Phagocytic Activities of Reactive Microglia and Astrocytes Associated with Prion Diseases Are Dysregulated in Opposite Directions
Open accessAbstract
Phagocytosis is one of the most important physiological functions of the glia directed at maintaining a healthy, homeostatic environment in the brain. Under a homeostatic environment, the phagocytic activities of astrocytes and microglia are tightly coordinated in time and space. In neurodegenerative diseases, both microglia and astrocytes contribute to neuroinflammation and disease pathogenesis, however, whether their phagocytic activities are up- or downregulated in reactive states is not known. To address this question, this current study isolated microglia and astrocytes from C57BL/6J mice infected with prions and tested their phagocytic activities in live-cell imaging assays that used synaptosomes and myelin debris as substrates. The phagocytic uptake by the reactive microglia was found to be significantly upregulated, whereas that of the reactive astrocytes was strongly downregulated. The up- and downregulation of phagocytosis by the two cell types were observed irrespective of whether disease-associated synaptosomes, normal synaptosomes, or myelin debris were used in the assays, indicating that dysregulations are dictated by cell reactive states, not substrates. Analysis of gene expression confirmed dysregulation of phagocytic functions in both cell types. Immunostaining of animal brains infected with prions revealed that at the terminal stage of disease, neuronal cell bodies were subject to engulfment by reactive microglia. This study suggests that imbalance in the phagocytic activities of the reactive microglia and astrocytes, which are dysregulated in opposite directions, is likely to lead to excessive microglia-mediated neuronal death on the one hand, and the inability of astrocytes to clear cell debris on the other hand, contributing to the neurotoxic effects of glia as a whole.
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Findings on the loss of homeostatic microglial proteins in terminal prion disease contrast with findings on RNA expression of the corresponding genes, since P2ry12 RNA expression has been shown to be relatively upregulated.
“Interestingly, these findings on the loss of homeostatic microglial proteins in terminal prion disease are in contrast to findings on the RNA expression of the corresponding genes, since P2ry12 RNA expression has been shown to be relatively upregulated [98,99].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [99]
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Self-citationLoss of Homeostatic Microglia Signature in Prion Diseases
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“Interestingly, these findings on the loss of homeostatic microglial proteins in terminal prion disease are in contrast to findings on the RNA expression of the corresponding genes, since P2ry12 RNA expression has been shown to be relatively upregulated [98,99].”
ResultGlial phagocytosis for synapse and toxic proteins in neurodegenerative diseases
Choi, Y., & Chung, W. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00870-9 · Cited by 12 · see citing works
Hay, A. J. D., Popichak, K. A., Mumford, G., Shirley, P. M., Bian, J., Wolfrath, L., Lei, S., Eggers, M., Nicholson, E. M., Tjalkens, R. B., et al. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1012582 · Cited by 10 · see citing works
Cell‐Surface LAMP1 is a Senescence Marker in Aging and Idiopathic Pulmonary Fibrosis
Meca-Laguna, G., Qiu, M., Hou, Y., Barkovskaya, A., Shankar, A., Dixit, B., Rae, M. J., Boominathan, A., & Sharma, A. (2025) · Aging Cell · doi:10.1111/acel.70141 · Cited by 9 · see citing works
Reactive astrocytes in prion diseases: Friend or foe?
Makarava, N., Kushwaha, R., & Baskakov, I. V. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1012286 · Cited by 6 · see citing works
Self-citationA real-time antibody-dependent cellular phagocytosis assay by live cell imaging
Shi, Y., Sun, Y., Seki, A., Rutz, S., Koerber, J. T., & Wang, J. (2024) · Journal of Immunological Methods · doi:10.1016/j.jim.2024.113715 · Cited by 5 · see citing works
The Role of Glial Cells in Neurobiology and Prion Neuropathology
Hay, A. J. D., Popichak, K. A., Moreno, J. A., & Zabel, M. D. (2024) · Cells · doi:10.3390/cells13100832 · Cited by 5 · see citing works
Soto‐Mercado, V., Mendivil‐Perez, M., Velez‐Pardo, C., & Jiménez-Del-Río, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157162 · Cited by 4 · see citing works
Adnan, M., Siddiqui, A. J., Bardakçi, F., Surti, M., Badraoui, R., & Patel, M. B. (2025) · Pharmaceuticals · doi:10.3390/ph18060921 · Cited by 4 · see citing works
Noguchi, H., Koyama, S., Yagita, K., Shijo, M., Matsuzono, K., Hamasaki, H., Kanemaru, T., Okamoto, T., Kai, K., Aishima, S., et al. (2022) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlac098 · Cited by 4 · see citing works
Dissecting surveying behavior of reactive microglia under chronic neurodegeneration
