Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system
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Glial fibrillary acidic protein (GFAP) is the hallmark intermediate filament (IF; also known as nanofilament) protein in astrocytes, a main type of glial cells in the central nervous system (CNS). Astrocytes have a range of control and homeostatic functions in health and disease. Astrocytes assume a reactive phenotype in acute CNS trauma, ischemia, and in neurodegenerative diseases. This coincides with an upregulation and rearrangement of the IFs, which form a highly complex system composed of GFAP (10 isoforms), vimentin, synemin, and nestin. We begin to unravel the function of the IF system of astrocytes and in this review we discuss its role as an important crisis-command center coordinating cell responses in situations connected to cellular stress, which is a central component of many neurological diseases.
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Gfap encodes a key intermediate filament protein in astrocytes that is involved in astrocytic reactivity during central nervous system injuries or neurodegeneration.
“Gfap encodes a key intermediate filament protein in astrocytes that is involved in astrocytic reactivity during central nervous system (CNS) injuries or neurodegeneration,39”
From hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data (2023) · cites this paper as [39]
GFAP and vimentin provide mechanical sustenance for astrocyte shape and support the functional profile of reactive astrocytes through transcriptional modulation of target genes involved in astroglial and microglial responsiveness.
“which not only provide mechanical sustenance for the maintenance of astrocyte shape, but also support the functional profile of reactive astrocytes through transcriptional modulation of target genes involved in astroglial and microglial responsiveness [44, 45].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [45]
The astroglial reactive response is a context-specific reaction influenced by brain region, pathology, disease stage, genetics, age, and comorbidities, and is characteristic of multiple brain pathologies including Alzheimer's disease.
“The astroglial reactive response is far from a uniform process. Rather, it is a context‐specific reaction influenced by brain region, pathology, disease stage, genetics, age, and comorbidities [15, 43, 45, 52], and it is characteristic of multiple brain pathologies, including Alzheimer's disease (AD).”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [45]
Reactive astroglia increases trophic support, glutamate uptake, isolates lesioned areas favoring regeneration, activates immune pathways, and promotes BBB repair.
“Although reactive astroglia increases trophic support and glutamate uptake, isolates lesioned areas favoring regeneration, activates immune pathways, and promotes BBB repair [38, 43, 45, 46, 47], astrocytes can become dysfunctional and acquire cytotoxic potential under prolonged stress [38, 43].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [45]
GFAP influences astrocyte morphology.
“Considering the differential abundance of GFAP in AD and APOEch, and as GFAP influences astrocyte morphology [45, 91, 92, 93], we analyzed morphometric descriptors related to the scale, complexity, and shape of both the astrocytes themselves and their spatial domains.”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [45]
Vimentin and GFAP link astrocyte structure and gliovascular function, and are associated with cytoplasmic proteins participating in signal transduction pathways.
“Vimentin and GFAP link astrocyte structure and gliovascular function [90, 92], and are associated with cytoplasmic proteins [92] participating in signal transduction pathways [44, 45, 106, 107].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [45]
Hypertrophied astrocytes display thicker intermediate filament bundles, highly upregulate GFAP and are associated with neuroprotection and postlesion regeneration.
“hypertrophied astrocytes display thicker intermediate filament bundles, highly upregulate GFAP [45, 109] and are associated with neuroprotection and postlesion regeneration [28, 45, 46, 47].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [45]
Atrophied astrocytes fail to maintain the glutamate‐glutamine shuttle and display insufficient glutamate clearance because of reduced synaptic coverage, contributing to synaptic extinction and cognitive deficiency.
“previous reports have shown that atrophied astrocytes fail to maintain the glutamate‐glutamine shuttle [28, 47] and display insufficient glutamate clearance [43] because of reduced synaptic coverage [45, 46, 47], contributing to synaptic extinction and cognitive deficiency [43].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [45]
Atrophied astrocytes are characterized by decreased cell size and reduction of complexity.
“Atrophied astrocytes are characterized by decreased cell size and reduction of complexity [45, 46, 47].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [45]
Ablation of reactive astrocytes prevents the reconstruction of injured blood-brain barrier (BBB).
