A neuroprotective role for microglia in prion diseases
Open accessAbstract
Microglial activation is a hallmark of most neurodegenerative disorders, and is particularly conspicuous in prion diseases. However, the role of microglia, which function as both primary immune effector cells and professional phagocytes in the central nervous system, remains contentious in the context of neurodegeneration. Here, we evaluated the effect of microglial depletion/deficiency on prion pathogenesis. We found that ganciclovir-mediated microglial ablation on tga20/CD11b-thymidine kinase of Herpes simplex virus (HSVTK) cerebellar organotypic cultured slices markedly aggravated prion-induced neurotoxicity. A similar deterioration of disease was recapitulated in in vivo microglial depletion in prion-infected tga20/CD11b-HSVTK mice. Additionally, deficiency of microglia in interleukin 34 knockout (IL34−/−) mice again resulted in significantly augmented proteinase K–resistant prion protein deposition and accelerated prion disease progression. These results provide unambiguous evidence for a general protective role of microglia in prion pathogenesis.
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Work on prion-infected organotypic brain-slice cultures supports prion clearing and neuroprotective functions of microglia.
“Work on prion-infected organotypic brain-slice cultures support the prion clearing and neuroprotective functions of microglia [50].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [50]
Reducing microglia numbers by knocking out IL-34 leads to augmented PrPSc deposition and shortened survival in a prion mouse model.
“In contrast, reducing microglia numbers by knocking out interleukin 34 (IL-34), an essential signaling molecule, led to augmented PrPSc deposition and shortened survival in a prion mouse model [50,51]”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [50]
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Cystatin F is a biomarker of prion pathogenesis in mice
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Self-citationReactive microglia partially envelop viable neurons in prion diseases
Makarava, N., Safadi, T., Bocharova, O. V., Mychko, O., Pandit, N. P., Molesworth, K., Baiardi, S., Zhang, L., Parchi, P., & Baskakov, I. V. (2024) · Journal of Clinical Investigation · doi:10.1172/jci181169 · Cited by 25 · see citing works
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Self-citationPrion protein and prion disease at a glance
Zhu, C., & Aguzzi, A. (2021) · Journal of Cell Science · doi:10.1242/jcs.245605 · Cited by 22 · see citing works
Self-citationNeurotoxic Antibodies against the Prion Protein Do Not Trigger Prion Replication
Frontzek, K., Pfammatter, M., Sorce, S., Senatore, A., Schwarz, P., Moos, R., Frauenknecht, K. B. M., Hornemann, S., & Aguzzi, A. (2016) · PLoS ONE · doi:10.1371/journal.pone.0163601 · Cited by 22 · see citing works
Self-citationShan, Z., Hirai, Y., Nakayama, M., Hayashi, R., Yamasaki, T., Hasebe, R., Song, C., & Horiuchi, M. (2017) · Journal of General Virology · doi:10.1099/jgv.0.000907 · Cited by 22 · see citing works
Early existence and biochemical evolution characterise acutely synaptotoxic PrPSc
Foliaki, S. T., Lewis, V., Islam, A. M. T., Ellett, L. J., Senesi, M., Finkelstein, D. I., Roberts, B. R., Lawson, V., Adlard, P. A., & Collins, S. J. (2019) · PLoS Pathogens · doi:10.1371/journal.ppat.1007712 · Cited by 21 · see citing works
The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis
Mabbott, N. A., Bradford, B. M., Pal, R., Young, R. A., & Donaldson, D. S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197299 · Cited by 20 · see citing works
A 3D cell culture approach for studying neuroinflammation
Carroll, J. A., Foliaki, S. T., & Haigh, C. L. (2021) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2021.109201 · Cited by 20 · see citing works
Flow Cytometric Detection of PrPScin Neurons and Glial Cells from Prion-Infected Mouse Brains
Yamasaki, T., Suzuki, A., Hasebe, R., & Horiuchi, M. (2017) · Journal of Virology · doi:10.1128/jvi.01457-17 · Cited by 20 · see citing works
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Prion disease pathogenesis in the absence of the commensal microbiota
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Astrocyte in prion disease: a double-edged sword
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The role of the immune system in prion infection
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Experimental models to study prion disease pathogenesis and identify potential therapeutic compounds
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Organoids for modeling prion diseases
