Five Questions on Prion Diseases

Aguzzi, Adriano; Zhu, Chuanbing

doi:10.1371/journal.ppat.1002651

Cited by 33 publications

(24 citation statements)

References 29 publications

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“…The opsonin Mfge8 is instrumental for microglia-dependent clearance of prions, possibly by bridging phospholipids trapped within PrP Sc to integrins expressed by microglia (Kranich, et al, 2010). However, the impact of Mfge8 is highly variable among different mouse strains, suggesting that additional molecules (which may be polymorphic in the mouse) play roles similar to Mfge8 in prion clearance (Aguzzi and Zhu, 2012). The identification of such additional molecules is of practical importance, since they may represent therapeutic targets for this group of diseases.…”

Section: Introductionmentioning

confidence: 99%

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

Zhu

Herrmann

et al. 2015

Neurobiology of Aging

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Dysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly up-regulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2(-/-) mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation but does not noticeably modulate the pathogenesis of experimental prion infections. | P a g e AbstractDysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly upregulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2 -/-mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation, but does not noticeably modulate the pathogenesis of experimental prion infections.

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Section: Introductionmentioning

confidence: 99%

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

Zhu

Herrmann

et al. 2015

Neurobiology of Aging

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“…Prion diseases, also known as transmissible spongiform encephalopathies, are a group of progressive and fatal neurodegenerative disorders affecting humans (such as Creutzfeldt-Jakob disease, kuru, Gerstmann-Sträussler-Scheinker disease, and fatal familiar insomnia) and several other mammals (such as scrapie in sheep and goats, bovine spongiform encephalopathy in cattle, and chronic wasting disease in deer, moose, and elk) (1,2). Prion diseases are characterized by the deposition of scrapie prion protein (PrP Sc ), a misfolded form of cellular prion protein (PrP C ), in the CNS.…”

Section: Introductionmentioning

confidence: 99%

Microglia in prion diseases

Aguzzi

Zhu

2017

Journal of Clinical Investigation

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“…These results indicate that microglial cells have the potential to induce neuronal cell death via an inflammatory response. However, microglial cells have been considered to play a key role in prion clearance [31]. Falsing et al (2008) observed a 15-fold increase in prion titers on organotypic cerebellar slices following ablation of microglia [32].…”

Section: Discussionmentioning

confidence: 99%

Prion Peptide Uptake in Microglial Cells – The Effect of Naturally Occurring Autoantibodies against Prion Protein

et al. 2013

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In prion disease, a profound microglial activation that precedes neurodegeneration has been observed in the CNS. It is still not fully elucidated whether microglial activation has beneficial effects in terms of prion clearance or whether microglial cells have a mainly detrimental function through the release of pro-inflammatory cytokines. To date, no disease-modifying therapy exists. Several immunization attempts have been performed as one therapeutic approach. Recently, naturally occurring autoantibodies against the prion protein (nAbs-PrP) have been detected. These autoantibodies are able to break down fibrils of the most commonly used mutant prion variant PrP106-126 A117V and prevent PrP106-126 A117V-induced toxicity in primary neurons. In this study, we examined the phagocytosis of the prion peptide PrP106-126 A117V by primary microglial cells and the effect of nAbs-PrP on microglia. nAbs-PrP considerably enhanced the uptake of PrP106-126 A117V without inducing an inflammatory response in microglial cells. PrP106-126 A117V uptake was at least partially mediated through scavenger receptors. Phagocytosis of PrP106-126 A117V with nAbs-PrP was inhibited by wortmannin, a potent phosphatidylinositol 3-kinase inhibitor, indicating a separate uptake mechanism for nAbs-PrP mediated phagocytosis. These data suggest the possible mechanisms of action of nAbs-PrP in prion disease.

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Five Questions on Prion Diseases

Cited by 33 publications

References 29 publications

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

Microglia in prion diseases

Prion Peptide Uptake in Microglial Cells – The Effect of Naturally Occurring Autoantibodies against Prion Protein

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