Data from: Elovanoids counteract oligomeric β-Amyloid-induced gene expression and protect photoreceptors
Funding
National Institutes of Health - National Eye Institute, Award: R01 EY005121
Eye Ear Nose & Throat Foundation
Abstract
The onset of neurodegenerative diseases activates inflammation that leads to progressive neuronal cell death and impairments in cognition (Alzheimer’s disease, AD) and sight (age-related macular degeneration, AMD). How neuroinflammation can be counteracted is not known. In AMD, amyloid β-peptide (Aβ) accumulates in subretinal drusen. In the 5xFAD retina, we found early functional deficiencies (ERG) without photoreceptor cell (PRC) death and identified early insufficiency in biosynthetic pathways of pro-homeostatic/neuroprotective mediators, neuroprotectin D1 (NPD1) and elovanoids (ELVs). To mimic an inflammatory milieu in wild-type (WT) mouse, we triggered retinal pigment epithelium (RPE) damage/PRC death by subretinally injected oligomeric β-Amyloid (OAβ) and observed that ELVs administration counteracted their effects, protecting these cells. In addition, ELVs prevented OAβ-induced changes in gene expression engaged in senescence, inflammation, autophagy, extracellular matrix remodeling and AMD. Moreover, since OAβ target the RPE, we used primary human RPE cell cultures and demonstrated that OAβ caused cell damage, while ELVs protected and restored gene expression as in mouse. Our data show OAβ activates senescence as reflected by enhanced expression of p16INK4a, MMP1, p53, p21, p27 and Il-6 and of senescence-associated secretory phenotype (SASP) secretome, followed by RPE and PRC demise and that elovanoids 32 and 34 blunt these events and elicits protection. In addition, ELVs counteracted OAβ-induced expression of genes engaged in AMD, autophagy and extracellular matrix (ECM) remodeling. Overall, our data uncovered that ELVs downplay OAβ-senescence program induction and inflammatory transcriptional events and protect RPE cells and PRC, and therefore have potential as a possible therapeutic avenue for AMD.