A2E

A2E, short for N-retinylidene-N-retinylethanolamine, is a pyridinium bis-retinoid that is a major component of lipofuscin in retinal pigment epithelium (RPE) cells. It forms non-enzymatically in lysosomes during the processing of photoreceptor outer segments, through the condensation of two all-trans-retinal molecules with one ethanolamine unit. Over time, A2E accumulates as lipofuscin within the RPE, with levels increasing in aging and in certain retinal diseases.

A2E is highly fluorescent, with excitation in the blue region (around 430 nm) and emission in the yellow-orange region (roughly 590–630 nm). It is photolabile and can generate reactive oxygen species upon blue-light exposure, contributing to oxidative stress. Its hydrophobic, lysosome-associated nature allows it to accumulate within lysosomal membranes and to perturb lysosomal pH and enzyme activity, potentially impairing cellular degradation pathways in RPE cells.

Biological significance: The buildup of A2E is implicated in retinal degeneration by compromising RPE function and the support of photoreceptors, and it is studied as a contributing factor in age-related macular degeneration and Stargardt disease, where ABCA4 mutations lead to excess all-trans-retinal and lipofuscin formation. A2E is also used as a research proxy for lipofuscin and blue-light–induced phototoxicity in the retina.

Detection and research use: A2E can be quantified and imaged using techniques such as high-performance liquid chromatography, fluorescence spectroscopy, and mass spectrometry. It serves as a model compound for studying lipofuscin biology and testing interventions aimed at reducing lipofuscin accumulation or mitigating phototoxic effects.