Targeted knock-down of cellular prion protein expression in myelinating Schwann cells does not alter mouse prion pathogenesis

Halliez, Sophie; Chesnais, Nathalie; Mallucci, Giovanna R.; Vilotte, Marthe; Langevin, Christelle; Jaumain, Emilie; Laude, Hubert; Vilotte, Jean Luc; Béringue, Vincent

doi:10.1099/vir.0.049619-0

Cited by 6 publications

(3 citation statements)

References 48 publications

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“…In contrast to mouse AD models, mouse prion disease, which is characterized by an accumulation of misfolded prion protein aggregates ( 3 , 15 , 25 ), results in progressive neuronal loss and eventual terminal disease ( 24 , 26 , 27 ). Here, we show that mouse prion disease shares a number of key features with AD that include a loss of hippocampal cholinergic innervation and a cholinergic deficit that results in defective learning and memory while maintaining postsynaptic muscarinic receptors and signaling.…”

Section: Introductionmentioning

confidence: 99%

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

Bradley¹,

Bourgognon²,

Sanger³

et al. 2016

Journal of Clinical Investigation

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The current frontline symptomatic treatment for Alzheimer’s disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR–selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.

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Section: Introductionmentioning

confidence: 99%

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

Bradley¹,

Bourgognon²,

Sanger³

et al. 2016

Journal of Clinical Investigation

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“…Oligodendrocytes have been reported as resistant to prion infection (14). Although Schwann cells have been reported as susceptible to prion infection (15), Schwann cells do not appear to be involved in the neurodegenerative process (16). It was reported that prions propagate in microglia isolated from PrP C -overexpressing mice (17) and that microglia isolated from CJD model mice possessed prion infectivity (18).…”

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confidence: 99%

Flow Cytometric Detection of PrP^Scin Neurons and Glial Cells from Prion-Infected Mouse Brains

Yamasaki

Suzuki

Hasebe

et al. 2018

J Virol

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In prion diseases, an abnormal isoform of prion protein (PrP) accumulates in neurons, astrocytes, and microglia in the brains of animals affected by prions. Detailed analyses of PrP-positive neurons and glial cells are required to clarify their pathophysiological roles in the disease. Here, we report a novel method for the detection of PrP in neurons and glial cells from the brains of prion-infected mice by flow cytometry using PrP-specific staining with monoclonal antibody (MAb) 132. The combination of PrP staining and immunolabeling of neural cell markers clearly distinguished neurons, astrocytes, and microglia that were positive for PrP from those that were PrP negative. The flow cytometric analysis of PrP revealed the appearance of PrP-positive neurons, astrocytes, and microglia at 60 days after intracerebral prion inoculation, suggesting the presence of PrP in the glial cells, as well as in neurons, from an early stage of infection. Moreover, the kinetic analysis of PrP revealed a continuous increase in the proportion of PrP-positive cells for all cell types with disease progression. Finally, we applied this method to isolate neurons, astrocytes, and microglia positive for PrP from a prion-infected mouse brain by florescence-activated cell sorting. The method described here enables comprehensive analyses specific to PrP-positive neurons, astrocytes, and microglia that will contribute to the understanding of the pathophysiological roles of neurons and glial cells in PrP-associated pathogenesis. Although formation of PrP in neurons is associated closely with neurodegeneration in prion diseases, the mechanism of neurodegeneration is not understood completely. On the other hand, recent studies proposed the important roles of glial cells in PrP-associated pathogenesis, such as the intracerebral spread of PrP and clearance of PrP from the brain. Despite the great need for detailed analyses of PrP-positive neurons and glial cells, methods available for cell type-specific analysis of PrP have been limited thus far to microscopic observations. Here, we have established a novel high-throughput method for flow cytometric detection of PrP in cells with more accurate quantitative performance. By applying this method, we succeeded in isolating PrP-positive cells from the prion-infected mouse brains via fluorescence-activated cell sorting. This allows us to perform further detailed analysis specific to PrP-positive neurons and glial cells for the clarification of pathological changes in neurons and pathophysiological roles of glial cells.

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“…In addition, PrP Sc aggregates traveled along neuritic projections in in vitro neuronal cultures [ 128 ]. To complement this finding, Schwann cells with ablated PrP C expression using two different transgenetic mouse models did not slow the progression and incubation period of scrapie after intraperitoneal inoculation in mice [ 129 , 130 ]. This further strengthens the overarching finding that prions invade the CNS through peripheral neuronal pathways and utilize axons to propagate along these pathways towards central structures.…”

Section: Cell Types Involved In Prion Transportmentioning

confidence: 99%

Transport of Prions in the Peripheral Nervous System: Pathways, Cell Types, and Mechanisms

Koshy

Kincaid

Bartz

2022

Viruses

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Prion diseases are transmissible protein misfolding disorders that occur in animals and humans where the endogenous prion protein, PrPC, undergoes a conformational change into self-templating aggregates termed PrPSc. Formation of PrPSc in the central nervous system (CNS) leads to gliosis, spongiosis, and cellular dysfunction that ultimately results in the death of the host. The spread of prions from peripheral inoculation sites to CNS structures occurs through neuroanatomical networks. While it has been established that endogenous PrPC is necessary for prion formation, and that the rate of prion spread is consistent with slow axonal transport, the mechanistic details of PrPSc transport remain elusive. Current research endeavors are primarily focused on the cellular mechanisms of prion transport associated with axons. This includes elucidating specific cell types involved, subcellular machinery, and potential cofactors present during this process.

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Targeted knock-down of cellular prion protein expression in myelinating Schwann cells does not alter mouse prion pathogenesis

Cited by 6 publications

References 48 publications

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

Flow Cytometric Detection of PrP^Scin Neurons and Glial Cells from Prion-Infected Mouse Brains

Transport of Prions in the Peripheral Nervous System: Pathways, Cell Types, and Mechanisms

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Targeted knock-down of cellular prion protein expression in myelinating Schwann cells does not alter mouse prion pathogenesis

Cited by 6 publications

References 48 publications

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss

Flow Cytometric Detection of PrPScin Neurons and Glial Cells from Prion-Infected Mouse Brains

Transport of Prions in the Peripheral Nervous System: Pathways, Cell Types, and Mechanisms

Contact Info

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Flow Cytometric Detection of PrP^Scin Neurons and Glial Cells from Prion-Infected Mouse Brains