Distinct microglia profile in Creutzfeldt-Jakob disease and Alzheimer’s disease is independent of disease kinetics
Open accessAbstract
Activated microglia represent a common pathological feature of neurodegenerative diseases. Sporadic Creutzfeldt–Jakob disease (sCJD) patients show more pronounced microglial activation than Alzheimer's disease (AD) patients. Whether these differences are due to differences in disease kinetics or represent disease‐specific changes is unknown. We investigated microglial phenotypes in brains of rapidly progressive AD (rpAD) and sCJD patients matched for clinical presentation, including disease duration. We immunostained the frontal cortex, basal ganglia and cerebellum in 16 patients with rpAD and sCJD using antibodies against markers of microglia and recruited monocytes (ionized calcium‐binding adaptor molecule 1, human leukocyte antigen DPQR, Cluster of Differentiation 68), an antibody unique to brain‐resident microglia (transmembrane protein 119 (TMEM119)), in addition to antibodies against a marker of astrocytes (glial fibrillary acidic protein), amyloid‐β (Aβ) and pathological prion protein. rpAD patients showed a distinct microglial phenotype with a high abundance of TMEM119‐positive microglia in all investigated regions. Presence of Aβ deposits seen in a sCJD patient with concomitant deposition of Aβ led to increase of TMEM119‐positive microglia. Our data suggest that in rpAD, activation of brain‐resident microglia significantly contributes to microgliosis, whereas in sCJD the TMEM119 signature of resident microglial cells is barely detectable. This is irrespective of disease duration and may indicate disease‐specific microglial reaction.
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The abundance of homeostatic microglia proteins such as TMEM119 and P2RY12 is significantly reduced in terminal prion disease.
“We recently showed that the abundance of homeostatic microglia proteins such as TMEM119 and P2RY12 is significantly reduced in terminal prion disease (Figure 4) [47,73,97].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [97]
While GFAP increase is also found in other neurodegenerative diseases such as AD, YKL-40 upregulation is more specific for human CJD and might serve as a diagnostic marker.
“However, while a GFAP increase is also found in other neurodegenerative diseases such as AD [97], YKL-40 upregulation is more specific for human CJD and might serve as a diagnostic marker [107].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [97]
TMEM119 protein level is significantly reduced in the brains of sCJD patients.
“We have previously shown that the TMEM119 protein level is significantly reduced in the brains of sCJD patients (Figure 6A) [97].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [97]
In terminal prion disease, while homeostatic markers are still abundant in the hippocampus, the homeostatic signature is almost completely lost in the thalamus, an effect especially severe for P2RY12.
“While the homeostatic markers are still abundant in the hippocampus, this signature is almost completely lost in the thalamus, an effect which is especially severe for P2RY12 (Figure 4) [47,73,97].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [97]
The microglia signature of sCJD patients differs from those of rapid AD, with significant downregulation of the microglia homeostatic marker TMEM119.
“The microglia signature of sCJD patients differ from those of rapid AD, with significant downregulation of the microglia homeostatic marker TMEM119 (Figure 7) [97].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [97]
The activation marker CD68 is increased in the frontal cortex of a patient with sCJD compared to AD patients.
“Moreover, the activation marker cluster of differentiation CD68 was increased in the frontal cortex of a patient with sCJD compared to AD patients (Figure 7) [97].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [97]
In recent experiments, the extensive loss of the homeostatic signature in prion diseases stands out remarkably.
“Moreover, in our recent experiments, the extensive loss of the homeostatic signature in prion diseases stands out remarkably [47,73,97].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [97]
The loss of the homeostatic marker seems more severe in sCJD compared to AD.
“Interestingly, the loss of the homeostatic marker seems more severe in sCJD compared to AD [97].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [97]
Patients with AD only show a moderate loss of TMEM119.
