Beyond the GFAP-Astrocyte Protein Markers in the Brain
Abstract
:1. Introduction
Astrocyte Functions in the Brain
2. General Astrocyte Markers
2.1. Structural Proteins
2.2. Transcription Factors
2.3. Membrane Proteins
2.4. Astrocyte Metabolic Markers
3. How Astrocytes Communicate with Other Cell Types
4. Astroglia Activation
4.1. What Activates Astrocytes, and What about A1/A2 Polarization?
4.2. Activated Astrocytes Markers
4.3. Structural and Membrane Proteins
4.4. Secreted Proteins
4.5. Intracellular Proteins
5. Heterogeneity of Astrocytes
6. Astroglial Markers in the Aging Brain
7. Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Specific Astrocytic Function | Marker Protein |
---|---|
Glucose uptake | GLUT1 |
Gluconeogenesis | G6PC, FBP, PC |
Glycogen synthesis and use | GS, GP |
Glycolytic metabolism | PFKFB3, PFK, PKM2, PC, PDK4 |
Lactate shuttle | LDH5, MCT4 |
Ketone body synthesis | HMGCS2 |
Fatty acid oxidation and transport | CPT1a, CPT2, FABP7 |
ECI1, ECI2, ABHD5, GK, GPAT3, IDI1 | |
Cholesterol synthesis | SCAP, HMGCR, LXR/RXR, APOE, ABCA7 |
Catabolism of glycogenic amino acids | GLDC, GPT2, HIBADH, SERHL, SDSL, PRODH, 3PGDH |
Glutamate–glutamine shuttle | GLUL, SNAT3, SNAT5 |
Excitatory amino-acid transporters | EAAT1, EAAT2 |
Water transport | AQP4 |
Protein Marker | Full Name | Information |
---|---|---|
Structural and Membrane Proteins | ||
AQP4 | aquaporin 4 | water homeostasis throughout the brain; localized in endfeet plasma membrane; highly expressed on Bergmann glia; not present at oligodendrocytes |
BEST1 | bestrophin 1 | calcium-dependent transport of chloride ions, permeable for GABA and glutamate; mainly expressed in astrocytes; in mice distributed closer to the glutamatergic synapses than GABAergic synapses |
CNN1 | calponin-1 | actin-related processes; enriched in astrocytes |
Cx26 | connexin 26 | forms gap junction channels in glial network to maintain homeostasis of the CNS |
Cx30 | connexin 30 | critical regulator of synaptic strength, controls location of astroglial processes and modulates glutamate transport; expressed only in mature astrocytes, mostly gray matter |
Cx43 | connexin 43 | key player in brain development; abundantly expressed in adult CNS astrocyte endfeet |
EAAT1 (GLAST) | excitatory amino acid transporter 1, glutamate aspartate transporter | glutamate uptake, co-compartmentalizes with mitochondria, supplying glutamate as a fuel for the brain; abundant in fine astrocyte processes, but also variably expressed by all cell types in the CNS |
EAAT2 (GLT1) | excitatory amino acid transporter 2; glutamate transporter-1 | glutamate uptake, co-compartmentalizes with mitochondria, supplying glutamate as a fuel for the brain; abundant in fine astrocyte processes, but also variably expressed by all cell types in the CNS |
ezrin | ezrin | protein anchoring the plasma membrane to cytoskeletal microfilaments; acts as stabilizer of filopodia (peripheral astrocyte processes) |
FMN2 | formin-2 | actin-related processes; enriched in astrocytes |
GAT-1 | sodium- and chloride-dependent GABA transporter 1 | GABA transporter; localized in distal astrocytic processes but in majority is expressed in neurons |
GAT-3 | sodium- and chloride-dependent GABA transporter 3 | GABA transporter; localized mostly in processes adjacent to neuronal synapses; most numerous subtype in astrocytes |
GFAP | glial fibrillary acidic protein | contributes to astroglial BBB mechanical support; expressed mainly by white matter astrocyte extensive branching and slightly their cell body; useful marker for studying complex astroglial morphology |
KIR4. 1 | potassium inwardly-rectifying channels | controls cell hyperpolarization during resting potential, uptake of K+ from the synaptic cleft or its redistribution; in the normal adult CNS, KIR4.1 levels vary significantly in gray matter astroglia, downregulated in pathological conditions |
NEBL | LIM zinc-binding domain-containing Nebulette | actin-related processes; enriched in astrocytes |
