Exendin-4 protects photoreceptors from retinal damage by restoring GLP-1R/PKA/CREB1 signaling

Atrophic macular degeneration, encompassing dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1), represents a significant cause of irreversible blindness with no effective therapies. A key pathological driver in both conditions is the accumulation of all-trans-retinal (atRAL) due to visual cycle disruption, leading to retinal atrophy. The precise downstream targets of atRAL-induced damage remain unclear. Exendin-4 (EX-4), a natural glucagon-like peptide-1 receptor (GLP-1R) agonist, has shown promise, with retrospective clinical studies suggesting GLP-1R agonists like exenatide may lower the 5-year risk of developing dry AMD. This study aimed to elucidate EX-4's protective mechanism against atRAL-linked retinal degeneration.

Researchers generated cell and animal models of STGD1 and dry AMD using atRAL-loaded 661W cells and light-exposed Abca4-/-Rdh8-/- mice, respectively. They investigated the protective effects of Exendin-4 (EX-4) against retinal degeneration. A comprehensive suite of assays was employed, including RNA-sequencing, cell viability assays, morphometric analysis, annexin V/propidium-iodide staining via flow cytometry, quantitative polymerase chain reaction (qPCR), western blotting, immunofluorescence, electroretinography (ERG), fundus photography, hematoxylin and eosin (H&E) histology, and TUNEL staining. These methods were integrated to delineate EX-4's anti-apoptotic actions and uncover its underlying protective mechanism.

The GLP-1R/cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP response element-binding protein 1 (CREB1) signaling pathway was markedly downregulated in both atRAL-challenged 661W cells and the neural retina of light-exposed Abca4-/-Rdh8-/- mice. Treatment with Exendin-4 successfully reinstated this crucial pathway. This restoration led to a suppression of caspase-3 activation and DNA damage, effectively curtailing apoptosis in both cellular and tissue contexts. The specificity of this mechanism was further confirmed: > Silencing of Glp1r or the PKA catalytic subunits by small interfering RNA (siRNA) completely abrogated Exendin-4-induced activation of the PKA/CREB1 axis in atRAL-loaded 661W cells. Pharmacologic blockade of CREB1 phosphorylation also interfered with the protective effects, underscoring the central role of this signaling cascade.