Deep in the inner galaxy of the central nervous system, a rogue power wreaks havoc.
It appears when disasters occur and carries out deadly disruption.

It is known simply as ‘A1’ and its origin has been shrouded in mystery throughout the modern era of medical science. 
Until this year, that is, when a small army of whitecoats made a major advance.

They concluded that this star-shaped menace – a ‘helper’ cell, or astrocyte, gone bad – may be contributing to damage caused by brain injury and disease.

Their new report has given greater clarity on why and how the A1 astrocyte turns toxic and destroys neurones.

It has also opened up new possibilities for future treatments of trauma injuries and neurodegenerative diseases.

Announcing the news to the world, Standford University’s Ben Barres declared: “Astrocytes aren’t always the good guys. An aberrant version of them turns up in suspicious abundance in the wrong places.”

Astrocytes are non-neuronal ‘glia’ cells in
the central nervous system, outnumbering neurones five to one. It was long believed that they merely served as structural support for neurones. More recently it was discovered they vitally help neurones, enhancing their survival and shaping the connections between them.

It’s also known that traumatic brain injury, stroke, infection and disease can transform benign ‘resting’ astrocytes into reactive ones with different behaviours.

In 2012 two distinct types of reactive astrocytes were identified; A1 and A2. A2s are induced by oxygen deprivation in the brain, which occurs during stroke. They produce substances supporting neurone growth, health and survival near the stroke site.

A1s, on the other hand, are primed to produce pro-inflammatory substances. They were observed in the presence of LPS, a component found in the cell walls of bacteria; but neither their function or origin could be explained. Scientists have now answered both questions – and are hopeful their work will catalyse new treatments for neurological disorders.

Lead author Dr Shane Liddelow, of the department of pharmacology and therapeutics at Melbourne University, and the department of neurobiology at Stanford University, says: “For too long, academic and pharmaceutical science has focused heavily on the neuronal side of neurodegeneration.

“The glia side has been largely ignored, partly because of a lack
 of knowledge and also because we’ve not had the technology to explore it. As a result, none of the treatments for such conditions have been particularly powerful. None have 
stopped disease or, indeed, the devastating impact of a trauma.

“Astrocytes make up 60 to 70% of cells in the brain, so it just seems like such low hanging fruit if we can target them instead of neurones. For the first time, we might be able to treat these diseases and traumatic injuries.

“Preliminary evidence says, if we modulate 
just the reactivity of astrocytes, we can stop neurones dying and help synapses to form. This could be hugely important in the context of regeneration and recovery. All of the planets are essentially aligning and we are now ramping up experiments to find a treatable avenue.”

His study, published in Nature, showed that A1 astrocytes lose the ability to promote neuronal survival, and induce the death of neurones
and oligodendrocytes (which also support neurones). Liddelow also discovered that the protein secreted by A1s is toxic to neurones but not other cells in the brain. In the spinal cord, it only kills certain motor-neurones.

“We are getting very close to characterising exactly what that toxin is. That will enable us
to find an antibody that could at least stop neurones being killed.”

The research also found that the death of neurones in vivo was prevented when the formation of A1 was blocked. Even if such a treatment could be applied safely in humans, however, doctors would have a limited window of opportunity to use it.

Research suggest that A1 astrocytes are formed in the immediate aftermath of a trauma.

A more exciting prospect would be a treatment that could deactivate A1 astrocytes. This could have huge implications for diseases such as Alzheimer’s, Huntington’s, Parkinson’s, amyotrophic lateral sclerosis and multiple sclerosis.

Researchers found A1s in abundance in every one of these conditions, as well as in brain and spinal injury cases. Liddelow hopes to eventually translate positive initial lab tests into clinical trials.

“We’ve been able to grow pure astrocytes in a Petri dish, uncontaminated by other cells. The most surprising thing about the study is that we can flick a switch that makes them reactive or non-reactive, using pharmaceutical agents.”

Reactive A2 astrocytes are the main cellular component in glial scarring, aiding the healing process in the central nervous system. The challenge facing Liddelow and his colleagues is activating and deactivating A1s without affecting A2s, since too much or too little scarring could be detrimental to the healing process.

“We can be very targeted with culture dish experiments, which are fantastic for looking
 at mechanisms, but are not always 
biologically relevant.

“A lot of the drugs involved are already approved in the US by the FDA but we would have to change the treatment paradigm as some are not used in the context of neurodegeneration.

“The next step in the longer term would be to see, if we can stop neurones dying, can we then regenerate them? Could we bring about a return of lost abilities like motor functions, bladder control and sexual function?

“I couldn’t put a timescale on it, but we’re definitely optimistic.”

With new in vivo studies currently underway, NR Times hopes to report on further progress 
in this field later this year.