The Contribution of Reactive Astrocytes to Neurodegeneration
Neurodegenerative diseases have a strong inflammatory component, the dysregulation of the immune system in the brain, with consequences to tissue function. In the process of astrogliosis, the supporting cells known as astrocytes react to damaging or inflammatory circumstances, and radically change their behavior. This can help in the short term for some forms of injury to the central nervous system, but is harmful when it continues for the long term. Like microglia, another supporting cell type, astrocytes can adopt different packages of behaviors, or phenotypes, and switch back and forth between them in response to circumstances. The primary distinction of interest in these is between (a) a supportive, regenerative phenotype, and (b) an aggressive, inflammatory phenotype. The latter tends to show up ever more often as aging progresses, and this imbalance is the cause of further harms.
Astrocytes are the most abundant cells with various structures and functions and are ubiquitous in all regions of the central nervous system (CNS). Astrocytes are associated with various aspects of physiological functions, including secretion of nutrients, maintenance of neuronal microenvironment, regulation of the permeability of the blood-brain barrier and the development of pathological processes in the brain. Studies on mouse models have shown that astrocytes play a complex role in the pathogenesis of neurodegenerative diseases, and the dysfunction of astrocytes may contribute to either neuronal death or the process of neural disturbances. It has been found that reactive astrocytes always lose their supportive role and gain toxic function in the progression of neurodegenerative diseases.
During brain insult or neurodegeneration process, astrocytes can respond to pathological changes by releasing extracellular molecules, such as neurotrophic factors (for example BDNF, VEGF, and bFGF), inflammatory factors (including IL-1β, TNF-α, and NO, etc.) and cytotoxins (such as Lcn2) through reactive astrogliosis. As a result, they play either a neuroprotective or neurotoxic role (such as provoking inflammation or increasing damages) in the CNS. It has been shown that the specific deletion of STAT3 in astrocytes can cause reactive gliosis, which leads to increased level of inflammation, tissue damage as well as compromised motor recovery after spinal cord injury. Interestingly, some studies have shown that the activation of NF-κB in astrocytes contributes to the pathogenesis of CNS, and inhibition of this signaling pathway can limit tissue damage.
These findings suggest that astrocytes may play a protective role through STAT3 signaling pathways in some neurodegenerative lesions, while NF-κB signals may mediate neurotoxicity. In analogy to the "M1" and "M2" phenotype categories for macrophages, recent studies have reported that neural inflammation and ischemia can induce two types of reactive astrocytes, termed "A1" and "A2", respectively. Gene transcriptome analysis of reactive astrocytes shows that A1 reactive astrocytes (A1s) can upregulate many classical complement cascade genes that are destructive to synapses, and secret neurotoxins that have not yet been well identified. In contrast, A2 reactive astrocytes (A2s) can upregulate many neurotrophic factors, which can promote either the survival and growth of neurons or the synaptic repair. Thus, A1s may have "harmful" features, while A2s may carry "useful" or repair functions. So far, it remains unclear what the possible signaling pathways have been involved in inducing the phenotypes of A1s and A2s in the process of different initiating CNS injuries.