Region-specific glial homeostatic signature in prion diseases is replaced by a uniform neuroinflammation signature, common for brain regions and prion strains with different cell tropism
Open accessAbstract
Chronic neuroinflammation is recognized as a major neuropathological hallmark in a broad spectrum of neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal Temporal Dementia, Amyotrophic Lateral Sclerosis, and prion diseases. Both microglia and astrocytes exhibit region-specific homeostatic transcriptional identities, which under chronic neurodegeneration, transform into reactive phenotypes in a region- and disease-specific manner. Little is known about region-specific identity of glia in prion diseases. The current study was designed to determine whether the region-specific homeostatic signature of glia changes with the progression of prion diseases, and whether these changes occur in a region-dependent or universal manner. Also of interest was whether different prion strains give rise to different reactive phenotypes. To answer these questions, we analyzed gene expression in the thalamus, cortex, hypothalamus and hippocampus of mice infected with 22L and ME7 prion strains using a Nanostring Neuroinflammation panel at the subclinical, early clinical and advanced stages of the disease. We found that at the preclinical stage of the disease, the region-specific homeostatic identities were preserved. However, with the appearance of clinical signs, the region-specific signatures were partially lost and replaced with a neuroinflammation signature. While the same sets of genes were activated by both prion strains, the timing of neuroinflammation and the degree of activation in different brain regions was strain-specific. Changes in astrocyte function scored at the top of the activated pathways. Moreover, clustering analysis suggested that the astrocyte function pathway responded to prion infection prior to the Activated Microglia or Neuron and Neurotransmission pathways. The current work established neuroinflammation gene expression signature associated with prion diseases. Our results illustrate that with the disease progression, the region-specific homeostatic transcriptome signatures are replaced by the region-independent neuroinflammation signature, which is common for prion strains with different cell tropism. The prion-associated neuroinflammation signature identified in the current study overlapped only partially with the microglia degenerative phenotype and the disease-associated microglia phenotype reported for animal models of other neurodegenerative diseases.
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Region-specific bulk transcriptomic analyses of brains infected with two different prion strains show comparable regional glia response despite the strains targeting different cell populations.
“The same outcome was recently published after region-specific bulk transcriptomic analyses of brains infected with two different prion strains [74]. Although these strains target different cell populations in the brain, the regional glia response was comparable.”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [74]
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Sialylation Controls Prion Fate in Vivo
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Self-citationTwo alternative pathways for generating transmissible prion disease de novo
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Region-Specific Sialylation Pattern of Prion Strains Provides Novel Insight into Prion Neurotropism
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‘Spikeopathy’: COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA
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Self-citationNeuroinflammation in Prion Disease
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Self-citationNon-cell autonomous astrocyte-mediated neuronal toxicity in prion diseases
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Self-citationMechanisms of prion-induced toxicity
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Reactive astrocytes associated with prion disease impair the blood brain barrier
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Self-citationRegion-Specific Sialylation Pattern of Prion Strains Provides Novel Insight into Prion Neurotropism
Makarava, N., Chang, J. C., & Baskakov, I. V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21030828 · Cited by 24 · see citing works
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On the reactive states of astrocytes in prion diseases
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Differential Accumulation of Misfolded Prion Strains in Natural Hosts of Prion Diseases
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Role of sialylation of N-linked glycans in prion pathogenesis
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Self-citationLoss of Homeostatic Microglia Signature in Prion Diseases
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“The same outcome was recently published after region-specific bulk transcriptomic analyses of brains infected with two different prion strains [74].”
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Self-citationEndoplasmic reticulum stress and ubiquitin-proteasome system impairment in natural scrapie
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Neurogranin and Neurofilament Light Chain as Preclinical Biomarkers in Scrapie
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Reactive astrocytes in prion diseases: Friend or foe?
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Self-citationLimbic system synaptic dysfunctions associated with prion disease onset
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Prion diseases: A rare group of neurodegenerative disorders
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Dissecting surveying behavior of reactive microglia under chronic neurodegenerationPreprint
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Self-citationPrion propensity of Betacoronaviruses including SARS-CoV-2
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Dissecting surveying behavior of reactive microglia under chronic neurodegeneration
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Strain-Dependent Morphology of Reactive Astrocytes in Human- and Animal-Vole-Adapted Prions
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Innate Immune Status of Glia Modulates Prion Propagation in Early Stage of Infection
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Self-citationPathological and Functional Brain Amyloids: A New Concept Explaining the Differences
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Excitatory neuron-prone prion propagation and excitatory neuronal loss in prion-infected mice
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Engulfment of viable neurons by reactive microglia in prion diseasesPreprint
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Self-citationReactive Microglia and Astrocytes as Therapeutic Targets in Prion Diseases
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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.107650.1
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
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Self-citationSlota, J. A., Sajesh, B. V., Frost, K. F., Medina, S. J., & Booth, S. A. (2022) · Figshare · doi:10.6084/m9.figshare.21532645
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Self-citationAge-associated microglial heterogeneity includes emergence of mobile microglial states
Subhramanian, S., Bocharova, O. V., Mychko, O., Makarava, N., & Baskakov, I. V. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1847223
Self-citationProtective role of Galectin‐3 in prion disease through regulation of microglial PrPSc uptake
Makarava, N., Safadi, T., Pandit, N. P., Mychko, O., Bocharova, O., Shevelkin, A., Molesworth, K., Lipinski, M. M., & Baskakov, I. (2026) · bioRxiv · doi:10.1111/bpa.70161 · Cited by 1 · see citing works
Self-citation
- Authors
- Makarava, N., Chang, J. C.-Y., Molesworth, K., & Baskakov, I. V.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Baskakov, Ilia V.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2020-04
- Volume
- 137
- Pages
- 104783
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC7052953
- OpenAlex
- W3003228785
- Cited by
- 64
- References
- 124
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 8 · 2023: 11 · 2022: 8 · 2021: 14 · 2020: 8
- FWCI
- 3.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Allergy and Infectious Diseases
- National Institute of Neurological Disorders and Stroke
- 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
- prion disease, neuroinflammation, astrocytes, microglia, prion strains, ME7 strain, cell tropism, disease progression, thalamus, cortex, hypothalamus, hippocampus, gene expression signatures, mouse model
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Disease Models, Animal, Inflammation, Mice, Inbred C57BL, Neuroglia, Neurons, Prion Diseases, Microglia
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