“These data are in line with recent findings that patients with AD only show a moderate loss of TMEM119 [95,97].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [97]
Cites
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · see citing works
Neuropathological alterations in Alzheimer disease
Serrano-Pozo, A., Frosch, M. P., Masliah, E., & Hyman, B. T. (2011) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006189 · Cited by 3,345 · see citing works
Hyman, B. T., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Carrillo, M. C., Dickson, D. W., Duyckaerts, C., Frosch, M. P., Masliah, E., et al. (2012) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.10.007 · Cited by 3,092 · see citing works
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979 · see citing works
Self-citationMicroglia Function in the Central Nervous System During Health and Neurodegeneration
Colonna, M., & Butovsky, O. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052358 · Cited by 2,894 · see citing works
Identification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543 · see citing works
New tools for studying microglia in the mouse and human CNS
Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525528113 · Cited by 1,804 · see citing works
Microglial priming in neurodegenerative disease
Perry, V. H., & Holmes, C. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.38 · Cited by 1,127 · see citing works
Murray, M. E., Graff-Radford, N. R., Ross, O. A., Petersen, R. C., Duara, R., & Dickson, D. W. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70156-9 · Cited by 972 · see citing works
Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease
Zerr, I., Kallenberg, K., Summers, D. M., Romero, C., Taratuto, A. L., Heinemann, U., Breithaupt, M., Varges, D., Meißner, B., Ladogana, A., et al. (2009) · Brain · doi:10.1093/brain/awp191 · Cited by 917 · see citing works
Self-citationMicroglia in Alzheimer's disease
Sarlus, H., & Heneka, M. T. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90606 · Cited by 911 · see citing works
Differential roles of microglia and monocytes in the inflamed central nervous system
Yamasaki, R., Lu, H., Butovsky, O., Ohno, N., Rietsch, A. M., Cialic, R., Wu, P. M., Doykan, C. E., Lin, J., Cotleur, A. C., et al. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20132477 · Cited by 855 · see citing works
Transcriptomic analysis of purified human cortical microglia reveals age-associated changes
Galatro, T. F., Holtman, I. R., Lerario, A. M., Vainchtein, I. D., Brouwer, N., Sola, P. R., Veras, M. M., Pereira, T. F., Leite, R. E. P., Möller, T., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4597 · Cited by 741 · see citing works
Hopperton, K. E., Mohammad, D., Trépanier, M. O., Giuliano, V, & Bazinet, R. P. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.246 · Cited by 567 · see citing works
Olmos-Alonso, A., Schetters, S. T. T., Sri, S., Askew, K., Mancuso, R., Vargas-Caballero, M., Holscher, C., Perry, V. H., & Gomez-Nicola, D. (2016) · Brain · doi:10.1093/brain/awv379 · Cited by 532 · see citing works
Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS
Butovsky, O., Siddiqui, S., Gabriely, G., Lanser, A. J., Dake, B., Murugaiyan, G., Doykan, C. E., Wu, P. M., Gali, R. R., Iyer, L. K., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62636 · Cited by 481 · see citing works
Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt–Jakob disease
Zerr, I., Pocchiari, M., Collins, S. J., Brandel, J., Cuesta, J. D. P., Knight, R., Bernheimer, H., Cardone, F., Delasnerie-Lauprêtre, N., Cuadrado‐Corrales, N., et al. (2000) · Neurology · doi:10.1212/wnl.55.6.811 · Cited by 477 · see citing works
Self-citationTMEM119 marks a subset of microglia in the human brain
Satoh, J., Kino, Y., Asahina, N., Takitani, M., Miyoshi, J., Ishida, T., & Saito, Y. (2016) · Neuropathology · doi:10.1111/neup.12235 · Cited by 434 · see citing works
