The role and potential therapeutic targets of astrocytes in central nervous system demyelinating diseases

Astrocytes play vital roles in the central nervous system, contributing significantly to both its normal functioning and pathological conditions. While their involvement in various diseases is increasingly recognized, their exact role in demyelinating lesions remains uncertain. Astrocytes have the potential to influence demyelination positively or negatively. They can produce and release inflammatory molecules that modulate the activation and movement of other immune cells. Moreover, they can aid in the clearance of myelin debris through phagocytosis and facilitate the recruitment and differentiation of oligodendrocyte precursor cells, thereby promoting axonal remyelination. However, excessive or prolonged astrocyte phagocytosis can exacerbate demyelination and lead to neurological impairments. This review provides an overview of the involvement of astrocytes in various demyelinating diseases, emphasizing the underlying mechanisms that contribute to demyelination. Additionally, we discuss the interactions between oligodendrocytes, oligodendrocyte precursor cells and astrocytes as therapeutic options to support myelin regeneration. Furthermore, we explore the role of astrocytes in repairing synaptic dysfunction, which is also a crucial pathological process in these disorders.


Role of astrocytes in demyelination in traumatic brain injury (TBI)
TBI is characterized by brain damage caused by external forces and is closely associated with demyelination, where the protective sheath around nerve fibers is lost (Table 1).The mechanisms behind this process are multifaceted.One of the key mechanisms is that physical trauma can cause direct breakage, crushing, or tearing of axons and myelin sheaths, causing myelin impairment (Shi et al., 2015).TBI can also expose neural antigens, originally hidden behind the BBB, to the immune system, such as myelin basic protein and neuron-specific enolase, which can induce autoimmune responses, causing autoimmune demyelination (Ying et al., 2018;Needham et al., 2021).Reduced blood flow to the brain caused by TBI can lead to vasospasm or thrombosis, thus causing ischemia and hypoxia of axons and myelin sheaths (Logsdon et al., 2015).The process can trigger a cascade of pathophysiological changes, such as energy metabolism disorders, intracellular calcium overload, and free radical production, resulting in myelin dysfunction or necrosis (Logsdon et al., 2015;Shi et al., 2015).
Additionally, TBI-induced oxidative stress can damage myelin.Astrocytes are involved in maintaining brain redox balance, but TBI may overwhelm antioxidant defense, resulting in demyelination.The hypoxiainducible factor-1α (HIF-1α) signaling pathway is implicated in TBI-related demyelination (Arias et al., 2023).Activated HIF-1α in astrocytes can influence energy metabolism and oxidative stress, affecting myelin integrity (Chen et al., 2020).Studies have suggested that the activation of HIF-1α in astrocytes promotes lactate production and release, while a reduction in fatty acid synthesis in oligodendrocytes leads to demyelination (Dimas et al., 2019;Afridi et al., 2020;Hou et al., 2023).
Conversely, astrocytes shield neurons and myelin by releasing neurotrophic factors like BDNF, NGF and IGF for neuronal survival and axonal growth.They secrete antioxidants like glutathione and superoxide dismutase, combatting oxidative stress and preventing neuronal and myelin damage (Wang et al., 2018;Chen et al., 2020;Zhu et al., 2022).Astrocytes also release anti-inflammatory factors (IL-10, TGF-β), cubing inflammation and promoting a conducive environment for neuronal and myelin repair (Burmeister and Marriott, 2018;Giovannoni and Quintana, 2020).Moreover, astrocytes facilitate extracellular matrix remodeling through secreting metalloproteinases (MMP) inhibitors, growth factors, and chondroitin sulfate proteoglycans (CSPGs) to provide a supportive environment for axonal growth (Cunningham et al., 2005;Lau et al., 2013;Hemati-Gourabi et al., 2022;Li L. et al., 2022).Astrocytes also provide trophic support to oligodendrocytes and OPCs, offering energy substrates and growth factors to enhance cell survival for effective axon myelination (Hibbits et al., 2012;Madadi et al., 2019;Tognatta et al., 2020).Overall, the intricate astrocyte-stroke-induced demyelination relationship underscores potential therapeutic avenues for neurological recovery.PD, characterized mainly by the loss of dopaminergic neurons in the substantia nigra and motor dysfunction, involves astrocytes in demyelination and neurodegenerative changes (Table 1) (Alcacer et al., 2017).One of the key mechanisms involves inflammation and reactive gliosis.Activated astrocytes release pro-inflammatory cytokines, contributing to neuroinflammation and the recruitment of immune cells like microglia, disrupting the integrity of myelin sheaths and exacerbating neuronal damage (Saijo et al., 2009;Qian et al., 2020;Zhang et al., 2022;Lawrence et al., 2023).During the immune dysregulation and the reactive gliosis environment in PD, the normal supportive functions to neurons and oligodendrocytes of astrocytes may be impaired, further contributing to the loss of myelin integrity (Haas et al., 2016;Troncoso-Escudero et al., 2018).
Astrocytes' involvement in iron and copper metabolism influences PD.They maintain brain iron balance, uptaking and storing excess iron in ferritin, releasing it as needed (Porras and Rouault, 2022).Astrocytes also transport iron to neurons, crucial in iron-demanding areas like the substantia nigra affected in PD (Booth et al., 2017;Reinert et al., 2019;Foley et al., 2022).Similarly, astrocytes are involved in copper metabolism.They regulate copper uptake, storage, and distribution (Dringen et al., 2013).Copper is a cofactor for various enzymes, including those involved in dopamine metabolism, which is particularly relevant to PD since dopamine plays a crucial role in the brain's movement control centers (Montes et al., 2014).Studies highlight iron/copper accumulation, oxidative stress, protein aggregation, mitochondrial dysfunction, and neuronal death interplay in PD pathology (Montes et al., 2014).Altered iron and copper metabolism may indirectly contribute to demyelination in PD.Their precise influence, along with astrocyte interactions, and demyelination in PD, necessitates further study.Specifics of astrocyte-driven PD demyelination within iron/copper metabolism remain unclear, requiring extensive exploration.

