APOE2 promotes the development and progression of subretinal neovascularization in age-related macular degeneration via MAPKs signaling pathway

Abstract

Background Neovascular age-related macular degeneration (nvAMD) is one of the main pathological features of wet AMD. Apolipoprotein E2 is involved in the formation of nvAMD but the molecular mechanism has not been reported. Methods The APOE alleles in AMD patients were detected by genotyping. Mouse models were divided into 4 groups according to transfection different gene segments and laser-induced treatment. APOE2, VEGF, PDGF-BB, b-FGF and inflammatory cytokines (including p-NF-κB, TNF-α, IL-1β and IL-6) were tested by ELISA in mice retinal lysate. The formation of nvAMD in the indicated treatment groups at 3rd, 7th and 14th day after laser-induced damage were detected by FFA. Besides, qRT-PCR was used to determine the mRNA levels of p38, JNK and ERK in ARPE-19 cells. Finally, the inflammatory cytokines and MAPK proteins (including P38, p-P38, JNK, p-JNK, ERK and p-ERK) were detected by western blot. Results The statistics of APOE alleles showed that APOE2 allele carriers were more likely to nvAMD. VEGF, PDGF-BB, b-FGF and related inflammatory cytokines were up-regulated significantly after treatment with APOE2, which were reduced after silencing the MAPK family genes, however. Further, the expression levels of neovascular growth factors and inflammatory cytokines were highly consistent between mouse models and ARPE-19 cells. Besides, the phosphorylation levels of p38, JNK and ERK were affected by APOE2. Conclusion nvAMD was affected directly by the overexpression of VEGF, PDGF-BB and b-FGF, which were regulated by APOE2 through activating MAPKs pathway.

Molecular Genetic Mechanisms in Age-Related Macular Degeneration

“…A large study of a Brazilian population failed to find an association between ApoE2 and AMD [ 225 ]. However, ApoE2 may play a role in the pathogenesis of MNV by upregulating angiogenic factors [ 230 ].…”

Understanding the Impact of Polyunsaturated Fatty Acids on Age-Related Macular Degeneration: A Review

“…Apolipoprotein E, involved in lipid homeostasis and functioning as a lipid and cholesterol transporter [33], has three allelic variants, from the most frequent to the less frequent in the human body: ApoE3, ApoE4 and ApoE2 [21]. Studies show that among these polymorphisms, the ApoE2 allele increases the risk of developing subretinal neovascularization [34], while ApoE4 seems to be protective [35]. On the contrary, Liutkeviciene et al suggested that ApoE4/E2 genotype could be protective [36], Viturino et al found no impact of ApoE2/E2 genotype on the increased risk of AMD [37], and Fernández-Vega et al described a protective role of ApoE2 allele in wet AMD in a Spanish population [38].…”

Apolipoprotein ε in Brain and Retinal Neurodegenerative Diseases

“…The effects of APOE isoforms on MAPK signaling in human RPE cells and laser-induced nvAMD mouse models expressing human APOE2 isoform were evaluated. Results demonstrated that APOE2 activates MAPKs signalling (p-ERK, p-JNK and p-p38) and induces the up-regulation of downstream target genes including VEGF, PDGF-BB and b-FGF growth factors and pro-inflammatory molecules such as TNF-a, IL-1b and IL-6, leading to retinal inflammation and nvAMD development [ 82 ]. These findings highlight the protective role that the APOE e4 allele plays in AD and the pro inflammatory role in AMD.…”