Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E-2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia

作者：Li Xianwu^*; Montine Kathleen S; Keene C Dirk; Montine Thomas J

来源：The FASEB Journal, 2015, 29(5): 1754-1762.

DOI：10.1096/fj.14-262683

• apolipoprotein E genotype
• PGE(2)
• Alzheimer disease
• neuroinflammation
• brain immunity

Several lines of evidence support immune response in brain as a mechanism of injury in Alzheimer disease (AD). Moreover, immune activation is heightened in apolipoprotein E (APOE) epsilon 4 carriers; inhibitors of prostaglandin (PG) synthesis show a partially protective effect on AD risk from APOE epsilon 4; and genetic variants in triggering receptor expressed on myeloid cells 2 (TREM2) are a rare but potent risk for AD. We tested the hypothesis that APOE epsilon 4 inheritance modulates both the PGE(2) pathway and TREM2 expression using primary murine microglia from targeted replacement (TR) APOE3/3 and APOE4/4 mice. Microglial cyclooxygenase-2, microsomal PGE synthase, and PGE(2) expression were increased 2- to 25-fold in both genotypes by TLR activators; however, this induction was significantly (P < 0.01) greater in TR APOE4/4 microglia with TLR3 and TLR4 activators. Microglial TREM2 expression was reduced approximately 85% by all TLR activators; this reduction was approximately one-third greater in microglia from TR APOE4/4 mice. Importantly, both receptor-associated protein and a nuclear factor -light-chain-enhancer inhibitor blocked TR APOE4/4-dependent effects on the PGE(2) pathway but not on TREM2 expression. These data demonstrate complementary, but mechanistically distinct, regulation of pro- and anti-inflammatory mediators in TR APOE4/4 murine microglia that yields a more proinflammatory state than with TR APOE3/3.Li, X., Montine, K. S., Keene, C. D., Montine, T. J. Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E-2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia.

• 出版日期2015-5