Reactive Astrocytes Kill Neurons in Neurodegenerative Conditions
Researchers here report on their investigations of human astrocytes, a class of supporting cells in the brain that are responsible for maintaining the correct function of neurons. Age-related neurodegenerative conditions have a strong inflammatory component to their progression. The chronic inflammation of aging is thought to drive supporting cells such as astrocytes and glia into harmful behaviors that damage and destroy neurons. This is coming to be seen as an important component of age-related neurodegeneration, and researchers have produced benefits in animal models of neurodegenerative conditions via means of removing the worst of harmful supporting cells in the brain.
Astrocytes, star-shaped cells that make up more than half the cells in the central nervous system, belong to a category of brain cells called glia which provide vital support for neurons in the brain. Astrocytes aid in metabolic processes, regulate connectivity of brain circuits, participate in inflammatory signaling, and help regulate blood flow across the blood-brain barrier, among other duties. They are a crucial component of brain function but are often overlooked in research and drug development, although recent mounting evidence implicates them in many neurological diseases.
"We observed in mice that astrocytes in inflammatory environments take on a reactive state, actually attacking neurons rather than supporting them. We found evidence of reactive astrocytes in the brains of patients with neurodegenerative diseases, but without a human stem cell model, it wasn't possible to figure out how they were created and what they are doing in patient brains."
Researchers used a new human stem cell model to determine if the outcome observed in mice could also be happening in humans. They exposed healthy stem-cell-derived astrocytes to inflammation - essentially mimicking the environment of the brain in neurodegenerative diseases - collected their byproducts, and then exposed these secretions to healthy neurons. "What we saw in the dish confirmed observations in mice: the neurons began to die. Observing this 'rogue astrocyte' phenomenon in a human model of disease suggests that it could be happening in actual patients and opens the door for new therapeutics that intervene in this process."
The team also saw that stem-cell-derived astrocytes exposed to inflammation lost their typical astrocyte functions: they did not support neuronal maturation or firing very well, and they didn't uptake as much glutamate. They also changed their morphology, losing their characteristic 'long arms' and taking on a more constricted star-like shape. "Along with secreting a toxin that kills neurons, we also saw that stem-cell-derived astrocytes in disease-like environments simply do not perform their typical jobs as well, and that could lead to neuronal dysfunction. For example, since they do not take up glutamate properly, too much glutamate is likely left around the neurons, which could cause a neuron to atrophy, and that's something we can potentially target in new therapies."