Traumatic Brain Injury Exacerbates Retinal Alzheimer’s Disease Histopathology in the TgF344 Rat Model

Abstract

AbstractBackgroundAlzheimer’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.