Elovanoids counteract oligomeric β-amyloid-induced gene expression and protect photoreceptors

Abstract

The onset of neurodegenerative diseases activates inflammation that leads to progressive neuronal cell death and impairments in cognition (Alzheimer’s disease) 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 prohomeostatic/neuroprotective mediators neuroprotectin D1 (NPD1) and elovanoids (ELVs). To mimic an inflammatory milieu in wild-type 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, as OAβ targets 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 phenotype secretome, followed by RPE and PRC demise, and that ELVs 32 and 34 blunt these events and elicit protection. In addition, ELVs counteracted OAβ-induced expression of genes engaged in AMD, autophagy, and extracellular matrix 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.

Novel RvD6 stereoisomer induces corneal nerve regeneration and wound healing post-injury by modulating trigeminal transcriptomic signature

“…LC-MS/MS analysis was performed in a Xevo TQ equipped with Acquity I class ultra-performance liquid chromatography (UPLC) with a flow-through needle (Waters Corporation, Milford, MA). As previously described 25,53 , samples were dried under N 2 , resuspended in 20 μl of MeOH/H 2 O (2:1), and injected into a CORTECS C18 2.7 μm 4.6 × 100 mm column (Water, MA). The column temperature was set at 45 °C with a flow of 0.6 ml/min.…”

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

“…In clinic, AMD displays the accumulation of Aβ in the drusen beneath the RPE, Aβ-targeted agents and anti-in ammatory therapies are still under evaluation for the treatment of AMD [18][19][20]. Accordingly, it is required to elucidate the mechanisms of AMD is of great importance to understand its pathogenesis and the effective treatments.…”

“…Hopefully, our preliminary results may represent a potential preventive and therapeutic approach for AMD treatment. The subretinal injection was performed according to the previous studies [18]. Twelve-week-old C57bl/6J mice were anesthetized by an intraperitoneal (IP) injection of 4% chloral hydrate, and the pupils were dilated with 1% tropicamide (Alcon, USA).…”

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

“…In clinic, AMD displays the accumulation of Aβ in the drusen beneath the RPE, Aβ-targeted agents and antiinflammatory therapies are still under evaluation for the treatment of AMD [18][19][20]. Accordingly, it is required to elucidate the mechanisms of AMD is of great importance to understand its pathogenesis and the effective treatments.…”

“…The subretinal injection was performed according to the previous studies [18]. Twelve-week-old C57bl/6J mice were anesthetized by an intraperitoneal (IP) injection of 4% chloral hydrate, and the pupils were dilated with 1% tropicamide (Alcon, USA).…”