Activation of microglia by retroviral infection correlates with transient clearance of prions from the brain but does not change incubation time
Open accessAbstract
Prion diseases are fatal transmissible diseases, where conversion of the endogenous prion protein (PrP C) into a misfolded isoform (PrP Sc) leads to neurodegeneration. Microglia, the immune cells of the brain, are activated in neurodegenerative disorders including prion diseases; however, their impact on prion disease pathophysiology is unclear with both beneficial PrP Sc‐clearing and detrimental potentially neurotoxic effects. Moreover, monocytes entering the brain from the periphery during disease course might add to disease pathophysiology. Here, the degree of microglia activation in the brain of prion infected mice with and without an additional intraperitoneal retrovirus infection was studied. Peripheral murine retrovirus infection leads to activation of parenchymal microglia without recruitment of monocytes. This activation correlated with transient clearance or delay in accumulation of infectious prions specifically from the brain at early time points in the diseases course. Microglia expression profiling showed upregulation of genes involved in protein degradation coinciding with prion clearance. This enforces a concept where microglia act beneficial in prion disease if adequately activated. Once microglia activation has ceased, prion disease reemerges leading to disease kinetics undistinguishable from the situation in prion‐only infected mice. This might be caused by the loss of microglial homeostatic function at clinical prion disease.
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Although microglia numbers are significantly increased in all four brain regions at the terminal stage, the increase is highest in the thalamus.
“Although microglia numbers were significantly increased in all four brain regions at the terminal stage, the increase was highest in the thalamus [45,46,47].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [47]
The region-specific increase in microglia numbers during the course of prion disease has been shown with several mouse-adapted prion strains and may be aggravated by systemic infection.
“The region-specific increase in microglia numbers during the course of a prion disease had already been shown with several mouse adapted prion strains [45,46,47] and may be aggravated by systemic infection [48,49].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [47]
Retroviral infection preceding prion infection in mice leads to stimulation of microglia at early disease time points with a reduction in infectious prions.
“Interestingly, retroviral infection preceding prion infection in mice led to a stimulation of microglia at early disease time points with a reduction in infectious prions [47]”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [47]
In terminal prion disease, microglia morphology changes from the ramified presentation typical in homeostasis to a bushy/reactive or even amoeboid morphology in a region-dependent manner.
“First, microglia morphology is changed from the ramified presentation typical in homeostasis to a bushy/reactive or even amoeboid morphology in a region-dependent manner (Figure 3A,B) [45,46,47].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [47]
The number of activated microglia is highest in the thalamus, a region where reactive microglia can already be detected at a preclinical time point.
“The number of activated microglia is highest in the thalamus, a region where reactive microglia can already be detected at a preclinical time point (see Figure 2) [45,46,47].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [47]
The appearance of reactive microglia starts before the onset of symptoms, can be detected at around day 70-80 in a region-dependent manner, and is visible mainly in the thalamus at this time point.
“Different groups have independently shown that the appearance of reactive microglia starts before the onset of symptoms, can be detected at around day 70–80 in a region-dependent manner, and is visible mainly in the thalamus at this time point (Figure 2) [45,46,47].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [47]
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 [47]
The loss of the homeostatic signature is especially severe in prion diseases compared to other neurodegenerative conditions.
“Fittingly, we found that the loss of the homeostatic signature is especially severe in prion diseases compared to other neurodegenerative conditions [47,55].”
From Loss of Homeostatic Microglia Signature in Prion Diseases (2022) · cites this paper as [47]
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 [47]
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 [47]
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References 64 · Cited by 23
- Authors
- Muth, C., Schröck, K., Madore, C., Hartmann, K., Fanek, Z., Butovsky, O., Glatzel, M., & Krasemann, S.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- Brigham and Women's Hospital (US)
- Corresponding author
- Glatzel, Markus
- Krasemann, Susanne
- Venue
- Brain Pathology
- Publisher
- Wiley
- Published
- 2016-11-21
- Volume
- 27
- Issue
- 5
- Pages
- 590-602
- ISSN
- 1015-6305 (ISSN-L)
- 1750-3639
- PMC
- PMC6625757
- OpenAlex
- W2513763972
- Cited by
- 23
- References
- 64
- Citations by year
- 2025: 1 · 2022: 1 · 2021: 6 · 2020: 8 · 2019: 3 · 2018: 1 · 2017: 3
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Pathology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS088137)
- 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, microglial activation, retroviral infection, prion clearance, incubation time, prion protein, monocyte recruitment, protein degradation, neurodegeneration, microglial homeostasis
- MeSH terms
- Animals, Brain, Monocytes, Prions, Retroviridae Infections, Prion Diseases, Microglia, Mice, Infectious Disease Incubation Period, Proteolysis
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