“ablation of reactive astrocytes prevents the reconstruction of injured BBB [28, 38, 45]”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [45]
Astrocyte reactivity is tightly linked to endothelial, which are in turn associated with loss of vascular structural integrity and opening of the BBB.
“Astrocyte reactivity is tightly linked to endothelial [50], which are in turn associated with loss of vascular structural integrity and opening of the BBB [15, 28, 38, 45, 107, 109, 121].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [45]
Cites
Long-term potentiation depends on release of d-serine from astrocytes
Henneberger, C., Papouin, T., Oliet, S. H. R., & Rusakov, D. A. (2010) · Nature · doi:10.1038/nature08673 · Cited by 1,389 · see citing works
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
Chung, W.-S., Clarke, L. E., Wang, G. X., Stafford, B. K., Sher, A., Chakraborty, C., Joung, J., Foo, L. C., Thompson, A., Chen, C., et al. (2013) · Nature · doi:10.1038/nature12776 · Cited by 1,377 · cited 1× · see citing works
“They are indispensable for proper brain development [5 ,6 ,7 ,8], play fundamental roles in maintaining ion, neurotransmitter, water [9] and energy homeostasis [10], and modulate neuronal signaling [11,12].”
BackgroundGliotransmitters Travel in Time and Space
Araque, A., Carmignoto, G., Haydon, P. G., Oliet, S. H. R., Robitaille, R., & Volterra, A. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.007 · Cited by 1,308 · see citing works
Middeldorp, J., & Hol, E. M. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.01.005 · Cited by 1,080 · see citing works
Self-citationWanner, I. B., Anderson, M. A., Song, B., Levine, J., Fernandez, A., Gray-Thompson, Z., Ao, Y., & Sofroniew, M. V. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2121-13.2013 · Cited by 839 · see citing works
Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors
Allen, N. J., Bennett, M. L., Foo, L. C., Wang, G. X., Chakraborty, C., Smith, S. J., & Barres, B. A. (2012) · Nature · doi:10.1038/nature11059 · Cited by 764 · see citing works
Wilhelmsson, U., Bushong, E. A., Price, D. L., Smarr, B. L., Phung, V., Terada, M., Ellisman, M. H., & Pekny, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602841103 · Cited by 643 · see citing works
Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC
Kucukdereli, H., Allen, N. J., Lee, A. T., Feng, A., Ozlu, M. I., Conatser, L. M., Chakraborty, C., Workman, G., Weaver, M., Sage, E. H., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1104977108 · Cited by 642 · see citing works
Protective Role of Reactive Astrocytes in Brain Ischemia
Li, L., Lundkvist, A., Andersson, D., Wilhelmsson, U., Nagai, N., Pardo, A. C., Nodin, C., Ståhlberg, A., Aprico, K., Larsson, K., et al. (2008) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600546 · Cited by 505 · see citing works
Self-citationWilhelmsson, U., Li, L., Pekna, M., Berthold, C.-H., Blom, S., Eliasson, C., Renner, O., Bushong, E., Ellisman, M., Morgan, T. E., et al. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0820-04.2004 · Cited by 455 · see citing works
Self-citationAttenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice
Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., et al. (2013) · The FASEB Journal · doi:10.1096/fj.12-208660 · Cited by 324 · cited 1× · see citing works
“We are still seeking the mechanistic understanding of some of these phenomena, but a number of studies linked the astrocyte IF system to cell migration [54], viscoelastic properties [74], vesicle trafficking [75–77], activation of Erk and c-fos [78], control of glutamate transport and astrocyte gap junctional communic…”