nestin | nestin | marker of stem or progenitor cells |
PDLIM7 | PDZ and LIM domain protein 7 | actin-related processes; enriched in astrocytes |
radixin | radixin | connect the plasma membrane with cytoskeletal microfilaments; act as stabilizer of filopodia (peripheral astrocyte processes) |
RSPH1 | radial spoke head 1 homolog | actin-related processes; astrocyte specific |
synemin | synemin | intermediate filament; co-expressed by immature astrocytes along with GFAP, vimentin and nestin |
SYNPO2 | synaptopodin-2 | actin-related processes; enriched in astrocytes |
transitin | transitin | intermediate filament; expressed by radial glia during CNS development |
vimentin | vimentin | role in differentiation and maturation of astrocytes; mostly expressed in some specialized glial cells such as Bergmann and radial glia or ependymal cells, white matter astrocytes |
Transcription Factors and Intracellular Proteins | ||
NF1A | nuclear factor 1 | maintains hippocampal astrocyte synapse-supporting functions; marker of glial lineages, including oligodendrocytes and astrocytes |
NF1B | nuclear factor 2 | expressed in the adult brain olfactory bulb, hippocampus, cortex, and brainstem where they co-localize with ALDH1L1, also observed in neurons |
NF1X | nuclear factor 3 | expressed in the adult brain olfactory bulb, hippocampus, cortex, and brainstem where they co-localize with ALDH1L1, also observed in neurons |
NKX2-1 | NK homeobox gene-coded protein | regulates GFAP expression; controls astroglia production spatiotemporally in embryos |
NKX3-1 | NK homeobox gene-coded protein | astrocytic region-specific transcription factor; exclusively expressed in astrocytes in olfactory bulb |
NKX6-1 | NK homeobox gene-coded protein | astrocytic region-specific transcription factor; exclusively expressed in astrocytes in brainstem |
SOX9 | SRY-related high mobility group (HMG) box gene 9 | nuclear marker; expressed almost exclusively in astrocytes; good astroglia marker in adult brain, outside the neurogenic zones, upregulated in reactive astrocytes |
S100β | S100 calcium-binding protein β | cytosolic Ca++-binding protein, also secreted; labels cell bodies of small astrocytes with less extended branchinga, also expressed in neonatal oligodendrocytes, adult NG2 glia, ependymocytes and spinal, medullar, pontine and cerebellar neurons |
Metabolic Markers | ||
Glucose Related | ||
ALDH1L1 | folate enzyme aldehyde dehydrogenase 1 family member L1 | converting NADP to NADPH; not homogenous expression, expressed in fibrous and protoplasmic astrocytes, and radial glia |
FBP | fructose 1,6-bisphosphate | gluconeogenesis; production of glucose during starvation, astrocyte specific |
G6PC | glucose 6-phosphatase | gluconeogenesis; production of glucose during starvation, astrocyte specific |
GLUT1 | glucose transporter | glucose transport; less glycosylated isoform (45 kDa) found in astrocytes, more heavily glycolsylated isoform (55 kDa) is predominant in microvascular endothelium |
GP | glycogen phosphorylase | glycogen utilization; astroglia-specific enzyme, degrades glycogen deposits in astroglia |
GS | glycogen synthase | glycogen synthesis; selective to astrocytes, glycogen storage |
LDH5 | lactate dehydrogenase | conversion of pyruvate to lactate; bidirectional enzyme biased towards the production of lactate, twofold enriched in astrocytes |
MCT1 | monocarboxylate transporter 1 | responsible for pyruvate, lactate and ketone bodies transfer; expressed in astrocytes and oligodendrocytes lower affinity for lactate than the neuronal MCT2, expression is age-dependent |
MCT4 | monocarboxylate transporter 4 | responsible for pyruvate, lactate and ketone bodies transfer; expressed only in astrocytes, much lower affinity for lactate than the neuronal MCT2, low affinity for ketone bodies |
PC | pyruvate carboxylase | converts pyruvate into oxaloacetate in glycolysis; glial-specific anaplerotic enzyme, providing oxaloacetate for the TCA cycle |
