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.

Risk factors and biomarkers of age-related macular degeneration

“…ApoE is the major apolipoprotein of the CNS and an important regulator of cholesterol and lipid transport (Klaver et al, 1998). Since then, the ApoE gene, found on chromosome 19q13.2 (Adams et al, 2011), has been consistently shown to play a significant role in the development of AMD (Baird et al, 2004; Levy et al, 2015; Paun et al, 2015). The ApoE polymorphism rs2075650 has been strongly associated with early AMD (P=1.1x10 −6 ) (Holliday et al, 2013).…”

Comprehensive analysis of mouse retinal mononuclear phagocytes

“…AMWAP transcription is rapidly induced in microglia from different retinal disease mouse models, including inherited photoreceptor dystrophies and different light challenge paradigms 7,32,33,39 . Another good marker to detect microglia reactivity is CCchemokine ligand 2 (CCL2, alias monocyte chemoattractant protein 1, MCP-1), which has a key role in pro-inflammatory mononuclear phagocyte chemotaxis and migration in the retina 14,40 .…”

Activated monocytes resist elimination by retinal pigment epithelium and downregulate their OTX2 expression via TNF‐α

“…In diseases such as AMD, subretinal immunosuppression is impaired and macrophages (Mϕ) accumulate subretinally around the RPE. They are found on the apical side of the RPE adjacent to atrophic zones that define geographic atrophy (GA, a late form of AMD), around choroidal neovascularizations, and around large drusen, sub‐RPE debris deposits observed in early AMD (Gupta et al ., ; Combadière et al ., ; Lad et al ., ; Levy et al ., ). Blood monocyte‐derived CD14 + CCR2 + Mϕs invariably participate in this infiltration (Sennlaub et al ., ).…”

“…The RPE also expresses immunosuppressive factors, such as Fas ligand (FasL), that lead to a quick elimination of leukocytes (Griffith et al ., ; Levy et al ., ) and participates in keeping the subretinal space physiologically devoid of immune cells (Gupta et al ., ; Combadière et al ., ; Lad et al ., ). In diseases such as AMD, subretinal immunosuppression is impaired and macrophages (Mϕ) accumulate subretinally around the RPE.…”