A team of scientists has unraveled the molecular mechanism behind the development of age-related macular degeneration (AMD). It has found that it develops because of abnormal activity of a set of white blood cells called neutrophils and that it can be stopped, and even reversed, by targeting it.
AMD is associated with retinal degeneration and loss of central vision and is the leading cause of blindness in the elderly. The new finding could help develop a treatment for the disease in future.
The journey of discovery began with a finding that people suffering from the disease had a significant accumulation of neutrophils in the retina of their eyes. The finding was unusual as the main role of neutrophils is to help the body in its fight against bacterial and other infections and it had nothing to do with the functioning of the retina.
Dr. Debasish Sinha with his colleagues at their lab.
The researchers probed further only to find that the patients also had high levels of an inflammatory molecule called interferon lambda. This was intriguing as it is also mainly produced in the case of an infection. Puzzled, they delved deeper and found that the retina and a set of cells called RPE on the retina’s surface in the eyes of the patients were transformed into an inflammatory state: a state that should normally occur only in the case of an infection.
Connecting the dots, the researchers thought that perhaps there were some abnormalities in an inflammatory pathway regulated by AKT2, which plays a role in the transformation of retina and RPE cells. They conducted tests in mice and found that their hypothesis was on the dot.
“We injected into our mouse model an inhibitor of the AKT2 pathway. It neutralized interferon-lambda signals, reduced neutrophil infiltration, and reversed age-related macular degeneration-like changes in the mouse. Thus, AKT2 inhibitors may have therapeutic potential,” said Dr. Debasish Sinha, leader of the study team, while speaking to India Science Wire.
It is well known that inflammation plays a key role in the pathogenesis of various age-related diseases including age-related macular degeneration and that dysregulation of the body’s immune system is critical for its onset. Several studies have shown that activation of various chemicals called cytokines/chemokines could be responsible for the condition. However, the role of neutrophils had remained largely unexplored. In addition, the molecular mechanisms involved in immune system activation and regulation in the condition had remained unknown.
To add to the problem, there was also lack of a comprehensive animal model of the disease. This limited the understanding of the cellular mechanisms in the critical early disease stages. The new study fills the gap. The researchers have developed a genetically engineered mouse model that exhibits a slow progressive early, dry AMD-like pathology.
Scientists from several institutions were involved in the study, with the majority of the work performed at University of Pittsburgh School of Medicine, USA and the Narayana Nethralaya Foundation, Bengaluru, India. They have published a report on their work in Communications Biology. (India Science Wire)
By Sunderarajan Padmanabhan