PDK4 | pyruvate dehydrogenase kinase 4 | phosphorylation-mediated inactivation of PDH; 30 times higher expression in astrocytes than in neurons; expressed also by microglial cells |
PFKFB3 | 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 | converts fructose-6-phosphate to fructose-2,6-bisphosphate, regulates glycolysis and gluconeogenesis; enriched in astrocytes, a magnitude lower expression in neurons due to continuous degradation |
PFK | phospho-fructokinase | higher expressed in astrocytes than in neurons |
PKM2 | pyruvate kinase muscle isoform-2 | converts phosphoenolpyruvate to pyruvate, regulates glycolysis; enriched in astrocytes, expressed also by other glial cells |
FAO Related | ||
ABCA7 | ATP-binding cassette transporter 7 | cholesterol transporter |
ABHD5 | 1-acylglycerol-3-phosphate O-acyltransferase 5 | membrane lipid metabolism and dynamics |
APOE | apolipoprotein E | forms lipoprotein complex with cholesterol and is secreted through the ABCAs; expressed mainly in astrocytes but also found in microglia, found in neurons under pathological conditions |
CTP1a | carnitine palmitoyltransferase 1a | citrate transporter protein, essential step for the mitochondrial uptake of long-chain fatty acids and beta-oxidation in mitochondrion; selective to astrocytes in outer membrane of mitochondrion, rate-limiting step of beta-oxidation |
CTP2 | carnitine palmitoyltransferase 2 | citrate transporter protein, essential step for the mitochondrial uptake of long-chain fatty acids and beta-oxidation in mitochondrion; localized in mitochondrion inner membrane |
DIO2 | type 2-deiodinase | removes iodide from L-thyroxine to produce 3, 3′5-triiodothyronine; thyroid hormone metabolism |
ECL1 | enoyl-CoA delta isomerase 1 | oxidation of unsaturated fatty acids |
ECL2 | enoyl-CoA delta isomerase 2 | oxidation of unsaturated fatty acids |
FABP7 | fatty acid-binding protein 7 | high affinity reversible binding of saturated and unsaturated long-chain fatty acids; expression in neural stem cells throughout development, in adulthood decreases and becomes restricted to radial glia-like cells and astrocytes, abundant in astrocytes rich in cytoplasmic granules |
GC-2 | mitochondrial glutamate carrier 2 | glutamate transport to the mitochondria; predominantly expressed in protoplasmic astrocyte cells but also in oligodendrocyte progenitor cells |
GDH | glutamate dehydrogenase | oxidative deamination of glutamate to alpha-ketoglutarate |
GK | glycerol kinase | membrane lipid metabolism and dynamics |
GLDC | glycine decarboxylase | catabolism of glycogenic amino acids |
GLP-1R | glucagon-like peptide-1 receptor | modulator of food intake and body weight |
GLUL | glutamine synthetase | converts glutamate to glutamine; selectively expressed by astrocytes |
GPAT3 | glycerol-3-phosphate acyltransferase | membrane lipid metabolism and dynamics |
GPT2 | alanine aminotransferase 2 | catabolism of glycogenic amino acids |
HADHA | hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase alpha | critical for the FAO regulation by T3; 95% of HADHA co-localize with GFAP in the brain |
HIBADH | 3-hydroxyisobutyrate dehydrogenase | catabolism of glycogenic amino acids |
HMGCR | 3-hydroxy-3-methylglutaryl-coenzyme A reductase | catalyzes the rate-limiting step in cholesterol synthesis |
HMGCS2 | 3-hydroxy-3-methylglutaryl-CoA synthase 2 | converts acetyl-CoA to acetoacetate; rate-limiting enzyme in ketone bodies production, astrocyte specific |
IDI1 | isopentenyl-diphosphate delta-isomerase 1 | membrane lipid metabolism and dynamics |
LXR/RXR | liver X receptor/retinoid X receptor | activates production of cholesterol and mediates transcription of its transport proteins APOE and ABCA7 |
PRODH | proline dehedrogenase 1 | catabolism of glycogenic amino acids |
SCAP | SREBP cleavage-activating protein | mediates cholesterol synthesis; expressed in astrocytes and oligodendrocytes |
SDSL | serine dehydratase-like | catabolism of glycogenic amino acids |
SERHL | serine hydrolase-like | catabolism of glycogenic amino acids |
