Age-Related Retinal Changes in Wild-Type C57BL/6J Mice Between 2 and 32 Months

Age-related cerebrovascular defects contribute to vascular cognitive impairment and dementia (VCID) as well as other forms of dementia. There has been great interest in developing biomarkers and other tools for studying cerebrovascular disease using more easily accessible tissues outside the brain such as the retina. Decreased circulating insulin-like growth factor 1 (IGF-1) levels in aging are thought to contribute to the development of cerebrovascular impairment, a hypothesis that has been supported by the use of IGF-1 deficient animal models. Here we evaluate vascular and other retinal phenotypes in animals with circulating IGF-1 deficiency and ask whether the retina mimics common age-related vascular changes in the brain such as the development of microhemorrhages. Using a hypertension-induced model, we confirm that IGF-1 deficient mice exhibited worsened microhemorrhages than controls. The retinas of IGF-1 deficient animals do not exhibit microhemorrhages but do exhibit signs of vascular damage and retinal stress such as patterns of vascular constriction and Müller cell activation. These signs of retinal stress are not accompanied by retinal degeneration or impaired neuronal function. These data suggest that the role of IGF-1 in the retina is complex, and while IGF-1 deficiency leads to vascular defects in both the brain and the retina, not all brain pathologies are evident in the retina.

Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Increased Susceptibility to Cerebral Microhemorrhages Is Associated With Imaging Signs of Microvascular Degeneration in the Retina in an Insulin-Like Growth Factor 1 Deficient Mouse Model of Accelerated Aging

Miller

Tarantini

Nyúl‐Tóth

et al. 2022

“…Several age-dependent cellular and molecular changes have been described in mouse retinas, such as, photoreceptor mislocalization (Sugita et al, 2020 ) and vascular and RPE changes (Hermenean et al, 2021 ). Regarding metrics captured by OCT, although some studies have found age-dependent alterations in mouse retinas, such as auto-fluorescence (Ferdous et al, 2021 ) and scattering diversity (Gardner et al, 2020 ), these cannot be directly compared with our results. Therefore, we can only speculate that some healthy age-dependent neural adaptations may be altered in transgenic animals.…”

Section: Discussionmentioning

confidence: 77%

Retinal Aging in 3× Tg-AD Mice Model of Alzheimer's Disease

Guimarães

Serranho²,

Martins³

et al. 2022

The retina, as part of the central nervous system (CNS), can be the perfect target for in vivo, in situ, and noninvasive neuropathology diagnosis and assessment of therapeutic efficacy. It has long been established that several age-related brain changes are more pronounced in Alzheimer's disease (AD). Nevertheless, in the retina such link is still under-explored. This study investigates the differences in the aging of the CNS through the retina of 3× Tg-AD and wild-type mice. A dedicated optical coherence tomograph imaged mice's retinas for 16 months. Two neural networks were developed to model independently each group's ages and were then applied to an independent set containing images from both groups. Our analysis shows a mean absolute error of 0.875±1.1 × 10−2 and 1.112±1.4 × 10−2 months, depending on training group. Our deep learning approach appears to be a reliable retinal OCT aging marker. We show that retina aging is distinct in the two classes: the presence of the three mutated human genes in the mouse genome has an impact on the aging of the retina. For mice over 4 months-old, transgenic mice consistently present a negative retina age-gap when compared to wild-type mice, regardless of training set. This appears to contradict AD observations in the brain. However, the ‘black-box” nature of deep-learning implies that one cannot infer reasoning. We can only speculate that some healthy age-dependent neural adaptations may be altered in transgenic animals.

“…However, it is worth noting that overall OFF-RGCs were significantly smaller than ON-RGCs in both age groups ( Figure 5H ) and the range of OFF-RGCs sampled in older eyes was narrower (0.93 × 10 5 –2.90 × 10 5 μm 3 ) than younger OFF-RGCs (0.65 × 10 5 –5.00 × 10 5 μm 3 ; Figure 5N ). It is less likely that the narrower range of OFF-RGCs was due to cell loss during normal aging as there was no significant cell nuclei reduction in the ganglion cell layer between 2 to 12 months of age ( Ferdous et al, 2021 ). Nonetheless, this narrower range of OFF-RGCs may have limited our capacity to find differences in OFF-RGCs with age.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Aging on Retinal Function and Retinal Ganglion Cell Morphology Following Intraocular Pressure Elevation

Lee

Zhao

Wong

et al. 2022

Aging and elevated intraocular pressure (IOP) are two major risk factors for glaucomatous optic neuropathy; a condition characterized by the selective, progressive injury, and subsequent loss of retinal ganglion cells (RGCs). We examined how age modified the capacity for RGCs to functionally recover following a reproducible IOP elevation (50 mmHg for 30 min). We found that RGC functional recovery (measured using electroretinography) was complete by 7 days in 3-month-old mice but was delayed in 12-month-old mice until 14 days. At the 7-day recovery endpoint when RGC function had recovered in young but not older eyes, we examined RGC structural responses to IOP-related stress by analyzing RGC dendritic morphology. ON-RGC cell volume was attenuated following IOP elevation in both young and older mice. We also found that following IOP elevation OFF-RGC dendritic morphology became less complex per cell volume in young mice, an effect that was not observed in older eyes. Our data suggest that adaptations in OFF-RGCs in young eyes were associated with better functional recovery 7 days after IOP elevation. Loss of RGC cellular adaptations may account for delayed functional recovery in older eyes.