A role for astroglia in prion diseases

Aguzzi, Adriano; Liu, Yingjun

doi:10.1084/jem.20172045

Cited by 22 publications

(15 citation statements)

References 23 publications

(25 reference statements)

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“…Astrocytes have also been suggested to actively replicated PrP Sc and contribute to PrP Sc production and disease progression [16, 37] or even to spreading of PrP Sc [27, 60]. Since most of these studies have been performed in vitro, it is still controversial, if astrocytic PrP Sc formation alone is sufficient to mount a clinical prion disease in vivo [2, 30, 44, 54]. Astrocyte subtypes might contribute differentially to the features ascribed to astrocytes in prion diseases with C3 + -PrP Sc -reactive astrocytes potentially acting beneficial as suggested by our study.…”

Section: Discussionmentioning

confidence: 99%

Complement 3+-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia

Hartmann

Sepulveda‐Falla

Rose

et al. 2019

acta neuropathol commun

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Astrogliosis and activation of microglia are hallmarks of prion diseases in humans and animals. Both were viewed to be rather independent events in disease pathophysiology, with proinflammatory microglia considered to be the potential neurotoxic species at late disease stages. Recent investigations have provided substantial evidence that a proinflammatory microglial cytokine cocktail containing TNF-α, IL-1α and C1qa reprograms a subset of astrocytes to change their expression profile and phenotype, thus becoming neurotoxic (designated as A1-astrocytes). Knockout or antibody blockage of the three cytokines abolish formation of A1-astrocytes, therefore, this pathway is of high therapeutic interest in neurodegenerative diseases. Since astrocyte polarization profiles have never been investigated in prion diseases, we performed several analyses and could show that C3 + -PrP Sc -reactive-astrocytes, which may represent a subtype of A1-astrocytes, are highly abundant in prion disease mouse models and human prion diseases. To investigate their impact on prion disease pathophysiology and to evaluate their potential therapeutic targeting, we infected TNF-α, IL-1α, and C1qa Triple-KO mice (TKO-mice), which do not transit astrocytes into A1, with prions. Although formation of C3 + -astrocytes was significantly reduced in prion infected Triple-KO-mice, this did not affect the amount of PrP Sc deposition or titers of infectious prions. Detailed characterization of the astrocyte activation signature in thalamus tissue showed that astrocytes in prion diseases are highly activated, showing a mixed phenotype that is distinct from other neurodegenerative diseases and were therefore termed C3 + -PrP Sc -reactive-astrocytes. Unexpectedly, Triple-KO led to a significant acceleration of prion disease course. While pan-astrocyte and -microglia marker upregulation was unchanged compared to WT-brains, microglial homeostatic markers were lost early in disease in TKO-mice, pointing towards important functions of different glia cell types in prion diseases. Electronic supplementary material The online version of this article (10.1186/s40478-019-0735-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Complement 3+-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia

Hartmann

Sepulveda‐Falla

Rose

et al. 2019

acta neuropathol commun

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“…Consequently, establishing a cell culture model consisting of stably infected astrocytes would help to understand the exact role of astrocytes in prion propagation better. Currently, there is only one ovine microglia cell line available for propagation of sheep prions (36) and human stem cell-derived astrocytes that can propagate human prions (37,38). Although most work in prion cell culture was done with mouse-adapted prion strains like 22L, RML, and ME7, there is currently no murine astrocyte cell culture model available that can be persistently infected with mouse prions.…”

Section: Discussionmentioning

confidence: 99%

“…Of note, with a few exceptions, such cell line models do not show side effects as would be expected from prion pathogenesis in vivo (31,32), an issue that can be better addressed in primary cells (33), cerebral organoids (34), and slice culture models (35). There was a shortage of glia cell models, with ovine microglia cells for propagation of sheep prions (36) and human stem cell-derived astrocytes replicating even human prions (37,38).…”

