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Faulty molecular master switch identified as possible contributing factor to AMD

Scientists from the US National Institutes of Health (NIH) have found the interruption of transforming growth factor beta (TGF-beta) signals to immune cells could be involved in the progression of age-related macular degeneration (AMD).

According to the research team from the NIH’s National Eye Institute (NEI) when TGF-beta’s signals to immune cells, called microglia, are interrupted, it causes the cells to enter into an activated and inflammatory state.

In this activated state the microglia causes damage to the retina, of which the cellular effects are similar to those found in AMD.

Scientists have know for some time that particular variations in genes in the TGF-beta pathway may be more at risk for advanced AMD, suggesting that the signaling molecule might play a part in the development of the disease. This new research focused on identifying the specifics of this connection.

“Communication between neurons and microglia in the retina is going on all the time. Neurons tell the microglia how to behave and how to be of service to the rest of the retina,” Dr Wai Wong, chief of the NEI section on neuron-glia interactions in retinal disease, said.

"The TGF-beta pathway may be one of the buttons on immune cells that one can tweak, in order to move the immune system in the retina one way or the other, in ways that are beneficial to disease outcome."
Wai Wong, Nei

“We wanted to know whether there was a connection between this genetic risk involving TGF-beta and abnormal retinal microglia, which are often found in AMD.”

Wong and team developed genetically-modified mice for the study, in which they could turn off the microglial cells’ ability to sense TGF-beta.

When the cells stopped sensing TGF-beta they immediately changed shape, moved to incorrect locations, and began to multiply. The microglia also decreased their expression of their “sensome,” a collection of proteins that the microglia use to sense their environment. Instead, the microglia started expressing proteins used in their activated state.

“While microglia are critical for maintaining healthy neurons, decreased TGF-beta activity switches microglia to a pro-inflammatory mode, which is worse than having no microglia at all,” Wong said, pointing out that activated microglia and the corresponding loss of microglial support of retinal cells, has cascading effects on the retina.

In mice models, Wong’s team found that another group of retinal support cells, called Müller glia, began to show signs of distress, and retinal neurons began to fail and die.

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Additionally, abnormal microglia drastically exacerbated the growth of new blood vessels in a model of AMD. All these pathological changes are similar to what happens in the progression to late AMD, indicating that microglia and TGF-beta signaling may help drive the progression of the disease in humans.

According to Wong, TGF-beta may represent an important therapeutic target for treating AMD.

“The TGF-beta pathway may be one of the buttons on immune cells that one can tweak, in order to move the immune system in the retina one way or the other, in ways that are beneficial to disease outcome,” Wong added.

The findings were published in the journal eLife.

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