earlier age of onset of Alzheimer disease (Lynch et al, 2003). A large number of studies have explored whether APOE contributes to MS susceptibility or influences the disease course.…”

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

“…ApoE, in an isoform-specific fashion, regulates the time of onset and amount of Ah deposition via effects on Ah clearance and fibrillogenesis in APP transgenic mice (Bales et al, 1997;DeMattos et al, 2004;Fagan et al, 2002;Holtzman et al, 2000). In addition, it has been proposed that apoE may also influence AD and other central nervous system (CNS) disorders by influencing additional biological processes such as neural repair and inflammation (Buttini et al, 1999;Lynch et al, 2003;Teter, 2000). Understanding the nature of interactions between apoE and other molecules in the brain is likely to provide important insights into its normal function as well as its role in disease.…”