Abstract by Mariana Yolotzin Garcia Bermudez
Alzheimer's disease (AD) is a progressive neurodegenerative disorder distinguished by the accumulation of abnormal proteins, impaired energy metabolism, and chronic inflammation, leading to widespread neurodegeneration in the brain, as well as the eye. Several studies have shown that retinal changes in AD models and patients closely resemble those in the brain, often reflecting the neuronal loss associated with AD, particularly the dysfunction and loss of retinal ganglion cells (RGCs). However, most studies correlating retinal changes with AD in the brain have only focused on later stages of the disease. In this study, we propose that similar retinal changes may also occur in the early stages of AD. Ultimately, examining these retinal changes may pave the way for earlier detection and improved monitoring of AD in patients.
In the present thesis, we examined changes in retinal energy metabolism and inflammation in early murine models of AD, with a focus on understanding how these factors may contribute to neurodegeneration. Given a higher prevalence of AD among females, we also explored how differences in sex affect susceptibility to neuroinflammation in AD pathology, in both the brain and retina. Additionally, as ketogenic diets have previously shown to provide an alternative energy substrate enhancing energy metabolism in the AD brain, we investigated the effect of a Medium-Chain-Triglyceride (MCT) diet on RGC survival and function in early AD. Finally, to consider the retina as a window to the brain, we examined the complex interplay between abnormal protein aggregation, impaired energy metabolism, inflammation and neurodegeneration.
Exploring the potential of retinal biomarkers, the first paper highlights how they may enhance early detection of AD. The second paper explored the potential of retinal biomarkers in the TgSwDI (APP-Swedish, Dutch, Iowa) mouse model at 7 months of age, representing an early stage of AD. After evaluating retinal viability, RGC specific survival, energy metabolism and inflammation, the TgSwDI mouse model exhibited an inflammatory response, which we suggest may potentially confer neuroprotection to RGCs. Considering the higher prevalence of AD in females, the third paper analyzed the impact of early neuroinflammation on cell viability and energy metabolism in the retina and brain, with a particular focus on sex-specific factors. Compared to male mice, our results indicated that the female retina and hippocampus are more vulnerable to neuroinflammation-induced alterations in glucose metabolism. Lastly, we evaluated the effect of a ketogenic diet based on MCT to examine whether or not it enhances retinal glucose metabolism in early stages of AD using the 5xFAD (B6SJL) mouse model. However, we found no significant differences in energy metabolism compared to a control diet, indicating that while no adverse effects were evident, the same cannot be said for neuroprotective benefits. This finding, however, paves the way for further research into the neuroprotective effects of the diet.
Overall, this thesis focuses on exploring retinal changes seen in early AD, particularly regarding alterations in energy metabolism, inflammation and neurodegeneration. An understanding of these early retinal alterations in AD is of vital importance to understand disease development and identifying potential biomarkers, which could enhance future diagnosis and monitoring of early AD in patients.
