title: APOE Isoforms Control Pathogenic Subretinal Inflammation in Age-Related Macular Degeneration.
abstract: Contrary to Alzheimer's disease (AD), the APOE2 allele increases and the APOE4 allele reduces the risk to develop age-related macular degeneration (AMD) compared with the most common APOE3 allele. The underlying mechanism for this association with AMD and the reason for the puzzling difference with AD are unknown. We previously demonstrated that pathogenic subretinal mononuclear phagocytes (MPs) accumulate in Cx3cr1-deficient mice due to the overexpression of APOE, interleukin-6, and CC chemokine ligand 2 (CCL2). We here show using targeted replacement mice expressing the human APOE isoforms (TRE2, TRE3, and TRE4) that MPs of TRE2 mice express increased levels of APOE, interleukin-6, and CCL2 and develop subretinal MP accumulation, photoreceptor degeneration, and exaggerated choroidal neovascularization similar to AMD. Pharmacological inhibition of the cytokine induction inhibited the pathogenic subretinal inflammation. In the context of APOE-dependent subretinal inflammation in Cx3cr1(GFP/GFP) mice, the APOE4 allele led to diminished APOE and CCL2 levels and protected Cx3cr1(GFP/GFP) mice against harmful subretinal MP accumulation observed in Cx3cr1(GFP/GFP)TRE3 mice. Our study shows that pathogenic subretinal inflammation is APOE isoform-dependent and provides the rationale for the previously unexplained implication of the APOE2 isoform as a risk factor and the APOE4 isoform as a protective factor in AMD pathogenesis.
  
  
  CONCLUSIONS
  The understanding of how genetic predisposing factors, which play a major role in age-related macular degeneration (AMD), participate in its pathogenesis is an important clue to decipher the pathomechanism and develop efficient therapies. In this study, we used transgenic, targeted replacement mice that carry the three human APOE isoform-defining sequences at the mouse APOE chromosomal location and express the human APOE isoforms. Our study is the first to show how APOE2 provokes and APOE4 inhibits the cardinal AMD features, inflammation, degeneration, and exaggerated neovascularization. Our findings reflect the clinical association of the genetic predisposition that was recently confirmed in a major pooled analysis. They emphasize the role of APOE in inflammation and inflammation in AMD.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 968, Paris, F-75012, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche S 968, Institut de la Vision, Paris, F-75012, France, CNRS, Unité Mixte de Recherche 7210, Paris, F-75012, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Levy
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 968, Paris, F-75012, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche S 968, Institut de la Vision, Paris, F-75012, France, CNRS, Unité Mixte de Recherche 7210, Paris, F-75012, France.
authors.forename: Sophie
authors.identifier: http://orcid.org/0000-0001-5029-2724
authors.initials: S
authors.lastname: Lavalette
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 968, Paris, F-75012, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche S 968, Institut de la Vision, Paris, F-75012, France, CNRS, Unité Mixte de Recherche 7210, Paris, F-75012, France.
authors.forename: Shulong J
authors.initials: SJ
authors.lastname: Hu
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 968, Paris, F-75012, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche S 968, Institut de la Vision, Paris, F-75012, France, CNRS, Unité Mixte de Recherche 7210, Paris, F-75012, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Housset
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 968, Paris, F-75012, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche S 968, Institut de la Vision, Paris, F-75012, France, CNRS, Unité Mixte de Recherche 7210, Paris, F-75012, France.
authors.forename: William
authors.initials: W
authors.lastname: Raoul
authors.affiliation: Department of Surgical Sciences, Eye Clinic, University of Torino, Torino, Italy, and.
authors.forename: Chiara
authors.initials: C
authors.lastname: Eandi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 968, Paris, F-75012, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche S 968, Institut de la Vision, Paris, F-75012, France, CNRS, Unité Mixte de Recherche 7210, Paris, F-75012, France, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Institut National de la Santé et de la Recherche Médicale-DHOS CIC 503, Paris, F-75012, France.
authors.forename: José-Alain
authors.identifier: http://orcid.org/0000-0002-4831-1153
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: Department of Medicine, Centers for Aging and Geriatric Research Education and Clinical Center, Durham Veteran Affairs Medical Center, Duke University, Durham, North Carolina 27710.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sullivan
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 968, Paris, F-75012, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche S 968, Institut de la Vision, Paris, F-75012, France, CNRS, Unité Mixte de Recherche 7210, Paris, F-75012, France.
authors.forename: Xavier
authors.identifier: http://orcid.org/0000-0001-7379-3935
authors.initials: X
authors.lastname: Guillonneau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U 968, Paris, F-75012, France, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Unité Mixte de Recherche S 968, Institut de la Vision, Paris, F-75012, France, CNRS, Unité Mixte de Recherche 7210, Paris, F-75012, France, florian.sennlaub@inserm.fr.
authors.forename: Florian
authors.identifier: http://orcid.org/0000-0003-4412-1341
authors.initials: F
authors.lastname: Sennlaub
mesh_terms: D000375:Aging; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000235:genetics; D007834:Lasers / Q000009:adverse effects; D008268:Macular Degeneration / Q000150:complications* / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics; D012160:Retina / Q000166:cytology
chemical_list: C491049:Aif1 protein, mouse; D001057:Apolipoproteins E; C448939:CRB1 protein, human; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005136:Eye Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D019707:Receptors, Chemokine
keywords: apolipoprotein E; mononuclear phagocyte; neurodegeneration; neuroinflammation