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Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice

Creators: Maezawa, Izumi, Maeda, Nobuyo, Montine, Thomas J, Montine, Kathleen S

File Type: pdf | Filesize: 394.9 KB | Date Added: 2012-09-05 | Date Created: 2006-04-07

Abstract Background Inheritance of the three different alleles of the human apolipoprotein (apo) E gene (APOE) are associated with varying risk or clinical outcome from a variety of neurologic diseases. ApoE isoform-specific modulation of several pathogenic processes, in addition to amyloid &#946; metabolism in Alzheimer's disease, have been proposed: one of these is innate immune response by glia. Previously we have shown that primary microglia cultures from targeted replacement (TR) APOE mice have apoE isoform-dependent innate immune activation and paracrine damage to neurons that is greatest with TR by the &#949;4 allele (TR APOE4) and that derives from p38 mitogen-activated protein kinase (p38MAPK) activity. Methods Primary cultures of TR APOE2, TR APOE3 and TR APOE4 astrocytes were stimulated with lipopolysaccharide (LPS). ApoE secretion, cytokine production, and nuclear factor-kappa B (NF-&#954;B) subunit activity were measured and compared. Results Here we showed that activation of primary astrocytes from TR APOE mice with LPS led to TR APOE-dependent differences in cytokine secretion that were greatest in TR APOE2 and that were associated with differences in NF-&#954;B subunit activity. Conclusion Our results suggest that LPS activation of innate immune response in TR APOE glia results in opposing outcomes from microglia and astrocytes as a result of TR APOE-dependent activation of p38MAPK or NF-&#954;B signaling in these two cell types.