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A literature review evaluated recent findings regarding changes in signaling modalities and interactions of astrocytes in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). Astrocytes, the most abundant CNS glial cells, are critical for CNS health and function and have, therefore, gained attention for investigation in MS. 

A new study published in Current Opinion in Cell Biology reviewed the literature from the past 10 years to investigate the changes in astrocyte signaling and interactions in MS.

Impact of Astrocytic Dysfunction in Multiple Sclerosis

Astrocytes support oligodendrocytes by providing crucial lipids like cholesterol that are necessary for maintaining myelin integrity, a function that is disrupted in MS. In a mouse model of MS, researchers noted a decrease in astrocytic gene expression related to cholesterol biosynthesis during demyelination peaks in specific regions, including the spinal cord, cerebellum, and optic nerve. Studies on postmortem MS brain tissues revealed reduced cholesterol synthesis as well as loss of astrocytic homeostatic functions that regulate glutamate and potassium transport, potentially leading to neuronal death.

Neuroinflammatory Roles of Astrocytes in Multiple Sclerosis

Additionally, astrocytes in MS gain neuroinflammatory functions, secreting molecules that exacerbate inflammation and affect interactions with oligodendrocytes, microglia, and neurons. Various neuroinflammatory gene expression changes were observed in these astrocytes in MS, including upregulation of GFAP, APOE, VIM, S100B, SOD1, Complement 3, mammalian target of rapamycin (mTOR), X-box binding protein 1 (XBP1), as well as downregulation of nuclear factor erythroid 2-related factor 2 (NRF2) and activation of the inflammasome absent in melanoma-2 (AIM2). 

Targeting these pathways showed promise by mitigating MS symptoms in animal models. Findings suggest that therapeutic targeting of certain astrocyte subtypes could limit MS progression, highlighting the need for further research. It is unclear whether the function of astrocytes in establishing and maintaining neuronal circuits is altered in MS, and this needs further investigation for potential therapeutic targeting.

Impairment of Astrocyte–Oligodendrocyte Communication Noted in Multiple Sclerosis

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Oligodendrocyte survival, maturation, and myelination are dependent on astrocyte-secreted factors and astrocytic gap junction coupling through connexins. Expression of connexins is substantially altered in MS. Astrocytes secrete glial-cell-derived neurotrophic factor (GDNF) for oligodendrocyte proliferation. However, reduced GDNF secretion by astrocytes in MS mice hampers myelin repair. 

Loss of cholesterol secretion by astrocytes could contribute to demyelination along with impairment of myelin repair. Studies link impaired cholesterol synthesis with compromised remyelination. Research shows compensation by neurons and microglia in cholesterol synthesis to aid remyelination and oligodendrogenesis after demyelination. However, the efficiency of remyelination diminishes over time in MS, along with sustained astrocyte reactivity, indicating continuous maladaptive astrocyte–oligodendrocyte communication.

Maladaptive Astrocyte–Microglia Signaling Leads to Neuroinflammation and Synapse Loss

Signaling between astrocytes and microglia is essential for neuronal homeostasis and is altered in MS. In MS, microglia signal to astrocytes through axon-guidance cues or pro-inflammatory cytokines, triggering inflammatory neurotoxic responses in astrocytes that aggravate the disease, such as increased complement 3 expression. Complement activation triggers aberrant synapse pruning and synapse loss in MS. However, some microglial-secreted signals, like amphiregulin, can protect against demyelination, offering potential therapeutic avenues.

Source:

Ortiz, C. C., & Eroğlu, Ç. (2024). Astrocyte signaling and interactions in Multiple Sclerosis. Current Opinion in Cell Biology, 86, 102307. https://doi.org/10.1016/j.ceb.2023.102307