Alzheimer’s proteins linked to age-related vision loss

A recently published study has demonstrated a close correlation between proteins linked to age-related vision loss and Alzheimer’s disease.

Alzheimer’s proteins linked to age-related vision loss
Image Credit: University of Southampton.

The results could pave the way for novel therapies for patients suffering from deteriorating vision and, through this analysis, researchers hope to decrease the need for using animals in upcoming studies on vision blinding conditions.

Amyloid beta (AB) proteins are the main driver of Alzheimer’s disease, but they also tend to build up in the retina as individuals grow older. Donor eyes of patients who experienced age-related macular degeneration (AMD)—the most common source of blindness among adults in the United Kingdom—have been demonstrated to contain elevated levels of AB in their retinas.

This recent study, published in the Cells journal, builds on earlier studies, which revealed that AB accumulates around a cell layer, known as retinal pigment epithelium (RPE), to determine the extent of damage caused to RPE cells by these toxic proteins.

The researchers exposed the RPE cells of normal mouse eyes and also the cells in culture to AB.

The mouse model allowed the team to examine the effect of protein on the living eye tissue using non-invasive imaging methods that are typically employed in ophthalmology clinics. The researchers’ results have demonstrated that retinal pathology, which developed in the mouse eyes, was remarkably analogous to the AMD that occurs in humans.

This was an important study which also showed that mouse numbers used for experiments of this kind can be significantly reduced in the future. We were able to develop a robust model to study AMD-like retinal pathology driven by AB without using transgenic animals, which are often used by researchers in the field.”

Dr Arjuna Ratnayaka, Study Lead and Lecturer, Vision Sciences, University of Southampton

Transgenic or genetically engineered mice can take up to a year and typically longer before AB causes pathology in the retina, which we can achieve within two weeks. This reduces the need to develop more transgenic models and improves animal welfare,” added Ratnayaka.

The researchers also utilized the cell models—which additionally decreased the use of mice in these experiments—to demonstrate that toxic AB proteins penetrated the RPE cells and quickly accumulated in lysosomes, which act as the waste disposal system for cells.

While cells executed their normal activity of boosting enzymes inside the lysosomes to disintegrate this unnecessary cargo, the analysis revealed that about 85% of AB persisted within the lysosomes, which means that over time, toxic molecules would continue to build up within the RPE cells.

The team also found that once lysosomes had been attacked by AB, approximately 20% fewer lysosomes were available to disintegrate the outer segments of the photoreceptor, a function that is regularly performed by lysosomes as part of the day-to-day visual cycle.

This is a further indication of how cells in the eye can deteriorate over time because of these toxic molecules collecting inside RPE cells. This could be a new pathway that no-one has explored before. Our discoveries have also strengthened the link between diseases of the eye and the brain. The eye is part of the brain and we have shown how AB which is known to drive major neurological conditions such as Alzheimer’s disease can also causes significant damage to cells in retina.”

Dr Arjuna Ratnayaka, Study Lead and Lecturer, Vision Sciences, University of Southampton

Researchers believe that one of the subsequent steps would be to re-purpose the anti-amyloid beta drugs, which were previously tested in Alzheimer’s patients, and to test them as a potential therapy for age-related macular degeneration. Since most of these drugs have already been approved by regulators in the European Union and the United States, this field could be investigated much more quickly.

The research work may also help broader efforts to largely overcome the use of animal testing wherever possible so that certain aspects of the testing of novel clinical therapies can directly switch from cell models to patients.

The study was financially supported by the National Center for the Replacement, Refinement, and Reduction of animals in research (NC3Rs).

This is an impactful study that demonstrates the scientific, practical and 3Rs benefits to studying AMD-like retinal pathology in vitro.”

Dr Katie Bates, Head of Research Funding, National Centre for the Replacement Refinement & Reduction of Animals in Research

Source:
Journal reference:

Lynn, S. A., et al. (2021) Oligomeric Aβ1-42 Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function. Cells. doi.org/10.3390/cells10020413.

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