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confidence: 99%

An astrocyte cell line that differentially propagates murine prions

Tahir

Abdulrahman

Abdelaziz

et al. 2020

Journal of Biological Chemistry

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Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the pathological isoform PrPSc. Elucidating the molecular and cellular mechanisms underlying prion propagation may help to develop disease interventions. Cell culture systems for prion propagation have greatly advanced molecular insights into prion biology, but translation of in vitro to in vivo findings is often disappointing. A wider range of cell culture systems might help overcome these shortcomings. Here, we describe an immortalized mouse neuronal astrocyte cell line (C8D1A) that can be infected with murine prions. Both PrPC protein and mRNA levels in astrocytes were comparable to those in neuronal and nonneuronal cell lines permitting persistent prion infection. We challenged astrocytes with three mouse-adapted prion strains (22L, RML, and ME7) and cultured them for six passages. Immunoblotting results revealed that the astrocytes propagated 22L prions well over all six passages, whereas ME7 prions did not replicate, and RML prions only very weakly after five passages. Immunofluorescence analysis indicated similar results for PrPSc. Interestingly, when we used prion conversion activity as a read-out in real-time quaking-induced conversion (RT-QuIC) assays with RML-infected cell lysates, we observed a strong signal over all six passages, comparable to that for 22L-infected cells. These data indicate that the C8D1A cell line is permissive to prion infection. Moreover, the propagated prions differed in conversion and proteinase K–resistance levels in these astrocytes. We propose that the C8D1A cell line could be used to decipher prion strain biology.

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“…Astrocytes contribute to the maintenance of health and function of the CNS and are considered important in neurodegenerative diseases (Phatnani and Maniatis, 2015) including prion disease (Aguzzi and Liu, 2017). Reactive astrocytes were identified by immunostaining for the intermediate filament GFAP and their altered morphology (Figure 5B, lower row).…”

Section: Resultsmentioning

confidence: 99%

Discrimination of Prion Strain Targeting in the Central Nervous System via Reactive Astrocyte Heterogeneity in CD44 Expression

Bradford

Wijaya

Mabbott

2019

Front. Cell. Neurosci.

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Prion diseases or transmissible spongiform encephalopathies are fatal, progressive, neurodegenerative, protein-misfolding disorders. Prion diseases may arise spontaneously, be inherited genetically or be acquired by infection and affect a variety of mammalian species including humans. Prion infections in the central nervous system (CNS) cause extensive neuropathology, including abnormal accumulations of misfolded host prion protein, vacuolar change resulting in sponge-like (spongiform) appearance of CNS tissue, neurodegeneration and reactive glial responses. Many different prion agent strains exist and these can differ based on disease duration, clinical signs and the targeting and distribution of the neuropathology in distinct brain areas. Reactive astrocytes are a prominent feature in the prion disease affected CNS as revealed by distinct morphological changes and upregulation of glial fibrillary acidic protein (GFAP). The CD44 antigen is a transmembrane glycoprotein involved in cell-cell interactions, cell adhesion and migration. Here we show that CD44 is also highly expressed in a subset of reactive astrocytes in regions of the CNS targeted by prions. Astrocyte heterogeneity revealed by differential CD44 upregulation occurs coincident with the earliest neuropathological changes during the pre-clinical phase of disease, and is not affected by the route of infection. The expression and distribution of CD44 was compared in brains from a large collection of 15 distinct prion agent strains transmitted to mice of different prion protein (Prnp) genotype backgrounds. Our data show that the pattern of CD44 upregulation observed in the hippocampus in each prion agent strain and host Prnp genotype combination was unique. Many mouse-adapted prion strains and hosts have previously been characterized based on the pattern of the distribution of the spongiform pathology or the misfolded PrP deposition within the brain. Our data show that CD44 expression also provides a reliable discriminatory marker of prion infection with a greater dynamic range than misfolded prion protein deposition, aiding strain identification. Together, our data reveal CD44 as a novel marker to detect reactive astrocyte heterogeneity during CNS prion disease and for enhanced identification of distinct prion agent strains.

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A role for astroglia in prion diseases

Cited by 22 publications

References 23 publications

Complement 3+-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia

Complement 3+-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia

An astrocyte cell line that differentially propagates murine prions

Discrimination of Prion Strain Targeting in the Central Nervous System via Reactive Astrocyte Heterogeneity in CD44 Expression

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