Astrocytes are usually the good guys. Although they are four times as plentiful in the brain as neurons, they happily play a supporting role, serving as packing peanuts or facilitating the formation and pruning of neuronal connections. Yet good astrocytes, or resting astrocytes, can become what are known as reactive astrocytes, some of which turn evil, destroying nerve cells and likely driving many neurodegenerative diseases.
The dark turn, which may be instigated by infection or trauma, has been detailed by scientists based at Stanford University Medical Center, who suggest that a broad range of brain disorders may be treatable by blocking astrocytes' metamorphosis into toxic cells, or by pharmaceutically countering the neuron-killing toxin these harmful cells almost certainly secrete.
Aberrant astrocytes, “turn up in suspicious abundance in all the wrong places,” says Stanford’s Ben Barres, M.D., Ph.D., a professor of neurobiology, developmental biology, and neurology and neurological sciences. Dr. Barres and colleagues have found that these cells appear in brain-tissue samples from patients with brain injuries and major neurological disorders from Alzheimer's and Parkinson's to multiple sclerosis.
These findings appeared January 18 in the journal Nature, in an article entitled “Neurotoxic Reactive Astrocytes Are Induced by Activated Microglia.” Besides demonstrating that aberrant astrocytes tend to be prevalent where injury is most dire or disease most acute, the article’s authors determined that microglia play a role in transforming benign astrocytes to killer astrocytes. Finally, they obtained results suggesting that aberrant astrocytes secrete a neuron-killing toxin.
“Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia,” wrote the article’s authors. “We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes.”
In 2012, Barres and his colleagues resolved that ambiguity when they identified two distinct types of reactive astrocytes, which they called A1 and A2. In the presence of lipopolysaccharide (LPS), a component found in the cell walls of bacteria, they observed that resting astrocytes somehow wind up getting transformed into A1s, which are primed to produce large volumes of proinflammatory substances. A2s, on the other hand, are induced by oxygen deprivation in the brain, which occurs during strokes. A2s produce substances supporting neuron growth, health, and survival near the stroke site.
In the current study, Barres and co-workers followed up on these results by showing that the brain's immune cells, microglia, which are known to become activated by LPS exposure as well as in most brain injuries and diseases, begin spewing out proinflammatory factors that change astrocytes' behavior.
Next, the researchers confirmed that A1s jettison the nurturing qualities they'd had as resting astrocytes, which Barres' group has shown are essential to the formation and functioning of synapses, and instead became toxic to neurons.
“A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes,” the authors of the Nature paper indicated. “Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked.”
In vertebrates, nerve cells called retinal ganglion cells (RGCs) send information from the retina to vision-processing centers in the brain. RGCs can thrive in culture, but only if accompanied by astrocytes. The scientists cultured rodent RGCs with either resting or A1 astrocytes and counted the resulting synapse numbers. RGCs cultured in combination with A1s produced only half as many synapses as RGCs grown with resting astrocytes, and those that formed didn't work very well.
Indeed, when the researchers cultured healthy RGCs with increasingly stronger concentrations of the broth in which A1s had been bathing, almost all the RGCs eventually died. This and other experiments showed that A1s secrete a powerful, neuron-killing toxin.
The same treatment killed many other types of neurons, including both the spinal motor neurons that die in amyotrophic lateral sclerosis and the human dopaminergic neurons whose mysterious loss is the cause of Parkinson's disease. A1 bathwater also impaired the development of yet another class of non-neuron brain cells called oligodendrocytes—essentially fat-filled flapjacks that wrap themselves around nerve fibers, providing electrical insulation that speeds long-distance signal propagation. Autoimmune destruction of oligodendrocytes and their fatty contents gives rise to multiple sclerosis.
In another experiment, the researchers severed rodents' optic nerves—an act ordinarily lethal to RGCs, whose outgoing fibers, called axons, constitute the optic nerve. In the central nervous system, severing axons causes the entire neuron to die quickly, but why they die has been a mystery. The investigators determined the cause: A1s. They observed that those reactive astrocytes formed quickly after axons were severed, but that neutralizing tumor necrosis factor-alpha (TNF-alpha), interleukin-1-alpha (IL-1-alpha), and C1q with antibodies to these three substances prevented A1 formation and RGC death in the animals.
Finally, the researchers analyzed samples of human brain tissue from patients with Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In every case, they observed large numbers of A1s preferentially clustering where the disease was most active. For example, in the samples from Alzheimer's patients, nearly 60% of the astrocytes present in the prefrontal cortex, a region where the disease takes a great toll, were of the A1 variety. Because A1s are highly toxic to both neurons and oligodendrocytes, these findings strongly imply that A1 formation is helping to drive neurodegeneration in these diseases.
An effort to identify the neurotoxin secreted by A1 astrocytes is underway, informed Dr. Barres. “We're very excited by the discovery of neurotoxic reactive astrocytes,” he said, “because our findings imply that acute injuries of the retina, brain, and spinal cord and neurodegenerative diseases may all be much more highly treatable than has been thought.”
