title: Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia.
abstract: 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) ε4 carriers; inhibitors of prostaglandin (PG) synthesis show a partially protective effect on AD risk from APOE ε4; 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 ε4 inheritance modulates both the PGE2 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 PGE2 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 κ-light-chain-enhancer inhibitor blocked TR APOE4/4-dependent effects on the PGE2 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.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA xli@uw.edu.
authors.forename: Xianwu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3 / Q000502:physiology*; D053327:Apolipoprotein E4 / Q000502:physiology*; D001057:Apolipoproteins E / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; C498716:Trem2 protein, mouse; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone
keywords: Alzheimer disease; PGE2; apolipoprotein E genotype; brain immunity; neuroinflammation