SLCO1C1 | solute carrier organic anion transporter family member 1C1 transporter | transports L-thyroxine from the blood; thyroid hormone metabolism |
SNAT3 | sodium-coupled neutral amino acid transporter 3 | glutamine transporter; suited for glutamine release |
SNAT5 | sodium-coupled neutral amino acid transporter 5 | glutamine transporter; suited for glutamine release |
Protein Marker | Full Name | Information |
---|---|---|
Structural and Membrane Proteins | ||
CD109 | cluster of differentiation receptor 109 | upregulated in pro-inflammatory astroglial activation, specific for astrocytes, low expression after LPS, high after MCAO |
CD14 | cluster of differentiation receptor 14 | upregulated in pro-inflammatory astroglial activation |
CD36 | cluster of differentiation receptor 36 | fatty acid transporter; upregulated in reactive astrocytes |
CD44 | cluster of differentiation receptor 44 | surface receptor for hyaluronan; responsible for astroglia morphological changes; detected on long, unbranched human astrocytes |
Cx30 | connexin 30 | transmembrane protein; strongly engaged in inflammatory activation of astrocytes |
Cx43 | connexin 43 | transmembrane protein channel; engaged in inflammatory reactive astrogliosis |
EMP1 | epithelial membrane protein | small membrane glycoprotein; regulates cellular proliferation |
FABP7/BLBP | fatty acid-binding protein/brain lipid-binding protein | expressed in Bergmann and radial glia, and also by injured astrocytes |
GFAP | glial fibrillary acidic protein | cytoskeleton-building protein; strong increase in expression observed in most pathological conditions including neurodegeneration and injuries; variability in its basal levels between structures |
nestin | nestin | intermediate filament; expression increases after astrocyte activation by MCAO or stroke but not LPS |
S1P3 | sphingosine-1 phosphate receptor 3 | cell-membrane protein; overexpressed by astrocytes in neuroinflammation, confirmed in rodents and humans; ability to modulate BBB permeability, activated by MCAO |
STEAP4 | six transmembrane epithelial antigen of prostate 4 | membrane protein reducing Fe3+ and Cu++ ions; upregulated in inflammation, although not exclusive for astroglia |
synemin | synemin | intermediate filament; expression increases after astrocyte activation |
TGM1 | transglutaminase 1 | membrane-bound enzyme; creates mechanical barrier against infectious agents, specific for astrocytes, low expression after LPS, high after MCAO |
vimentin | vimentin | intermediate filament; expression increases after astrocyte activation, both after MCAO and LPS |
Secreted Proteins | ||
C3 | complement component 3 | upregulated in course of neurodegenerative diseases, also expressed by microglia |
CFB | complement factor B | element of alternate complement pathway activation modulating proliferation and degradation of blood cellular components during inflammation |
CXCL10 | C-X-C motif chemokine 10 | pro-inflammatory protein; mediates an inflammatory response between neurons and glia |
LCN2 | lipocalin 2 | secreted protein-binding iron ions; participates in innate immunity and apoptotic mechanisms, strong upregulation during reactive astrogliosis, expressed also by endothelial cells and microglia; colocalizes with GLAST |
MFG-E8 | milk fat globulin protein E8 | secreted protein; responsible for removal of damaged neurons |
MT | metallothionein | Metal-binding protein; found overexpressed in neurodegenerative diseases |
MX1S | interferon-induced GTP-binding protein | acts against viral nucleic acids |
PK2 | prokineticin-2 | chemokine-like protein; stimulates and promotes shift of astroglia phenotype into immunosuppressive when overexpressed by neurons and astrocytes |
PTX3 | pentraxin 3 | directly related to the innate immunity response to pathogens; responsible for astroglial support of BBB integrity after ischemic stroke; activates classical complement pathway, specific for astrocytes, low expression after LPS, high after MCAO |