Role of astrocytes in demyelination in
Alzheimer's disease (AD) AD, a neurodegenerative disease marked by progressive memory loss and cognitive decline, impacts white matter alongside grey matter (Table 1).White matter loss and demyelination, indicative of its progression, stem from the malfunctioning of oligodendrocytes and myelin-forming glial cells (Chen et al., 2021).Demyelination in AD involves varied pathways.Firstly, the accumulation of amyloid beta (Aβ), a hallmark pathological marker of AD, can directly impact oligodendrocytes and myelin by binding to myelin, inducing oxidative stress, activating immune cells, and inhibiting OPCs differentiation (Chen et al., 2021;Han et al., 2022).Astrocytes-involved Aβ metabolism and clearance can also affect myelin stability and function (Chen et al., 2021).Secondly, oxidative stress in AD results from Aβ, tau protein, iron overload, and mitochondrial dysfunction, disrupting myelin structure and function through lipid oxidation, DNA damage, and inflammation (Nunomura et al., 2006;Wang et al., 2014;Simunkova et al., 2019;Llanos-González et al., 2020).Moreover, excitotoxicity, caused by overstimulation of neuronal N-methyl-Daspartic acid (NMDA) receptors, also contributes to demyelination in AD by increasing ROS production, activating calcium-dependent proteases, and inducing autophagy (Zhang et al., 2020;Chen et al., 2021).
In summary, astrocytes' involvement in AD-related demyelination spans Aβ metabolism, inflammation, energy metabolism, and altered morphology and function.Comprehending these mechanisms is crucial for developing targeted therapeutic strategies to preserve myelin integrity and alleviate neurodegeneration in AD.
On the other hand, astrocytes have the potential to inhibit OPC differentiation.As shown in Figure 1, for instance, the release of inflammation/immune factors (like TNF-, interferon-gamma, CXCL2 and CXCL10) can prevent OPC development (Nutma et al., 2020;Traiffort et al., 2020).Astrocyte-derived Endothelin-1 also impedes OPC differentiation and myelinating by Notch activation, binding to Notch-1 receptor on OPC via induction of Jagged-1 expression in reactive astrocytes (Hammond et al., 2014).Moreover, astrocytes may curb OPC proliferation by secreting CH3L1, which binds to the CRTH2 receptor, triggering lipid apoptosis (Li et al., 2018).Therefore, enhancing astrocytes' protective ability over OPCs by targeting these pathways could promote myelin regeneration.
In summary, astrocytes wield significant influence over OPCs, impacting signaling pathways crucial for OPC proliferation, differentiation, migration, positioning, and metabolism.Disruptions, especially amid reactive astrocytes and inflammation, can hinder remyelination and worsen demyelinating disorders.Grasping these complex signaling pathways is crucial for designing targeted therapies to promote remyelination and safeguard myelin integrity in demyelinating diseases.

