Retinal Functional and Structural Changes in the 5xFAD Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer's disease is characterized by the aberrant deposition of protein in the brain and is the leading cause of dementia worldwide. Increasingly, there have been reports of the presence of these protein hallmarks in the retina. In this study, we assayed the retina of 5xFAD mice, a transgenic model of amyloid deposition known to exhibit dementia-like symptoms with age. Using OCT, we found that the retinal nerve fiber layer was thinner in 5xFAD at 6, 12, and 17 months of age compared with wild-type littermates, but the inner plexiform layer was thicker at 6 months old. Retinal function showed reduced ganglion cell responses to light in 5xFAD at 6, 12, and 17 months of age. This functional loss was observed in the outer retina at 17 months of age but not in younger mice. We showed using immunohistochemistry and ELISA that soluble and insoluble amyloid was present in the retina and brain at all ages. In conclusion, we report that amyloid is present in brain and retina of 5xFAD mice and that the pattern of neuronal dysfunction occurs in the inner retina at the early ages and progresses to encompass the outer retina with age. This implies that the inner retina is more sensitive to amyloid changes in early disease and that the outer retina is also affected with disease progression.

Rod pathway and cone pathway retinal dysfunction in the 5xFAD mouse model of Alzheimer’s disease

“…Criscuolo et al 18 also reported reduced pERG amplitude in the same mice, suggesting RGC dysfunction. Likewise, Lim et al 22 showed small b-wave amplitude losses in the 5xFAD mice at 6 and 12 months of age that did not meet the threshold for statistical significance. For older 5xFAD mice (17 months) they reported that the b-wave amplitude elicited by a high luminance flash was significantly reduced, and reductions in the a-wave were also noted 22 .…”

“…Likewise, Lim et al 22 showed small b-wave amplitude losses in the 5xFAD mice at 6 and 12 months of age that did not meet the threshold for statistical significance. For older 5xFAD mice (17 months) they reported that the b-wave amplitude elicited by a high luminance flash was significantly reduced, and reductions in the a-wave were also noted 22 . Lim et al 22 found the scotopic threshold response to be reduced at all ages, which also suggested RGC dysfunction.…”

“…For older 5xFAD mice (17 months) they reported that the b-wave amplitude elicited by a high luminance flash was significantly reduced, and reductions in the a-wave were also noted 22 . Lim et al 22 found the scotopic threshold response to be reduced at all ages, which also suggested RGC dysfunction. Taken together, the results of the present report, as well as those of previous reports 18 , 21 , 22 , indicate post-receptor retinal abnormalities in the 5xFAD model of AD under dark-adapted conditions.…”

“…The available reports show Aβ peptide elevation in the retina 17 – 20 , consistent with the findings in the brain, which may occur as early as one month of age 18 . The electroretinogram (ERG) has been used to evaluate retinal function in this model 18 , 20 – 22 , with the most complete report of ERG findings provided by Lim et al 22 For 17-month-old 5xFAD mice, photoreceptor function (inferred from a-wave analyses), bipolar cell function (inferred from b-wave analyses), and ganglion cell function (inferred from the scotopic threshold response) were all significantly abnormal 22 . For younger mice (6–12 month-old), trends for bipolar cell abnormalities were apparent for stimulus luminance greater than approximately 0.001 cd-s-m −2 , but these did not reach statistical significance.…”

“…Although previous work has informed our understanding of rod-pathway-mediated retinal dysfunction in the 5xFAD model of AD 18 , 21 , 22 , the extent to which the cone-pathway is affected is less clear. To date, the full-field ERG has not been assessed under light-adapted conditions in 5xFAD mice.…”