The cumulative knowledge of retina development has been instrumental in the generation of retinal organoid systems from pluripotent stem cells; and these three-dimensional organoid models, in turn, have provided unprecedented opportunities for retinal research and translational applications, including the ability to model disease in a human setting and to apply these models to the development and validation of therapeutic drugs. In this review article, we examine how retinal organoids can also contribute to our understanding of retinal developmental mechanisms, how this knowledge can be applied to modeling developmental abnormalities, and highlight some of the avenues that remain to be explored.

BackgroundAlzheimer’s disease (AD) is a neurodegenerative condition of the central nervous system that affects both the brain and the retina, and can lead to visual impairment. However, the factors that modulate AD pathophysiology leading to the wide range of clinical presentations are not well understood. Notably, traumatic brain injury (TBI), which can arise from sport concussions, military combat and other causes, is associated with a 2.3‐fold higher risk of developing AD and AD‐related dementias. Yet the pathophysiological link between TBI and AD remains poorly understood. In this study we set out to evaluate the effects of TBI, AD, and their combination, on retinal histopathology, by taking advantage of a transgenic rat model (Tg‐F344‐AD) shown to recapitulate the main features of human AD pathology, and combining it with a controlled cortical impact paradigm of repetitive mild TBI (rmTBI).MethodsMale Tg‐F344‐AD rats and F344 wild‐type controls were aged to 12 months and randomly selected to undergo a two‐time unilateral controlled cortical impact (2xCCI; one week apart) that mimics rmTBI, or a sham procedure. The animals were sacrificed at four months post‐CCI to evaluate long‐term effects of the procedure, and the eyes were collected and analyzed using immunofluorescence and standard histological staining techniques to evaluate Alzheimer’s histopathology.ResultsHistopathological analyses at four months post‐impact confirm the presence of AD markers in Tg‐F344‐AD retinas. Moreover, we found that AD increases Aβ deposition and neuroinflammation in the retina, and that TBI enhances the severity of this phenotype by increasing the formation of dense core amyloid plaques.ConclusionsWe have developed and characterized a model to study the pathophysiology of AD in relation to rmTBI in the retina, which could lead to better treatments and to the development of retinal biomarkers for improved AD diagnosis.

Alzheimer's disease (AD) is a neurodegenerative condition that affects 5.7 million people in the U.S. alone, representing the leading form of dementia. Additionally, traumatic brain injury (TBI), which can arise from sport concussions, military combat and other causes, is associated with a 2.3‐fold higher risk of developing AD and AD‐related dementias. Moreover, AD can also lead to visual impairment, and recent studies have found that AD histopathology manifests in the retina, which is an extension of the central nervous system. However, the pathophysiological link between TBI and AD remains poorly understood. In this study we set out to evaluate the effects of TBI, AD, and their combination, on retinal histopathology. Several animal models have been developed to investigate the mechanisms of AD but have been limited by imperfect recapitulation of human pathology. Here we take advantage of a transgenic rat model (Tg‐F344) that more faithfully mimics human AD pathology, and subject it to a TBI paradigm. Wild‐type and transgenic rats were randomly selected to undergo a unilateral controlled cortical impact (CCI). At 15 months of age, the rats were sacrificed and the eyes subsequently removed, fixed, and processed. Retinas were sectioned and analyzed using immunofluorescent and standard histological staining techniques. Our results confirm the presence of AD markers in transgenic retinas, and an increased severity of AD pathology due to TBI. This has meaningful implications in understanding the pathophysiology of AD in relation to TBI within the retina, which could lead to better treatments and to the development of retinal biomarkers for improved AD diagnosis.

Alzheimer's disease (AD) is a neurodegenerative condition that affects 6.2 million people age 65 and older in the U.S. alone, and is the leading cause of dementia. Moreover, AD can lead to visual impairment, and AD histopathology also manifests in the retina. However, the factors that modulate AD pathophysiology and lead to varied susceptibility and presentation in the population are not well understood. In this context, traumatic brain injury (TBI), which can arise from sport concussions, military combat, and other causes, is associated with a 2.3-fold higher risk of developing AD and AD-related dementias (ADRD). Thus, we set out to evaluate the effects of TBI, AD, and their combination, on retinal histopathology. Several animal models have been developed to investigate the mechanisms underlying AD, but many have been limited by imperfect recapitulation of human pathology, and no model of TBI-associated AD (AD-TBI) has been characterized. To address this gap, we generated an innovative model of AD-TBI by taking advantage of a transgenic rat model (Tg-F344-AD) shown to recapitulate the main features of human AD pathology, and combining it with a two-time unilateral controlled cortical impact paradigm to mimic repetitive mild TBI (rmTBI). Histopathological analyses at four months post-impact confirm the presence of AD markers in transgenic retinas, and an increased severity of AD pathology due to TBI. Together, these results contribute to our understanding of the effects of TBI on AD retinopathy, with implications for patient care and therapeutic development.