Astrocyte-oligodendrocyte crosstalk: balancing myelination
The dynamic interplay between astrocytes and oligodendrocytes is pivotal for CNS health (Figure 1B).Astrocytes are crucial for regulating the maturation and remyelination through diverse mechanisms.Firstly, astrocytes boost oligodendrocyte proliferation and differentiation through growth factors, including FGF, IGF-1, and PDGF.These mitogens enhance oligodendrocyte survival and myelination (Kıray et al., 2016;Nutma et al., 2020).Secondly, neurotrophic factors (like BDNF, GDNF, CNTF) released by astrocytes, further bolster oligodendrocyte function and remyelination post-demyelination (Miyamoto et al., 2015;Nutma et al., 2020).Thirdly, astrocytes are key regulators of the extracellular environment, vital for ion and water balance crucial to oligodendrocyte health.Disruption here can lead to osmotic stress and impaired oligodendrocyte function (Sofroniew and Vinters, 2010).
Oligodendrocytes reciprocate by influencing astrocytes' calcium signaling and metabolism through ATP, adenosine, and glutamate release (Cakir et al., 2007;Takano et al., 2020).Specific molecules, such as N-cadherin, facilitate their interaction, crucial for nervous system development, myelin restoration, and cognitive functions (Linnerbauer et al., 2020;Chen et al., 2023).Boosting astrocyte protection of oligodendrocytes along these pathways emerges as a promising therapeutic avenue for myelin regeneration.
These mechanisms showcase astrocytes' indispensable role in sustaining synaptic health, fostering plasticity, and promoting neural recovery.Targeting astrocyte-mediated pathways holds the potential for addressing synaptic-related disorders and advancing neurological treatments.A comprehensive understanding of astrocyte contributions promises groundbreaking insights into brain dynamics and innovative approaches to synaptic dysregulation.

Conclusion and outlook
In conclusion, astrocytes play a multifaceted role in demyelinating diseases, either promoting remyelination or exacerbating myelin disruption through inflammatory responses.Emerging therapeutic strategies target reactive astrocytes in various CNS disorders.Notably, bumetanide and VEGF inhibitors show promise for traumatic brain injury (TBI) (Michinaga and Koyama, 2021), while monoamine oxidase B (MAO-B) inhibitors and A2A receptor antagonists hold potential for AD (Sanmarco et al., 2021;Nam et al., 2023).Innovative approaches, including spinal cord injury treatment with synthetic nanoparticles, highlight astrocyte-focused interventions (Wang et al., 2008;Nance et al., 2015;Zhang et al., 2016).
Advanced technologies, such as transgenic techniques, in vivo imaging, optogenetics, chemogenetics, in situ sequencing, and single-cell RNA sequencing (scRNA-seq), have unveiled specific astrocytic molecules influencing various diseases.These molecules offer therapeutic targets for neurological and neuropsychiatric disorders.However, crucial challenges persist.Establishing correlations between transcriptionally defined astrocyte subpopulations and real-time neuronal activity, behavior, and disease characteristics remains pivotal.Understanding unique and shared roles of astrocytes across diseases, their distribution in the CNS, and common pathogenic mechanisms is essential.Addressing these questions is critical for harnessing astrocyte-mediated pathways for targeted therapies.
The intricate role of astrocytes and their interactions in health and disease underscores their potential as viable therapeutic targets for a broad spectrum of neurological and neuropsychiatric disorders.Future research should focus on unraveling astrocyte-specific mechanisms, clarifying their contributions to disease progression, and developing precise interventions to preserve myelin integrity and restore CNS function.By unlocking the full potential of astrocytetargeted strategies, we pave the way for innovative treatments and transformative insights into the complex landscape of demyelinating diseases.

TABLE 1
The etiology of demyelination in various CNS disorders and the involvement of astrocytes in these processes.