Digging in to the Mechanisms of A2E in Macular Degeneration

An accumulation of the metabolic waste compound A2E in the retina is associated with the progression of degenerative blindness via conditions such as macular degeneration, and there is strong indirect evidence for it to be a cause of the condition. This is one of numerous forms of waste that accumulate to form lipofuscin deposits inside and outside cells in the retina, but most likely the most important form. The easiest way to prove that causation beyond doubt, and hopefully also develop therapies that actually reverse retinal damage, is to selectively break down and remove A2E. An effort based on drug candidates developed at the SENS Research Foundation is currently underway at Ichor Therapeutics, but sadly this class of intervention, addressing root causes, has never been a priority in the research community as a whole. That point is somewhat illustrated in this open access paper, in which researchers investigate the role of A2E, and conclude by deciding that one of the downstream changes caused by A2E should be a target for therapy rather than the A2E accumulation itself.

Age-related macular degeneration (ARMD) is the leading cause of vision loss in developed countries. Hallmarks of the disease are well known; indeed, this pathology is characterized by lipofuscin accumulation, is principally composed of lipid-containing residues of lysosomal digestion. The N-retinyl-N-retinylidene ethanolamine (A2E) retinoid which is thought to be a cytotoxic component for retinal pigment epithelium (RPE) is the best-characterized component of lipofuscin so far. Even if no direct correlation between A2E spatial distribution and lipofuscin fluorescence has been established in aged human RPE, modified forms or metabolites of A2E could be involved in ARMD pathology.

Mitogen-activated protein kinase (MAPK) pathways have been involved in many pathologies, but not in ARMD. Therefore, we wanted to analyze the effects of A2E on MAPKs in polarized ARPE19 and isolated mouse RPE cells. We showed that long-term exposure of polarized ARPE19 cells to low A2E dose induces a strong decrease of the extracellular signal-regulated kinases' (ERK1/2) activity. In addition, we showed that A2E, via ERK1/2 decrease, induces a significant decrease of the retinal pigment epithelium-specific protein 65 kDa (RPE65) expression in ARPE19 cells and isolated mouse RPE. In the meantime, we showed that the decrease of ERK1/2 activity mediates an increase of basic fibroblast growth factor (bFGF) mRNA expression and secretion that induces an increase in phagocytosis via a paracrine effect. We suggest that the accumulation of deposits coming from outer segments (OS) could be explained by both an increase of bFGF-induced phagocytosis and by the decrease of clearance by A2E. The bFGF angiogenic protein may therefore be an attractive target to treat ARMD.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331064/


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