A neuroprotective role for microglia in prion diseases

Zhu, Chuanbing; Herrmann, U.; Falsig, Jeppe; Абакумова, Ирина; Nuvolone, Mario; Schwarz, Petra; Frauenknecht, Katrin; Rushing, Elisabeth J.; Aguzzi, Adriano

doi:10.1084/jem.20151000

Cited by 121 publications

(102 citation statements)

References 44 publications

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“…It has recently been demonstrated that activation of microglia contributes an over-all protective role against prion pathology, probably by phagocytosing harmful prion aggregates or cellular debris28. Our observation of shortened clinical duration in Neil3 KO mice could therefore be a result of compromised microglial activation in this genotype.…”

Section: Discussionmentioning

confidence: 55%

Neil3 induced neurogenesis protects against prion disease during the clinical phase

Jalland

Scheffler

Benestad

et al. 2016

Sci Rep

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Base excision repair (BER) is the major pathway for repair of oxidative DNA damage. Mice with genetic knockout of the BER enzyme Neil3 display compromised neurogenesis in the sub-ventricular zone of the lateral ventricle and sub-granular layer of the dentate gyrus of the hippocampus. To elucidate the impact of oxidative DNA damage-induced neurogenesis on prion disease we applied the experimental prion disease model on Neil3-deficient mice. The incubation period for the disease was similar in both wild type and Neil3−/− mice and the overall neuropathology appeared unaffected by Neil3 function. However, disease in the Neil3−/− mice was of shorter clinical duration. We observed a mildly reduced astrogliosis in the hippocampus and striatum in the Neil3-deficient mice. Brain expression levels of neuronal progenitor markers, nestin (Nestin), sex determining region Box 2 (Sox2), Class III beta-tubulin (Tuj1) decreased towards end-stage prion disease whereas doublecortin (Dcx) levels were less affected. Neuronal nuclei (NeuN), a marker for mature neurons declined during prion disease and more pronounced in the Neil3−/− group. Microglial activation was prominent and appeared unaffected by loss of Neil3. Our data suggest that neurogenesis induced by Neil3 repair of oxidative DNA damage protects against prion disease during the clinical phase.

show abstract

Section: Discussionmentioning

confidence: 55%

Neil3 induced neurogenesis protects against prion disease during the clinical phase

Jalland

Scheffler

Benestad

et al. 2016

Sci Rep

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“…Microglia also play a role in autoimmune demyelination (experimental autoimmune encephalomyelitis [EAE]), with a specific role in clearing myelin debris (37). Notably, microglia differed phenotypically and in terms of microglia phagocytosis has been demonstrated in the context of prion disease, in which microglia depletion resulted in accelerated disease progression, probably due to diminished prion clearance (57).…”

Section: Discussionmentioning

confidence: 99%

Microglia are required for protection against lethal coronavirus encephalitis in mice

Wheeler¹,

Sariol²,

Meyerholz³

et al. 2018

Journal of Clinical Investigation

156

214

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Recent findings have highlighted the role of microglia in orchestrating normal development and refining neural network connectivity in the healthy CNS. Microglia are not only vital cells in maintaining CNS homeostasis, but also respond to injury, infection, and disease by undergoing proliferation and changes in transcription and morphology. A better understanding of the specific role of microglia in responding to viral infection is complicated by the presence of nonmicroglial myeloid cells with potentially overlapping function in the healthy brain and by the rapid infiltration of hematopoietic myeloid cells into the brain in diseased states. Here, we used an inhibitor of colony-stimulating factor 1 receptor (CSF1R) that depletes microglia to examine the specific roles of microglia in response to infection with the mouse hepatitis virus (MHV), a neurotropic coronavirus. Our results show that microglia were required during the early days after infection to limit MHV replication and subsequent morbidity and lethality. Additionally, microglia depletion resulted in ineffective T cell responses. These results reveal nonredundant, critical roles for microglia in the early innate and virus-specific T cell responses and for subsequent host protection from viral encephalitis.

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“…The same ex vivo model was used to determine the effect of microglial depletion on prion-induced neurodegeneration. After microglial depletion, not only PrP Sc accumulation but also neurotoxicity of prions were drastically enhanced, and prion pathology was markedly aggravated (47). Moreover, while the tga20/ CD11b-HSVTK transgenic mice were intracerebrally infected with prions, followed by implantation of osmotic minipumps containing ganciclovir to deliver the drug directly into the brain, the incubation time of prion-infected microglia-depleted mice was significantly shortened (47).…”

Section: Microglial Activation and Cytokine Release In Prion Diseasesmentioning

confidence: 99%

“…Moreover, while the tga20/ CD11b-HSVTK transgenic mice were intracerebrally infected with prions, followed by implantation of osmotic minipumps containing ganciclovir to deliver the drug directly into the brain, the incubation time of prion-infected microglia-depleted mice was significantly shortened (47). Additionally, when prions were inoculated into Il34 -/-mice, which contain fewer microglia because of impaired microglial development and maintenance (48,49), PrP Sc deposition was augmented and prion progression was accelerated in comparison with infected WT littermates (47). Therefore, we contend that microglia play a generally neuroprotective rather than deleterious role in prion pathogenesis ( Figure 2).…”

Section: Microglial Activation and Cytokine Release In Prion Diseasesmentioning

confidence: 99%

Microglia in prion diseases

Aguzzi

Zhu

2017

Journal of Clinical Investigation

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A neuroprotective role for microglia in prion diseases

Abstract: Microglial activation is a hallmark of most neurodegenerative disorders, yet it is not clear if it plays beneficial or deleterious roles. Zhu et al. provide evidence for a general protective role of microglia in the pathogenesis of prion diseases.

Cited by 121 publications

References 44 publications

Neil3 induced neurogenesis protects against prion disease during the clinical phase

Neil3 induced neurogenesis protects against prion disease during the clinical phase

Microglia are required for protection against lethal coronavirus encephalitis in mice

Microglia in prion diseases

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