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Khanh Do, Marie-Audrey Ines Kautzmann, Nicolas G Bazan; Elovanoids (ELV) counteract Aβ peptide-induced retinal pigment epithelial cell senescence progression.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2483. doi: https://doi.org/.
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Aβ42, an end product of the amyloidogenic pathway, is a component of drusen in age-related macular degeneration (AMD), and of senile plaques in Alzheimer’s disease (AD) (Bazan NG. Future Neurol. 2016). Previously, we showed that NPD1 rescues RPE cells from damage mediated by Aβ oligomers (OAβ). In this study, we aim to determine how OAβ induces senescence in the mouse retina, and if the newly discovered elovanoids (Bhattacharjee S, et al. Sci Adv. 2017; Jun B, et al. Sci Rep. 2017) counteract the progression of this deleterious action.
To mimic the effect of OAβ in vivo, the 6-month-old mice were used and sub-retinally injected with OAβ alone, OAβ+ELVs and ELVs alone. The no injection mice were used as negative control while the PBS injected mice were used as the sham. The injection volume was 2 µl containing of PBS, 10 μM of OAβ, 10 μM of OAβ + 200 ng ELV-32, 200 ng ELV-32 alone, 10 μM of OAβ + 200 ng ELV-34 or 200 ng ELV-34 alone. At day 3 after injection, mRNA from eyecup was isolated and analyzed the gene expression using q-PCR. Then, at day 7, the mice were subjected to Optical Coherence Tomography (OCT) analysis and then the eyes were enucleated and processed for histology, whole mount RPE staining, and western blotting (WB).
OCT and histology showed that OAβ induced retinal degeneration, the thickness of retina was thinner in OAβ injected group when compared to the controls as well as ELVs treatment groups. The whole-mount staining with ZO-1 revealed that the tight junction was disrupted by OAβ also. Interestingly, the co-injection of ELVs and OAβ showed that ELVs were able to restore the morphology and homeostasis of RPE layer. Furthermore, in the WB analysis, the protein level of p16INK4a, a senescence marker, was up-regulated in OAβ group but was suppressed in ELVs co-treatment and control groups. Finally, the gene expression analysis showed that ELVs reduced the level of both senescent and AMD markers, which were triggered by OAβ injection, while it induced the expression of RPE functional genes, which were down-regulated in OAβ-injected group.
Our study demonstrated that ELV-32 and ELV-34 protect RPE and retina from OAβ induced senescence by down-regulating senescence, AMD, and inflammation-associated gene expression, and by preserving the expression of RPE-functional genes, resulting in restored retinal structure and sustained homeostasis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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