BackgroundSelf-citationGomi, H., Yokoyama, T., Fujimoto, K., Ikeda, T., Katoh, A., Itoh, T., & Itohara, S. (1995) · Neuron · doi:10.1016/0896-6273(95)90238-4 · Cited by 256 · see citing works
Messing, A., Brenner, M., Feany, M. B., Nedergaard, M., & Goldman, J. E. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5384-11.2012 · Cited by 250 · see citing works
Reactive glia show increased immunoproteasome activity in Alzheimer’s disease
Orre, M., Kamphuis, W., Dooves, S., Kooijman, L., Chan, E. T., Kirk, C. J., Dimayuga Smith, V., Koot, S., Mamber, C., Jansen, A. H., et al. (2013) · Brain · doi:10.1093/brain/awt083 · Cited by 180 · see citing works
Self-citationReactive glial cells: increased stiffness correlates with increased intermediate filament expression
Lu, Y., Iandiev, I., Hollborn, M., Körber, N., Ulbricht, E., Hirrlinger, P. G., Pannicke, T., Wei, E., Bringmann, A., Wolburg, H., et al. (2011) · The FASEB Journal · doi:10.1096/fj.10-163790 · Cited by 172 · see citing works
Self-citationNakazawa, T., Takeda, M., Lewis, G. P., Cho, K.-S., Jiao, J., Wilhelmsson, U., Fisher, S. K., Pekny, M., Chen, D. F., & Miller, J. W. (2007) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.06-1398 · Cited by 168 · see citing works
Self-citationDifferential cell proliferation in the cortex of the appsweps1de9 alzheimer's disease mouse model
Kamphuis, W., Orre, M., Kooijman, L., Dahmen, M., & Hol, E. M. (2012) · Glia · doi:10.1002/glia.22295 · Cited by 137 · see citing works
Self-citationVardjan, N., Gabrijel, M., Potokar, M., Švajger, U., Kreft, M., Jeras, M., de Pablo, Y., Faiz, M., Pekny, M., & Zorec, R. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-144 · Cited by 117 · see citing works
Self-citationJing, R., Wilhelmsson, U., Goodwill, W., Li, L., Pan, Y., Pekny, M., & Skalli, O. (2007) · Journal of Cell Science · doi:10.1242/jcs.03423 · Cited by 110 · see citing works
Self-citationScrapie in Mice Deficient in Apolipoprotein E or Glial Fibrillary Acidic Protein
Tatzelt, J., Maeda, N., Pekny, M., Yang, S.-L., Betsholtz, C., Eliasson, C., Cayetano, J., Camerino, A. P., DeArmond, S. J., & Prusiner, S. B. (1996) · Neurology · doi:10.1212/wnl.47.2.449 · Cited by 59 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Reactive astrocyte nomenclature, definitions, and future directions
Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00783-4 · Cited by 2,533 · see citing works
Self-citationhdWGCNA identifies co-expression networks in high-dimensional transcriptomics data
Morabito, S., Reese, F., Rahimzadeh, N., Miyoshi, E., & Swarup, V. (2023) · Cell Reports Methods · doi:10.1016/j.crmeth.2023.100498 · Cited by 773 · see citing works
Sakaguchi, H., Kadoshima, T., Soen, M., Narii, N., Ishida, Y., Ohgushi, M., Takahashi, J., Eiraku, M., & Sasai, Y. (2015) · Nature Communications · doi:10.1038/ncomms9896 · Cited by 542 · see citing works
Beyond the GFAP-Astrocyte Protein Markers in the Brain
Jurga, A. M., Paleczna, M., Kadluczka, J., & Kuter, K. Z. (2021) · Biomolecules · doi:10.3390/biom11091361 · Cited by 319 · see citing works
GFAP as a Potential Biomarker for Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Kim, K. Y., Shin, K. Y., & Chang, K.-A. (2023) · Cells · doi:10.3390/cells12091309 · Cited by 309 · see citing works
Ceyzériat, K., Ben Haim, L., Denizot, A., Pommier, D., Matos, M., Guillemaud, O., Palomares, M.-A., Abjean, L., Petit, F., Gipchtein, P., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0606-1 · Cited by 256 · see citing works
The complex STATes of astrocyte reactivity: How are they controlled by the JAK-STAT3 pathway?