Serpin A3N | serine protease inhibitor A3N | expression in resting state cells is below detection level; upregulated only in activated astrocytes; colocalizes with GLAST |
Serpin G1 | plasma protease C1 inhibitor | interferes with C3 and CFB by physical binding influencing the alternate complement activation, increased in LPS activation |
TIMP1 | tissue inhibitor of metalloproteinase 1 | forms complexes with MMPs irreversibly inactivating them; able to induce reactive astrogliosis; produced by astrocytes in response to pathophysiological threat |
TN-C | tenascin | extracellular matrix protein; engaged in astroglia development and synaptic plasticity, marker of reactive astrocytes in stroke, neuronal injury or glial scar formation, induced by MCAO |
TSP-1 | thrombospondin-1 | STAT-3-regulated factor; stimulates synaptogenesis, found upregulated after motor neuron injury along with GFAP |
Intracellular Proteins | ||
ALDOC | fructose-bisphosphate aldolase C | glycolytic enzyme; upregulated after spinal or brain injuries |
ARG1 | arginase 1 | hydrolase; enzyme converting L-arginine in urea cycle, expressed in microglia but also in some astrocytes |
FABP7 | fatty acid-binding protein | expressed by injured astrocytes and is specific to them |
GBP2 | guanylate-binding protein 2 | transducer; reduces GTP by hydrolyzation, anti-viral properties |
HSPB1/HSP27 | heat shock factor-binding protein 1 | chaperones; overexpressed in neurodegenerative diseases |
HSPB5 | alpha-B crystallin | chaperones; overexpressed in neurodegenerative diseases |
iNOS | inducible NO synthetase | cytoplasmic enzyme; engaged in cytokine-induced NO production during inflammatory response, strongly upregulated not only in microglia but also in reactive astrocytes |
MAO-B | monoamine oxidase B | increase is a marker in neurodegenerative conditions affecting neurons releasing monoamines |
NDRG2 | N-Myc downstream-regulated gene 2 | developmental protein; tumor suppressor and cellular stress-related protein associated with cell proliferation and differentiation; exclusively expressed by astrocytes |
NFAT | nuclear factor of activated T cells | transcription factor |
NRF2 | nuclear factor erythroid 2-related factor 2 | transcription factor; regulates gene expression related to oxidative stress and redox reactions; expressed exclusively in astrocytes in course of Parkinson’s disease, but additionally in microglia and neurons in Alzheimer’s disease |
PTGS2 | prostaglandin G/H synthase 2 | responsible for stimulation of prostaglandin production; expression increased in injury and inflammation-related reactive astrogliosis |
S100β | protein S100-B | cytosolic Ca++-binding protein; labels cell bodies of small astrocytes with less extended branching; preferentially marks gray matter cells complementing GFAP staining; actively secreted from astrocytes during cellular stress along with downregulation of its expression intracellularly |
SOX9 | SRY-box transcription factor 9 | almost exclusively expressed by astrocytes in adult human CNS, strong upregulation reported in rodent ALS model |
SPHK1 | sphingosine kinase-1 | catalyzes phosphorylation of sphingosine activating NFκB signaling and IL-17 secretion |
STAT3 | signal transducer and activator of transcription 3 | JAK-STAT pathway element; necessary for astroglial differentiation; overexpressed by astroglia in injury-induced inflammation, but expressed by other cells |
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Jurga, A.M.; Paleczna, M.; Kadluczka, J.; Kuter, K.Z. Beyond the GFAP-Astrocyte Protein Markers in the Brain. Biomolecules 2021, 11, 1361. https://doi.org/10.3390/biom11091361
Jurga AM, Paleczna M, Kadluczka J, Kuter KZ. Beyond the GFAP-Astrocyte Protein Markers in the Brain. Biomolecules. 2021; 11(9):1361. https://doi.org/10.3390/biom11091361
Chicago/Turabian StyleJurga, Agnieszka M., Martyna Paleczna, Justyna Kadluczka, and Katarzyna Z. Kuter. 2021. "Beyond the GFAP-Astrocyte Protein Markers in the Brain" Biomolecules 11, no. 9: 1361. https://doi.org/10.3390/biom11091361