Regulation of Microglial Proliferation during Chronic Neurodegeneration
Gómez-Nicola, D., Fransen, N. L., Suzzi, S., & Perry, V. H. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.4440-12.2013 · Cited by 407 · see citing works
Mildner, A., Schlevogt, B., Kierdorf, K., Böttcher, C., Erny, D., Kummer, M. P., Quinn, M., Brück, W., Bechmann, I., Heneka, M. T., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6209-10.2011 · Cited by 351 · see citing works
Microglial Dynamics and Role in the Healthy and Diseased Brain: A Paradigm of Functional Plasticity
Gomez-Nicola, D., & Perry, V. H. (2015) · The Neuroscientist · doi:10.1177/1073858414530512 · Cited by 340 · see citing works
Pocchiari, M. (2004) · Brain · doi:10.1093/brain/awh249 · Cited by 303 · see citing works
Malm, T. M., Koistinaho, M., Pärepalo, M., Vatanen, T., Ooka, A., Karlsson, S., & Koistinaho, J. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.09.009 · Cited by 301 · see citing works
London, A., Cohen, M., & Schwartz, M. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00034 · Cited by 282 · see citing works
The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases
Rey, N. L., Wesson, D. W., & Brundin, P. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.12.013 · Cited by 257 · see citing works
Targeting neuroinflammation in Alzheimer’s disease
Bronzuoli, M. R., Iacomino, A., Steardo, L., & Scuderi, C. (2016) · Journal of Inflammation Research · doi:10.2147/jir.s86958 · Cited by 255 · see citing works
Davies, D. S., Ma, J., Jegathees, T., & Goldsbury, C. (2017) · Brain Pathology · doi:10.1111/bpa.12456 · Cited by 251 · see citing works
Rapid and Sensitive RT-QuIC Detection of Human Creutzfeldt-Jakob Disease Using Cerebrospinal Fluid
Orru, C. D., Groveman, B. R., Hughson, A. G., Zanusso, G., Coulthart, M. B., & Caughey, B. W. (2015) · mBio · doi:10.1128/mbio.02451-14 · Cited by 248 · see citing works
Parchi, P., de Boni, L., Saverioni, D., Cohen, M. L., Ferrer, I., Gambetti, P. L., Gelpí, E., Giaccone, G., Hauw, J., Höftberger, R., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-1002-8 · Cited by 228 · see citing works
Chaudhari, K. S., Tiwari, N. R., Tiwari, R. R., & Sharma, R. S. (2017) · Annals of Neurosciences · doi:10.1159/000475900 · Cited by 167 · see citing works
Lattanzio, F., Abu‐Rumeileh, S., Franceschini, A., Kai, H., Amore, G., Poggiolini, I., Rossi, M., Baiardi, S., McGuire, L. I., Ladogana, A., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1683-0 · Cited by 163 · see citing works
Martin, E., Boucher, C., Fontaine, B., & Delarasse, C. (2017) · Aging Cell · doi:10.1111/acel.12522 · Cited by 156 · see citing works
Stimulating the Release of Exosomes Increases the Intercellular Transfer of Prions
Guo, B. B., Bellingham, S. A., & Hill, A. F. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.684258 · Cited by 149 · see citing works
Sepulveda-Falla, D., Barrera-Ocampo, A., Hagel, C., Korwitz, A., Vinueza-Veloz, M. F., Zhou, K., Schonewille, M., Zhou, H., Velazquez-Perez, L., Rodriguez-Labrada, R., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci66407 · Cited by 135 · see citing works
Self-citationAguzzi, A., & Zhu, C. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90605 · Cited by 122 · see citing works
Analysis of Prion Strains by PrPSc Profiling in Sporadic Creutzfeldt–Jakob Disease
Schoch, G., Seeger, H., Bogousslavsky, J., et al. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0030014 · Cited by 103 · see citing works
Rapidly Progressive Alzheimer's Disease: A Multicenter Update
Schmidt, C., Haı̈k, S., Satoh, K., Rábano, A., Martínez‐Martín, P., Roeber, S., Brandel, J., Calero, M., de Pedro‐Cuesta, J., Laplanche, J., et al. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120007 · Cited by 73 · see citing works
Self-citationVan Everbroeck, B., Dobbeleir, I., De Waele, M., De Leenheir, E., Lübke, U., Martin, J.-J., & Cras, P. (2004) · Acta Neuropathologica · doi:10.1007/s00401-004-0879-2 · Cited by 66 · see citing works
