Astrocytes are star-shaped cells in the brain and spinal cord, cells that helps neurones to function properly. I attended a Biochemical Society meeting “Astrocytes in Health and Disease” held in late April at the Institute of Child Health in London. The meeting brought together some of the top world scientists in this area as well as a lot of early-career scientists and scientists who are planning to begin research with astrocytes.
I was pleased to be in good company: Janine Kirby and Fiona Menzies, both on the MND Association Biomedical Research Advisory Panel (BRAP) were there, showing that many Motor Neurone Disease researchers consider astrocytes to be relevant to the development and progression of the disease, and that better understanding the role of astrocytes may help us get closer to discovery of better medicines.
So what’s the story about astrocytes, and what new came out of the meeting. And how does this relate to Motor Neurone Disease?
There are just as many astrocytes in the brain and spinal cord as there are neurones (usual estimate is 1,000,0000,000), and in the recent period research on these cells has accelerated. We no longer think of them as silent supporters of neuronal function, (glue) but as active and essential partners. We are in the era of astrocyte recognition and liberation.
The meeting had several speakers: Pierre Magistretti (Lausanne, Switzerland), Mike Sofroniew (Los Angeles, USA), Milos Pekny (Göteburg, Sweden) and Alexej Verkhratsky (Manchester, UK) and Vlad Parpura (Birmingham, USA) who are world-leaders in the forefront of the development of the field and have all made major and direct contributions to this increased understanding. In their own styles, these speakers each gave talks that explained the main features and functions of astrocytes, i.e. set out the latest view of what is established fact while also outlining the areas of uncertainty where more research needs to be done.
Pierre Magistretti showed some elegant work aimed to understand what astrocytes do normally. Astrocytes sit between the small blood vessels in the brain (capillaries) and the neurones and Magistretti was one of the first to identify how astrocytes take up the nutrients which neurones require to be active, particularly glucose. Astrocytes extract glucose from the bloodstream, can store some of it in the form of glycogen (just like muscles do) and, when needed, supply neurones with their fuel: which he believes is mostly lactate, derived from breakdown of glycogen or glucose.
His data showed that knocking out parts of the system in astrocytes which allow them to provide lactate to neurones can effect essential neuronal functions. Several other speakers, notably Vlad Parpura, explained that astrocytes have a far more active role than once believed, for example they are responsive to their environment, and show changes in calcium levels and can release chemicals “gliotransmitters” which activate or inhibit neurones. In other words we now know them to behave in ways that show them to be very active cells.
So astrocytes are complex cells..
Several pictures presented showed their true glorious shape to be less star-like but more bush-like with thousands of little branches (filopodia). The filopodia surround synapses and respond to neurones and communicate with neurones by releasing chemical transmitters. They are the brain and spinal cord’s muscle – storing reserves of energy as glycogen, and feeding neurones, particularly at times when they need the most energy.
After brain injury and during neurodegenerative diseases – including Motor Neurone Disease – astrocytes change shape, and the fine “skeleton” inside each cell (intermediate filaments containing GFAP, glial fibrillary acidic protein) becomes thicker. Generally this is thought to be a bad thing – reactive astrocytes have been considered to always lose their protective functions and contribute to neuronal damage. Several of the speakers critically examined aspects of this concept.
Mike Sofroniew’s main message was to explain that astrocyte reactivity can be regarded as a protective function in the brain, and has compared the process of reactivity to the scarring that occurs in skin following an injury such as a cut. He showed that reactive astrocytes can form scars that are a protective barrier to prevent the infiltration of inflammatory cells which are extremely damaging to neurones. Milos Pekny’s data echoed this view, he has created system where the ability of astrocytes to become reactive and form scars is abolished. In a model of Alzheimer’s Disease blocking reactivity in this way worsened features of the disease. Verkhrasky has looked at reactivity too, and showed that reactive astrocytes accumulate in the areas where neurones are most damaged in an Alzheimer’s model, perhaps forming a barrier which prevents the damage spreading. He also presented the very novel concept of “atrophic” astrocytes. In some disease models he sees these wizened astrocytes, and proposes that these impoverished cells are dysfunctional.
Two speakers provided information on astrocyte changes in other disease states, particularly in rare childhood diseases termed neuronal ceroid lipofuscinoses – that include Batten’s disease. Jon Cooper (London, UK) showed that astrocyte reactivity is a very early feature in animal models of the disease, the change occurs far before neurones become abnormal. Mark Sands (St Louis, USA) showed data suggesting that reduction of the ability of astrocytes to become reactive, worsened disease outcomes.
Astrocytes in MND differ to other neurodegenerative diseases
So the simple view that astrocyte reactivity is invariably bad in every neurodegenerative disease was thrown out of the window at this meeting. Everyone agrees that reactive astrocytes are a component of every neurodegenerative disease, but it was shown that astrocyte reactivity can provide some protective functions, and as well as reactivity we have atrophy.
Should this new insight make us abandon the way we think about astrocytes in Motor Neurone Disease? Not quite yet. There is strong evidence that astrocyte reactivity is associated with disease worsening in Motor Neurone Disease. Milos Pekny showed some data to further support this concept and Laura Ferraiuolo (Columbus, USA) provided some very exciting data – fresh from the lab – that astrocyte-like cells derived from patient samples (iNPC technology) convey toxicity to neurones. Therefore the role of astrocytes in Motor Neurone Disease progression seems to be different to their role in the progression of Alzheimer’s Disease.
What I came out of the meeting with:
I’m biased, because I work in this area already, but I have taken from the meeting the importance of further developing work on astrocytes in the context of Motor Neurone Disease. If we better understand the features of astrocytes as the disease progresses and those which contribute to neuronal damage, we can design strategies to block these toxic processes and to promote their beneficial functions. One of the best things about the meeting was the number of early-career scientists there with the enthusiasm to develop new work and contribute to this emerging field.
So the future is bright – like a star.
Marcus Rattray is Professor of Pharmacology and Head of Bradford School of Pharmacy at the University of Bradford. He is a member of the MND Association BRAP. Follow Marcus on Twitter @MarcusRattray