Molecular genetic background for the development of early neurodegenerative processes in retina

Abstract

All neurodegenerative retinal diseases are characterized by decreased metabolic and regenerative processes, impaired microcirculation, and structural abnormalities of the retina. Age is a significant risk factor for age-related macular degeneration (AMD), which is the primary cause of irreversible vision loss in individuals aged over 60 years. Since its pathogenesis is not completely understood, there is currently no effective treatment for AMD. The pathogenesis of age-related retinal changes is still uncertain, despite being grounded on alterations in characteristic features of the retina due to aging. The molecular events preceding and accompanying clinical disease manifestations pose a challenge for human study. The retina shares a uniform basic structure throughout all vertebrate species, enabling the use of animals in exploring the mechanisms responsible for maintaining a healthy physiological structure of the retina and for the pathogenesis of numerous diseases. With the knowledge acquired, novel remedies for these ailments can be developed for humans [1]. The study analyzed the OXYS rat line, known for its premature aging and retinopathy which mimics the dry form of AMD in humans. The aim was to examine how postnatal retinal neurogenesis changes contribute to the development of AMD-like retinopathy in these rats. By approximately 3–4 months of age, all structural components of the retina in OXYS rats demonstrate pathological changes, including vessels (both choroidal and intraretinal), Bruch’s membrane, photoreceptors, ganglion neurons, interneurons, and RPE. This is supported by our research findings [2, 3]. By approximately 3–4 months of age, all structural components of the retina in OXYS rats demonstrate pathological changes, including vessels (both choroidal and intraretinal), Bruch’s membrane, photoreceptors, ganglion neurons, interneurons, and RPE. One hundred percent of OXYS rats exhibit clinical symptoms of retinopathy. As they age, pathological changes intensify and coincide with photoreceptor death, hindered autophagy, and active gliosis [3–5]. Due to its limited capacity for neurogenesis, the adult mammalian retina’s structural and functional properties during its development can exert lasting impacts on ontogeny. We discovered that OXYS rats exhibited a notable reduction in the population of amacrine neurons during birth, along with an increment in the populations of ganglion and horizontal neurons in the retina as a form of compensation. The postnatal development of the rat retina is finished by the 20th day of life. In OXYS rats, this development is distinct in that it causes a shift in the timing of differentiation of bipolar cells and photoreceptors, leading to the later formation of the outer retinal layer. This layer is composed of synapses between photoreceptors, bipolar cells, and horizontal cells. The delayed onset of synaptogenesis in the OXYS rat retina results in elevated apoptosis levels and a heightened reduction of neurons. Consequently, the processes of photoreceptor differentiation and synaptogenesis remain incomplete by the time of eye opening in OXYS rats. This incomplete development can significantly impact the retina’s structure and functions. These findings indicate that a delay in retinal formation could serve as a predictor of the development of AMD in OXYS rats, and potentially this disease in humans.