There is increasing evidence that long-lasting morphologic and functional consequences can be present in the human visual system after repetitive mild traumatic brain injury (r-mTBI). The exact location and extent of the damage in this condition are not well understood. Using a recently developed mouse model of r-mTBI, we assessed the effects on the retina and optic nerve using histology and immunohistochemistry, electroretinography (ERG), and spectral-domain optical coherence tomography (SD-OCT) at 10 and 13 weeks after injury. Control mice received repetitive anesthesia alone (r-sham). We observed decreased optic nerve diameters and increased cellularity and areas of demyelination in optic nerves in r-mTBI versus r-sham mice. There were concomitant areas of decreased cellularity in the retinal ganglion cell layer and approximately 67% decrease in brain-specific homeobox/POU domain protein 3A-positive retinal ganglion cells in retinal flat mounts. Furthermore, SD-OCT demonstrated a detectable thinning of the inner retina; ERG demonstrated a decrease in the amplitude of the photopic negative response without any change in a- or b-wave amplitude or timing. Thus, the ERG and SD-OCT data correlated well with changes detected by morphometric, histologic, and immunohistochemical methods, thereby supporting the use of these noninvasive methods in the assessment of visual function and morphology in clinical cases of mTBI.

b-Secretase 1 (BACE1) represents an attractive target for the treatment of Alzheimer's disease. In the course of development of a novel small molecule BACE1 inhibitor (AMG-8718), retinal thinning was observed in a 1-month toxicity study in the rat. To further understand the lesion, an investigational study was conducted whereby rats were treated daily with AMG-8718 for 1 month followed by a 2-month treatment-free phase. The earliest detectable change in the retina was an increase in autofluorescent granules in the retinal pigment epithelium (RPE) on day 5; however, there were no treatment-related light microscopic changes observed in the neuroretina and no changes observed by fundus autofluorescence or routine ophthalmoscopic examination after 28 days of dosing. Following 2 months of recovery, there was significant retinal thinning attributed to loss of photoreceptor nuclei from the outer nuclear layer. Electroretinographic changes were observed as early as day 14, before any microscopic evidence of photoreceptor loss. BACE1 knockout rats were generated and found to have normal retinal morphology indicating that the retinal toxicity induced by AMG-8718 was likely off-target. These results suggest that AMG-8718 impairs phagolysosomal function in the rat RPE, which leads to photoreceptor dysfunction and ultimately loss of photoreceptors.