Astrocytes are the most numerous glia cells in the central nervous system (CNS). They help to maintain the health and function of the CNS, by providing metabolic support to neurons, clearing neurotransmitters from synapses, supporting blood-brain barrier endothelial cells, regulating extracellular ion concentrations, forming and maturating synapses, and modulating synaptic plasticity. Astrocytes have also been implicated in neurodegenerative diseases. CNS injury and disease induce astrocytes to undergo reactive astrogliosis, which involves both biochemical and structural changes to astrocytes. Previous studies from the lab of Dr. Ben Barres at Stanford University School of Medicine characterized two different types of reactive astrocytes they termed A1 and A2. A1 astrocytes, which are induced by injury, neuroinflammation, and neurodegenerative disease, produce proinflammatory molecules. On the other hand, A2 astrocytes secrete molecules that provide neurotrophic support and modulate inflammatory responses. This astrocyte phenotype is present following ischemia and has been shown to promote neuronal survival and tissue repair.
In a recent Nature paper, Barres’ research group has provided more insight into the induction and function of A1 astrocytes. The authors found that IL-1 alpha, TNF, and the Complement Component 1, Subcomponent q (C1q) produced by activated microglia work together to induce the A1 phenotype. They also showed that induction of A1 astrocytes can be prevented in vivo following exposure to bacterial lipopolysaccharide when all three of these cytokines are absent. Blocking this cytokine stimulation, though, did not revert already formed A1 astrocytes back to their nonreactive state. However, treating cultured A1 astrocytes with the anti-inflammatory molecules TGF-beta and FGF did return the cells to their nonreactive phenotype.
Dr. Barres and his colleagues also reported that A1 astrocytes lose many typical astrocytic functions. They showed that A1 astrocytes no longer promote neuronal survival, outgrowth, and synapse formation, or phagocytize synapses or debris. The authors did provide evidence that A1 astrocytes secrete a compound that is toxic to neural cells. Incubating cultured retinal ganglion cells (RGC), dopaminergic neurons, cortical neurons, embryonic spinal motor neurons, and mature oligodendrocytes with conditioned medium from A1 astrocytes induced cell death is these neural cell types. Additionally, they showed that A1 astrocytes are responsible for RGC death in vivo following axotomy, and that blocking IL-1 alpha, TNF, and C1q at the time of injury inhibited A1 formation and prevented RGC cell death.
The authors hypothesize that A1 astrocytes play a role in neurodegenerative disease. To start investigating this suggestion, they identified A1 astrocytes in post-mortem tissue from individuals with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington’s disease. To continue with this research, the authors are interested in identifying the toxic compound secreted by A1 astrocytes, and determining if A1 astrocytes promote neural cell death in neurodegenerative diseases.
Read the full article at Nature.