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Guijarro, I. M., Garcés, M., Andrés‐Benito, P., Marín, B., Otero, A., Barrio, T., Carmona, M., Ferrer, I., Badiola, J. J., & Monzón, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093231 · Cited by 15 · see citing works
Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling
Nuvolone, M., Paolucci, M., Sorce, S., Kana, V., Moos, R., Matozaki, T., & Aguzzi, A. (2017) · PLOS ONE · doi:10.1371/journal.pone.0177876 · Cited by 13 · see citing works
Self-citationCell adhesion molecule CD44 is dispensable for reactive astrocyte activation during prion disease
Bradford, B. M., Walmsley-Rowe, L., Reynolds, J., Verity, N., & Mabbott, N. A. (2024) · Scientific Reports · doi:10.1038/s41598-024-63464-3 · Cited by 13 · see citing works
Immunology of Prion Protein and Prions
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From Cell Culture to Organoids-Model Systems for Investigating Prion Strain Characteristics
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Loss of Homeostatic Microglia Signature in Prion Diseases
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“Work on prion-infected organotypic brain-slice cultures support the prion clearing and neuroprotective functions of microglia [50].”
BackgroundGlial phagocytosis for synapse and toxic proteins in neurodegenerative diseases
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Zhou, X., & Spittau, B. (2017) · Neurotoxicity Research · doi:10.1007/s12640-017-9842-6 · Cited by 12 · see citing works
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Prion pathogenesis is unaltered in a mouse strain with a permeable blood-brain barrier
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Genetically engineered cellular models of prion propagation
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Acute Neurotoxicity Models of Prion Disease
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Adipose-derived mesenchymal stromal cells decrease prion-induced glial inflammation in vitro
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Plasma cholesterol level determines in vivo prion propagation
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Redox mechanisms and their pathological role in prion diseases: The road to ruin
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The importance of prion research
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Biological functions and clinical implications of interleukin-34 in inflammatory diseases
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Innate Immune Tolerance in Microglia Does Not Impact on Central Nervous System Prion Disease
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The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis
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Self-citationMicroglia have limited influence on early prion pathogenesis, clearance, or replication
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Reactive astrocytes in prion diseases: Friend or foe?
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A neuroprotective role for microglia in prion diseases
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Interactions between Cytokines and the Pathogenesis of Prion Diseases: Insights and Implications
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Innate Immune Mechanisms in the Central Nervous System
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Neural transcriptomic signature of chronic wasting disease in white-tailed deer
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The Role of Glial Cells in Neurobiology and Prion Neuropathology
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Cell-based therapy against prion diseases
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- Authors
- Zhu, C., Herrmann, U. S., Falsig, J., Abakumova, I., Nuvolone, M., Schwarz, P., Frauenknecht, K., Rushing, E. J., & Aguzzi, A.
- Affiliations
- University Hospital Zurich (CH)
- Corresponding author
- Zhu, Caihong
- Aguzzi, Adriano
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2016-05-16
- Volume
- 213
- Issue
- 6
- Pages
- 1047-1059
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC4886355
- OpenAlex
- W2406691442
- Cited by
- 134
- References
- 44
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 9 · 2023: 7 · 2022: 17 · 2021: 11 · 2020: 12 · 2019: 17 · 2018: 17 · 2017: 25 · 2016: 5
- FWCI
- 11.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- European Research Council (250356)
- Swiss National Foundation
- Novartis Research Foundation
- Stavros Niarchos Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- microglia, prion disease, neuroprotection, microglial depletion, ganciclovir, IL-34, prion protein deposition, neurodegeneration
- MeSH terms
- Animals, Interleukins, Prions, Prion Diseases, Microglia, Mice, Knockout, Mice
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