NEW YORK—A new study in rodents has found that after a brain injury, cells that normally nourish nerves may actually kill them instead. This reactive phenomenon may be the driving factor behind neurodegenerative diseases like glaucoma, a leading cause of blindness. Led by researchers at NYU Grossman School of Medicine, the study examined what happens when pressure builds up in the eye and damages the nerve cells that connect the eyes and brain. Although experts have linked this condition to glaucoma, it remained unclear how the excess pressure led to cell death.
This investigation revealed that increased pressure drove astrocytes — a star-shaped glial cell of the central nervous system — to release as-yet-unidentified neuron-killing toxins, which may be meant to clear away damaged cells. But excess pressure had little effect on nerves when astrocytes weren’t present —and when astrocytes were prevented from reacting to pressure, neurons were damaged, but not as badly.
“Our findings point to astrocytes as the true culprits behind nerve cell death and highlight a new way of treating a neurodegenerative disease like glaucoma,” said Shane Liddelow, Ph.D., assistant professor in the Department of Neuroscience and Physiology and the Department of Ophthalmology at NYU Langone Health, and senior author of the study. “Perhaps targeting astrocytes after an injury may be the way to keep neurons healthy and help prevent further deterioration.”
Liddelow added that while half of all brain cells are astrocytes, most research on glaucoma has historically focused on neurons. He noted that the study findings make clear that in order to understand neurodegenerative diseases, experts must look beyond neurons to the cells that surround them, including astrocytes. Liddelow’s previous research in rodents has shown that astrocytes could become reactive immediately after nerves are physically damaged.
The new article, published June 23 in Cell Reports, is the first to show that reactive astrocytes kill cells over time in a process similar to what occurs in glaucoma, according to the authors. These findings may help explain why brain cells continue to die long after excess pressure has been controlled. Liddelow stated that dying neurons spill inflammatory compounds into the surrounding tissue, which could further aggravate astrocytes and lead to a continuous cycle of cell destruction.
For their investigation, study authors increased eye pressure for two weeks in several dozen rats and mice, some of which had been genetically engineered to lack these neuron-killing reactive astrocytes. Researchers found that while the unmodified mice lost up to half of the neurons in the injured area, those without toxic astrocytes saw little cell death. And the neurons that survived continued to send electrical signals.
To examine whether neurons survive if astrocytes are prevented from releasing toxins, the researchers increased pressure again — this time disrupting inflammation in some of the animals to prevent their astrocytes from becoming reactive.
“By inhibiting or knocking out IL-1α, TNF-α, and C1q, the factors secreted from microglia that induce neurotoxic reactive astrocytes, we can largely prevent the death of RGCs [retinal ganglion cells] induced following ONC [optic nerve crush] or following prolonged increases in IOP [intraocular pressure],” the article says. “The neurotoxicity of reactive astrocytes in glaucoma, combined with studies from other groups highlighting the contribution of this astrocytic response to models of Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease … suggests that neurotoxic reactive astrocytes may be a common feature in the complex and heterogeneous milieu of the CNS [central nervous system]’s response to prolonged injury.”
“In addition to showing that RGCs can be spared from death following acute axotomy and prolonged IOP, we found that spared RGCs are still functional, with many electrophysiological and morphological features similar to those of the uninjured retina of the contralateral eye. There are many ways to prevent cell death by eliminating final executioners of the cell death process. Unfortunately, surviving cells are sometimes irreversibly changed by the intracellular signaling processes that would normally lead to cell death or, in the case of neurons, may feature dramatically altered electrophysiological processes that make the surviving cell more detrimental to the normal function of a circuit than if the cell had simply died,” continues the article. “Thus, our observation that the electrophysiological and morphological features of RGCs spared from cell death were similar to those of the uninjured retina suggests that eliminating the factors that induce reactive astrocytes prevents many pathological changes that often occur before eventual cell death.”
Although the findings suggest that blocking astrocytes could be a means of preventing nerve damage in glaucoma patients, Liddelow pointed out that researchers do not yet know if the resulting effects are permanent, or what side effects may occur. The research team next plans to investigate whether this treatment can actually improve vision in animals with glaucoma, as well as studying astrocyte behavior in related diseases like Alzheimer’s, Parkinson’s and Lou Gehrig’s disease.
