New research from the Jackson Laboratory (JAX) has revealed how genetic variations influence the aging of the retina, a discovery that could have significant implications for diagnosing and treating neurodegenerative diseases such as Alzheimer’s. Published in Molecular Neurodegeneration, the study opens up new possibilities for utilizing the retina as a biomarker for both brain and eye health, with the potential to predict conditions like Alzheimer’s.
“The eye is a crucial organ, and this research fills an important gap in our understanding of aging,” said Gareth Howell, PhD, a glaucoma research professor at JAX. “But beyond that, the eye is a window into the brain. By understanding how the healthy eye ages, we may be able to develop methods to assess the risk of diseases like Alzheimer’s.”
The study investigated retinal aging in nine different mouse strains, each genetically distinct and designed to reflect the genetic diversity seen in humans. This variation allowed for a deeper exploration of the genetic and molecular changes in the retina over time, contrasting with earlier studies that relied on genetically identical mouse strains.
Researchers analyzed both young and older mice, conducting detailed genetic and protein examinations to track molecular changes. While all the mice showed expected age-related retinal degeneration, the severity and specific changes varied greatly across strains. Two strains, in particular—Watkins Star Line B (WSB) and New Zealand Obese (NZO)—emerged as promising models for human retinal diseases.
The WSB strain displayed characteristics of age-related macular degeneration (AMD) and retinitis pigmentosa (RP), while the NZO strain, known for severe obesity and diabetes, developed diabetic retinopathy (DR). The researchers found that gene and protein analysis of these mice predicted the later onset of age-related eye diseases.
“It was promising to see that the molecular data we generated predicted specific retinal cell abnormalities in these two strains,” said Olivia Marola, PhD, co-first author and postdoctoral researcher at JAX. “When we observed unique changes in NZO’s retinal ganglion cells at the molecular level, we saw drastic functional changes in those cells as well.”
This breakthrough has broader implications beyond vision research, particularly for neurodegenerative diseases. Since the retina is a direct extension of the brain, understanding how it ages could offer new insights into Alzheimer’s and other forms of dementia. The retinal changes observed in this study could eventually serve as noninvasive biomarkers to diagnose neurological decline before more obvious symptoms manifest.
In one of the study’s most notable findings, the WSB mice exhibited significant rod-specific photoreceptor loss with aging. This mirrored human RP, which typically affects peripheral vision first, while AMD impacts central vision. The WSB mice’s central retinal degeneration closely resembled AMD, providing a valuable model for human retinal diseases.
Additionally, the NZO strain displayed vascular changes similar to those in diabetic retinopathy, including microvascular dysfunction and retinal ganglion cell loss. This makes the NZO mice a more accurate model for studying diabetic retinopathy and its associated neurodegeneration.
The study also created a comprehensive, publicly accessible multi-omics dataset that will help researchers further investigate retinal aging across various genetic backgrounds. This open resource promises to advance the understanding of molecular mechanisms behind retinal aging and degeneration. The next phase of the research will focus on pinpointing the specific genes and proteins driving these changes and exploring how these findings might relate to brain health.
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