Artikel
APOE-isoform dependent effects on subretinal inflammation and cardinal features of AMD
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Autoren
Veröffentlicht: | 1. Oktober 2015 |
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Gliederung
Text
Background: It is well established that the APOE2-allele increases and the APOE4-allele reduces, the risk to develop age related macular degeneration (AMD) compared to the most common APOE3-allele. How the APOE isoforms affect AMD pathogenesis is unknown. We previously demonstrated that APOE promotes pathogenic subretinal inflammation, a main feature of AMD, concentration-dependently.
Results: Using targeted replacement mice expressing human isoforms we here show that APOE levels in eyes of APOE2-mice are increased and they develop age-, light-, and laser-induced subretinal mononuclear phagocyte (MP) accumulation associated with photoreceptor degeneration and excessive CNV. In the inflammatory context of Cx3cr1GFP/GFP-mice that develop pathogenic subretinal inflammation, the APOE4-allele led to diminished APOE levels and the APOE4-allele protected Cx3cr1GFP/GFP-mice against harmful subretinal MP accumulation observed in APOE3 carrying Cx3cr1-/-mice. In vitro, recombinant APOE4 was the least efficient isoform to activate the CD14-dependent innate immunity receptor cluster and induce cytokines, while APOE2 carrying MPs transcribed increased APOE and inflammatory cytokines. Inhibition of CD14 significantly reduced subretinal inflammation and CNV in the inflammation prone APOE2-mice in vivo.
Conclusion: Our study provides rationale for the previously unexplained implication of the APOE genotype in AMD, and open avenues toward therapies inhibiting pathogenic chronic inflammation in late AMD.