Cited by 64Prion Diseases and Protein MisfoldingNeuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatments

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

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Makarava, Natallia, Chang, Jennifer Chen-Yu, Molesworth, Kara, Baskakov, Ilia V.·2020·Neurobiology of Disease

Abstract

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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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)
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
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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