Kunyu Li1, Jiatong Li1, Jialin Zheng2, Song Qin1,*
1Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. 2Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People’s Hospital affiliated to Tongji University School of Medicine, Shanghai, China.
Astrocytes, the largest and most numerous glial cells in the central nervous system (CNS), play a variety of important roles in regulating homeostasis, increasing synaptic plasticity and providing neuroprotection, thus helping to maintain normal brain function. At the same time, astrocytes can participate in the inflammatory response and play a key role in the progression of neurodegenerative diseases. Reactive astrocytes are strongly induced by numerous pathological conditions in the CNS. Astrocyte reactivity is initially characterized by hypertrophy of soma and processes, triggered by different molecules. Recent studies have demonstrated that neuroinflammation and ischemia can elicit two different types of reactive astrocytes, termed A1s and A2s. However, in the case of astrocyte reactivity in different neurodegenerative diseases, the recently published research issues remain a high level of conflict and controversy. So far, we still know very little about whether and how the function or reactivity of astrocytes changes in the progression of different neurodegenerative diseases. In this review, we aimed to briefly discuss recent studies highlighting the complex contribution of astrocytes in the process of various neurodegenerative diseases, which may provide us with new prospects for the development of an excellent therapeutic target for neurodegenerative diseases.
Figure 1. Astrocytes play a critical role in supporting neurons in the CNS
Astrocytes support neuronal functions in multiple ways. Indeed, the extracellular levels of ions and neurotransmitters can affect the excitability of neurons. (1) High concentrations of extracellular potassium can trigger the glycolysis of astrocytes, which can enhance the release of lactate and pyruvate, thereby supporting neuronal metabolism. (2) Astrocytes can take up glutamate and convert it to glutamine, which is then released into the extracellular space and taken up by neurons to resynthesize glutamate. Any deregulation of these mechanisms is a common condition for neurodegenerative diseases. (3) Under the circumstances of brain injury, disease or inflammatory insult, toxic proinflammatory mediators are secreted and released by astrocytes, which will act on neurons and may affect the survival of neurons.
Inflammatory signaling through NF-κB
Glutamate and ATP release
Inflammatory mediators secretion (prostaglandinD2, IFN-γ, and TGF-β)
Table 1 The molecular expression changes between two different types of reactive astrocytes.
Figure 2. Roles of reactive astrocytes in the process of neuroinflammation or brain injury
Neuroinflammation mainly induces the formation of A1 reactive astrocytes (A1s), which exhibit differential expression of astrocytic receptors, transporters, transmitters, as well as the changes of protein release and inflammatory factors. These changes may result in loss of neuroprotective function or neurological toxicity, a collapse of the brain-blood barrier and an increase in inflammation of the brain, which eventually results in deaths of neurons and causes neurodegenerative diseases. While A1s can upregulate many genes that are destructive to synapses, A2 reactive astrocytes (A2s) can upregulate many neurotrophic factors promoting the survival of neurons.
Figure 3. Characteristics of reactive astrocytes in different neurodegenerative diseases
Various molecules can trigger the reactivity of astrocytes, which involves their morphological, transcriptional and functional changes. Different neurodegenerative diseases lead to a variety of changes in reactive astrocytes, which may ultimately cause them to release fewer neurotrophic factors and produce more inflammatory factors. This effect largely depends on different neurodegeneration-related factors, and the molecules they produce and secrete into the microenvironment surrounding the functional neurons in the brain. Aβ, amyloid β; SOD, superoxide dismutase-1; TDP-43, TAR DNA-binding protein 43; CN/NFAT, Calcineurin/Nuclear factor of activated T-cells; NOS, Nitric Oxide Synthase; JAK, Janus Kinase; ROS, reactive oxygen species; TGM6, Transglutaminase 6
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