Gómez‐Nicola, D., Schetters, S. T. T., & Perry, V. H. (2014) · Glia · doi:10.1002/glia.22660 · Cited by 59 · see citing works
Na, H. K., Kang, D. R., Kim, S. S., Seo, S. W., Heilman, K. M., Noh, Y., & Na, D. L. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.08.001 · Cited by 49 · see citing works
(2012) · PubMed · Cited by 42 · see citing works
Shi, Q., Xie, W.-L., Zhang, B., Chen, L., Xu, Y., Wang, K., Ren, K., Zhang, X.-M., Chen, C., Zhang, J., et al. (2013) · Virology Journal · doi:10.1186/1743-422x-10-216 · Cited by 37 · see citing works
Microglia‐targeted stem cell therapies for Alzheimer disease: A preclinical data review
Shen, Z., Li, X., Bao, X., & Wang, R. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24066 · Cited by 32 · see citing works
Bogner, S., Bernreuther, C., Matschke, J., Barrera-Ocampo, A. A., Falla, D. S., Leypoldt, F., Magnus, T. U., Haag, F., Bergmann, M., Brück, W., et al. (2013) · Neurodegenerative Diseases · doi:10.1159/000352020 · Cited by 28 · see citing works
Self-citationFranceschini, A., Strammiello, R., Capellari, S., Giese, A., & Parchi, P. (2018) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12461 · Cited by 24 · see citing works
Predictive Factors of Rapid Cognitive Decline in Patients with Alzheimer Disease
Barbe, C., Morrone, I., Novella, J., Dramé, M., Wolak‐Thierry, A., Aquino, J., Ankri, J., Jolly, D., & Mahmoudi, R. (2016) · Dementia and Geriatric Cognitive Disorders Extra · doi:10.1159/000450975 · Cited by 16 · see citing works
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Hartmann, K., Sepulveda-Falla, D., Rose, I. V. L., Madore, C., Muth, C., Matschke, J., Butovsky, O., Liddelow, S., Glatzel, M., & Krasemann, S. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0735-1 · Cited by 141 · see citing works
Self-citationPankiewicz, J. E., Lizińczyk, A. M., Franco, L. A., Diaz, J. R., Martá-Ariza, M., & Sadowski, M. J. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01261-z · Cited by 15 · see citing works
Loss of Homeostatic Microglia Signature in Prion Diseases
Wang, Y., Hartmann, K., Thies, E., Mohammadi, B., Altmeppen, H., Sepulveda-Falla, D., Glatzel, M., & Krasemann, S. (2022) · Cells · doi:10.3390/cells11192948 · Cited by 12 · see citing works
“While the homeostatic markers are still abundant in the hippocampus, this signature is almost completely lost in the thalamus, an effect which is especially severe for P2RY12 (Figure 4) [47,73,97].”
BackgroundResultInfluentialSelf-citation
- Authors
- Krbot, K., Hermann, P., Skorić, M. K., Zerr, I., Sepulveda‐Falla, D., Goebel, S., Matschke, J., Krasemann, S., & Glatzel, M.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- National TSE Reference Centre, Department of Neurology Georg‐August University Goettingen Germany
- University Hospital Centre Zagreb (HR)
- University of Göttingen (DE)
- Institute of Neuropathology University Medical Centre Hamburg‐Eppendorf Hamburg Germany
- Corresponding author
- Glatzel, Markus
- Venue
- Neuropathology
- Publisher
- Wiley
- Published
- 2018-10-15
- Volume
- 38
- Issue
- 6
- Pages
- 591-600
- ISSN
- 0919-6544 (ISSN-L)
- 1440-1789
- OpenAlex
- W2898080710
- Cited by
- 11
- References
- 46
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2022: 1 · 2021: 2 · 2019: 2
- FWCI
- 0.45
- Type
- journal article
- Language
- en
- Open access
- Locations
- Neuropathology (publishedVersion)
- PubMed (publishedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Funders
- Bundesministerium für Bildung und Forschung (UndoAD)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- Creutzfeldt-Jakob disease, Alzheimer's disease, microglial activation, TMEM119, microglial phenotype, amyloid-beta, prion protein, disease duration, neurodegenerative diseases
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Creutzfeldt-Jakob Syndrome, Male, Middle Aged, Microglia
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