Ceyzériat, K., Abjean, L., Carrillo-de Sauvage, M.-A., Ben Haim, L., & Escartin, C. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.05.043 · Cited by 185 · see citing works
Hol, E. M., & Capetanaki, Y. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a021642 · Cited by 144 · see citing works
Self-citationLista, S., Imbimbo, B. P., Grasso, M., Fidilio, A., Emanuele, E., Minoretti, P., López-Ortiz, S., Martín-Hernández, J., Gabelle, A., Caruso, G., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03163-y · Cited by 81 · see citing works
Biomaterial Approaches to Modulate Reactive Astroglial Response
Zuidema, J. M., Gilbert, R. J., & Gottipati, M. K. (2018) · Cells Tissues Organs · doi:10.1159/000494667 · Cited by 46 · see citing works
Morris-Schaffer, K., Merrill, A., Jew, K., Wong, C., Conrad, K., Harvey, K., Marvin, E., Sobolewski, M., Oberdörster, G., Elder, A., et al. (2019) · Particle and Fibre Toxicology · doi:10.1186/s12989-019-0293-5 · Cited by 44 · see citing works
Papageorgiou, I. E., Valous, N. A., Lahrmann, B., Janova, H., Klaft, Z., Koch, A., Schneider, U. C., Vajkoczy, P., Heppner, F. L., Grabe, N., et al. (2018) · Glia · doi:10.1002/glia.23292 · Cited by 31 · see citing works
Sinha, S., Patro, N., Tiwari, P. K., & Patro, I. K. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104877 · Cited by 28 · see citing works
Li, Q., Qian, X., Li, H. Y., Lai, K. L., Gao, Q., & Lee, W. Y. T. (2021) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2021.120226 · Cited by 26 · see citing works
Zeng, S., Zhang, T., Chen, Y., Chu-Tan, J., Jin, K., Lee, S.-R., Yam, M. X., Madigan, M. C., Fernando, N., Cioanca, A., et al. (2022) · Theranostics · doi:10.7150/thno.71038 · Cited by 22 · see citing works
Antos, Z., Żukow, X., Bursztynowicz, L., & Jakubów, P. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413658 · Cited by 21 · see citing works
Slota, J. A., Medina, S. J., Frost, K. L., & Booth, S. A. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.918811 · Cited by 16 · see citing works
Henao‐Restrepo, J., López‐Murillo, C., Valderrama‐Carmona, P., Orozco‐Santa, N., Gomez, J., Gutiérrez‐Vargas, J., Moraga, R., Toledo, J., Littau, J. L., Härtel, S., et al. (2023) · Brain Pathology · doi:10.1111/bpa.13119 · Cited by 11 · see citing works
An interpretable deep learning framework identifies proteomic drivers of Alzheimer’s disease
Panizza, E., & Cerione, R. A. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1379984 · Cited by 11 · see citing works
- Authors
- Hol, E. M., & Pekny, M.
- Affiliations
- Netherlands Institute for Neuroscience (NL)
- Florey Institute of Neuroscience and Mental Health (AU)
- Corresponding author
- Hol, Elly M
- Pekny, Milos
- Venue
- Current Opinion in Cell Biology
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 32
- Pages
- 121-130
- ISSN
- 0955-0674 (ISSN-L)
- OpenAlex
- W1983061009
- Cited by
- 917
- References
- 20
- Citations by year
- 2026: 72 · 2025: 112 · 2024: 105 · 2023: 113 · 2022: 115 · 2021: 86 · 2020: 87 · 2019: 64 · 2018: 49 · 2017: 58 · 2016: 35 · 2015: 21
- FWCI
- 5.36
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Licence
- Locations
- Current Opinion in Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Keywords
- glial fibrillary acidic protein, astrocytes, intermediate filaments, astrocyte activation, vimentin, synemin, nestin, CNS trauma, cerebral ischemia, neurodegenerative diseases, cellular stress, central nervous system disorders
- MeSH terms
- Animals, Astrocytes, Central Nervous System Diseases, Glial Fibrillary Acidic Protein, Humans, Intermediate Filaments, Up-Regulation, Protein Isoforms
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