Subhramanian, S., Bocharova, O. V., Makarava, N., Safadi, T., & Baskakov, I. V. (2026) · eLife · doi:10.7554/elife.107650.3 · Cited by 3 · see citing works
Self-citationThe Central Nervous System Source Modulates Microglia Function and Morphology In Vitro
Pinho, A. G., Monteiro, A., Fernandes, S., de Sousa, N., Salgado, A. J., Silva, N. A., & Monteiro, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24097685 · Cited by 2 · see citing works
Multiple steps of prion strain adaptation to a new host
Bocharova, O. V., Makarava, N., Pandit, N. P., Molesworth, K., & Baskakov, I. V. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1329010 · Cited by 2 · see citing works
Self-citationMallick, A. M., Chatterjee, A., Gurung, A. B., Uttarasili, P., Tripathi, A., Hembram, M., Srivastava, A. K., & Roy, R. S. (2025) · Biomaterials Science · doi:10.1039/d5bm00109a · Cited by 2 · see citing works
Hay, A. J. D., Popichak, K. A., Zabel, M. D., & Moreno, J. A. (2023) · Journal of Visualized Experiments · doi:10.3791/65565 · Cited by 1 · see citing works
Dominicci-Cotto, C., Vázquez, M., & Marie, B. (2024) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2024.1322771 · Cited by 1 · see citing works
Baidoe‐Ansah, D., Mirzapourdelavar, H., Aleshin, S. E., Schott, B. H., Seidenbecher, C. I., Kaushik, R., & Dityatev, A. E. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.26.577401 · Cited by 1 · see citing works
Engulfment of viable neurons by reactive microglia in prion diseasesPreprint
Makarava, N., Safadi, T., Mychko, O., Pandit, N. P., Molesworth, K., Baiardi, S., Zhang, L., Parchi, P., & Baskakov, I. V. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.06.583759 · Cited by 1 · see citing works
Self-citationPAK3 downregulation induces cognitive impairment following cranial irradiationPreprint
Lee, H., Kang, H., Moon, C., & Youn, B. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.30.547296
Modelling cognitive outcomes in the UK Biobank: Education, noradrenaline and frontoparietal networks
Bravo-Merodio, L., Olley-Williams, J. A., Russ, D., Gkoutos, G. V., Brosnan, M., Bellgrove, M., & Chechlacz, M. (2025) · bioRxiv · doi:10.1371/journal.pone.0350452
Alanko, V., Eroli, F., Végvári, Á., Solomon, A., Hartmann, T., Nilsson, P., Kivipelto, M., Maioli, S., & Matton, A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.23.614418
Reactive Microglia and Astrocytes as Therapeutic Targets in Prion Diseases
Makarava, N., Kushwaha, R., & Baskakov, I. V. (2025) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-031-97055-9_8
Self-citationDissecting surveying behavior of reactive microglia under chronic neurodegenerationPreprint
Subhramanian, S., Bocharova, O. V., Makarava, N., Safadi, T., & Baskakov, I. V. (2025) · eLife · doi:10.7554/elife.107650.2
Self-citationGlial control of extracellular α-synuclein propagation in LRRK2 Parkinson’s disease
Datta, I., & Sahu, D. D. (2026) · Advances in immunology · doi:10.1016/bs.ai.2026.04.005
Human CD34 + progenitor-derived DC2 and DC3 subsets support CD16G-mediated HIV-1 uptakePreprint
Laguía, F., Pinol, P., Vickers, M. A., Izquierdo-Pujol, J., Muñoz‐Fontela, C., Martínez‐Picado, J., & Resa‐Infante, P. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.21.753077
Srpčič, A., Miš, K., Gantar, B. Ž. B., Dolinar, K., Mjaaseth, U. N., Rustan, A. C., Kase, E. T., Lakota, K., Pirkmajer, K. P., & Pirkmajer, S. (2026) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00264.2026
Sakurada, N., Watanabe, A., Yoshimura, M., Sakae, N., Arahata, H., Yamamoto, A., Kanemaru, T., Noguchi, H., Mori, S., Shijo, M., et al. (2026) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlag099
Pozzolini, G., Haendeler, S., Amin, S., Baldi, R., CASCIO, A., Edenhofer, F., Taverna, E., Esk, C., Krenn, V., & Nicolis, S. K. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.23.761353
- Authors
- Sinha, A., Kushwaha, R., Molesworth, K., Mychko, O., Makarava, N., & Baskakov, I. V.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Baskakov, Ilia V.
- ORCID
- Baskakov, Ilia V.
- Venue
- Cells
- Publisher
- MDPI AG
- Published
- 2021-07-08
- Volume
- 10
- Issue
- 7
- Pages
- 1728
- ISSN
- 2073-4409 (ISSN-L)
- PMC
- PMC8304827
- OpenAlex
- W3179750557
- Cited by
- 42
- References
- 68
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 12 · 2023: 6 · 2022: 7
- FWCI
- 2.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cells (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- national institute of allergy and infectious diseases (AI128925)
- National Institute of Neurological Disorders and Stroke (NS045585)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- phagocytosis, reactive microglia, reactive astrocytes, prion disease, neuroinflammation, glial dysfunction, synaptosomes, myelin debris, neurodegeneration
- MeSH terms
- Animals, Astrocytes, Brain, Cells, Cultured, Female, Male, Mice, Inbred C57BL, Myelin Sheath, Neurons, Phagocytosis, Synaptosomes, Down-Regulation, Up-Regulation, Prion Diseases, Microglia, Mice
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