Toxic brain cells may drive many neurodegenerative disorders, a study has revealed.
A team led by researchers at the Stanford University School of Medicine has found that astrocytes, which perform many indispensable functions in the brain, can take on a villainous character, destroying nerve cells and likely driving many neurodegenerative diseases.
For every nerve cell in the human brain there are four astrocytes, but many people won’t have heard of them. These star-shaped connective tissue cells in the nervous system link nerve cells to blood vessels. They do this by wrapping round brain capillaries and helping to form the blood-brain barrier.
The study’s senior author, Ben Barres, MD, PhD, professor of neurological, of development biology and of neurology and neurological sciences, said: “We have learnt that astrocytes aren’t always the good guys. An aberrant vision of them turns up in suspicious abundance in all the wrong places in the brain-tissue samples from patients with brain injuries and major neurological disorders from Alzheimer’s and Parkinson’s to Multiple Sclerosis (MS). The implications if treating these diseases are profound.”
Barres, has spent the last three decades focusing on brain cells that aren’t nerve cells. Up to now, the pharmaceutical industry has mostly targeted nerve cells, also known as neurons. But now a broad range of brain disorders may be treatable by blocking astrocytes’ metamorphosis into toxic cells, or by pharmaceutically countering the neuron-killing toxin those cells have been found to secrete.
Based on previous research in 2012 the team had two main questions that they aimed to answer. How is the restrictive astrocytes A1 generated? And how do they behave once generated?
Addressing the first question, the study showed that the brain’s immune cells, microglia, which are known to become activated by Lipopolysaccharides (LPS) exposure as well as in most brain injuries and diseases, begin spewing out pro-inflammatory factors that change astrocytes’ behaviour.
In a series of experiments using laboratory mice, the scientists identified three pro-inflammatory factors whose production was ramped up after LPS exposure: TND-alpha, IL-1-alpha and C1q. In the brain all three of these substances are secreted exclusively by microglia. Each, by itself, had a partial A1-inducing effect on resting astrocytes. Combined, they propelled resting astrocytes into a fully-fledged A1 state.
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.
Further experiments showed that A1s lose resting astrocytes' capacity to prune synapses that are no longer needed or functional and whose continued existence undermines efficient brain function.
Indeed, when the researchers cultured healthy Regeneron Genetics Centres (RGC) 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, which is essentially fat-filled flapjacks that wrap themselves around nerve fibres, providing electrical insulation that speeds long-distance signal propagation. Autoimmune destruction of oligodendrocytes and their fatty contents gives rise to MS.
In another experiment, which focused on staving off A1 formation the researchers severed rodents' optic nerves – an act ordinarily lethal to RGCs, whose outgoing fibres, 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 neutralising TNF-alpha, IL-1-alpha and C1q with antibodies to these three substances prevented A1 formation and RGC death in the animals.
Finally, the researchers analysed samples of human brain tissue from patients with Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and MS. In every case, they observed large numbers of A1s preferentially clustering where the disease was most active.
An effort to identify the neurotoxin secreted by A1 astrocytes is underway, Barres said. "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."
Source: MS-UK (19/01/17)