Function and therapeutic value of astrocytes in neurological diseases

Abstract

Astrocytes are abundant glial cells in the central nervous system (CNS) that perform diverse functions in health and disease. Astrocyte dysfunction is found in numerous diseases, including multiple sclerosis, Alzheimer disease, Parkinson disease, Huntington disease and neuropsychiatric disorders. Astrocytes regulate glutamate and ion homeostasis, cholesterol and sphingolipid metabolism and respond to environmental factors, all of which have been implicated in neurological diseases. Astrocytes also exhibit significant heterogeneity, driven by developmental programmes and stimulus-specific cellular responses controlled by CNS location, cell-cell interactions and other mechanisms. In this Review, we highlight general mechanisms of astrocyte regulation and their potential as therapeutic targets, including drugs that alter astrocyte metabolism, and therapies that target transporters and receptors on astrocytes. Emerging ideas, such as engineered probiotics and glia-to-neuron conversion therapies, are also discussed. We further propose a concise nomenclature for astrocyte subsets that we use to highlight the roles of astrocytes and specific subsets in neurological diseases.

Fig. 1 |. Astrocyte roles in CNS inflammation.

Astrocytes are active players in central nervous system (CNS) inflammation, where they have both pro-inflammatory and anti-inflammatory activities. As a result of their interactions with other cells and molecules in the CNS, astrocytes secrete various cytokines, chemokines and neuromodulatory molecules. AHR, aryl hydrocarbon receptor; CCL2, C-C motif chemokine 2; cPLA2, cytosolic phospholipase A2; CXCL10, C-X-C motif chemokine ligand 10; DR5, death receptor 5; EGFR, epidermal growth factor receptor; EPHB3, ephrin type B receptor 3; EPHNB3, ephrinB3; GM-CSF, granulocyte–macrophage colony-stimulating factor; IFNγ, interferon-γ; LacCer, lactosylceramide; LAMP1, lysosome-associated membrane glycoprotein 1; MAFG, MAF bZIP transcription factor; MAVS, mitochondrial antiviral signalling protein; NF-κB, nuclear factor-κB; NK, natural killer; NOS2, nitric oxide synthase 2; PLXNB, plexin B; SEMA4D, semaphorin4D; S1P, sphingosine 1-phosphate receptor; SIGMAR1, sigma receptor 1; TGF, transforming growth factor; TNF, tumour necrosis factor; Tr1, type 1 regulatory T cell; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor; XBP1, X-box binding protein 1.

Fig. 2 |. Targeting astrocyte signalling in Alzheimer disease.

a | The accumulation of amyloid-β (Aβ) in the brain modulates glutamate uptake in astrocytes by inhibiting the glutamate transporter excitatory amino acid transporter 2 (EAAT2). This causes excessive activation of neuronally expressed glutamate receptors, which increases intracellular Ca²⁺ and promotes neuronal dysfunction. b | Enhanced intracellular Ca²⁺ waves in astrocytes increase the release of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. Aβ plaques and putrescine trigger monoamine oxidase B (MAOB)-mediated GABA release via the Ca²⁺-activated anion channel bestrophin 1 (BEST1). Increased GABA uptake by neurons impairs memory and synaptic plasticity. c | Astrocytes are the main producers of apolipoprotein E (APOE), which modulates blood–brain barrier (BBB) permeability. APOE4 secretion induces cyclophilin A (CYPA)–nuclear factor-κB (NF-κB)–metalloproteinase 9 (MMP9) signalling in pericytes, which leads to BBB breakdown via the lipoprotein receptor-related protein 1 (LRP1). This APOE4-mediated pericyte activation can be negatively regulated by the production of APOE3. Strategies to rescue neuronal dysfunction mediated by glutamate dysregulation and synaptic plasticity include controlling astrocyte glutamate uptake, Ca²⁺ homeostasis and GABA production. AMPAR, AMPA receptor; NMDAR, N-methyl-d-aspartate receptor; VGLUT, vesicular glutamate transporter.

Fig. 3 |. Targeting astrocyte signalling in Huntington disease.

a | Selective activation of G_i–G protein-coupled receptor (GPCR) signalling pathway can recover astrocyte functional impairments and correct synaptic dysfunction. b | Mutant huntingtin protein (mHTT) inclusions in astrocytes impair the expression of excitatory amino acid transporter 2 (EAAT2) and K⁺ ion channel K_ir4.1. Reduced glutamate transporter levels lead to robust mGlu_2/3-mediated Ca²⁺ signalling. This gain of evoked astrocyte Ca²⁺ signals is followed by the loss of spontaneous Ca²⁺ signalling. The elevation of extracellular K⁺ and glutamate levels leads to neuronal hyperexcitability and the development of neurodegeneration. c | Low glucose levels in the striatum of individuals with Huntington disease (HD) triggers metabolic reprogramming in astrocytes, which switch from using glucose to fatty acids. Fatty acid oxidation (FAO) sustains energy production but also elevates levels of reactive oxygen species (ROS), which induce damage. In HD, synaptic plasticity, Ca²⁺ signalling and GPCR signalling is impaired in striatal astrocytes. Strategies to rescue neurodegeneration in HD include targeting astrocyte glutamate uptake, metabolism and GPCR signalling. AMPAR, AMPA receptor; NMDAR, N-methyl-d-aspartate receptor; mGluR2/3, metabotropic glutamate receptor 2/3; DREADD, designer receptor exclusively activated by designer drugs.