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dc.contributor.authorKushwaha, Rajesh
dc.contributor.authorSinha, Anshuman
dc.contributor.authorMakarava, Natallia
dc.contributor.authorMolesworth, Kara
dc.contributor.authorBaskakov, Ilia V
dc.date.accessioned2021-02-22T17:54:30Z
dc.date.available2021-02-22T17:54:30Z
dc.date.issued2021-02-05
dc.identifier.urihttp://hdl.handle.net/10713/14744
dc.description.abstractUnder normal conditions, astrocytes perform a number of important physiological functions centered around neuronal support and synapse maintenance. In neurodegenerative diseases including Alzheimer’s, Parkinson’s and prion diseases, astrocytes acquire reactive phenotypes, which are sustained throughout the disease progression. It is not known whether in the reactive states associated with prion diseases, astrocytes lose their ability to perform physiological functions and whether the reactive states are neurotoxic or, on the contrary, neuroprotective. The current work addresses these questions by testing the effects of reactive astrocytes isolated from prion-infected C57BL/6J mice on primary neuronal cultures. We found that astrocytes isolated at the clinical stage of the disease exhibited reactive, pro-inflammatory phenotype, which also showed downregulation of genes involved in neurogenic and synaptogenic functions. In astrocyte-neuron co-cultures, astrocytes from prion-infected animals impaired neuronal growth, dendritic spine development and synapse maturation. Toward examining the role of factors secreted by reactive astrocytes, astrocyte-conditioned media was found to have detrimental effects on neuronal viability and synaptogenic functions via impairing synapse integrity, and by reducing spine size and density. Reactive microglia isolated from prion-infected animals were found to induce phenotypic changes in primary astrocytes reminiscent to those observed in prion-infected mice. In particular, astrocytes cultured with reactive microglia-conditioned media displayed hypertrophic morphology and a downregulation of genes involved in neurogenic and synaptogenic functions. In summary, the current study provided experimental support toward the non-cell autonomous mechanisms behind neurotoxicity in prion diseases and demonstrated that the astrocyte reactive phenotype associated with prion diseases is synaptotoxic. © 2021, The Author(s).en_US
dc.description.urihttps://doi.org/10.1186/s40478-021-01123-8en_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofActa Neuropathologica Communicationsen_US
dc.subjectAstrocytesen_US
dc.subjectMicrogliaen_US
dc.subjectNeuroinflammationen_US
dc.subjectPrion diseasesen_US
dc.subjectPrionsen_US
dc.subjectSynaptic toxicityen_US
dc.titleNon-cell autonomous astrocyte-mediated neuronal toxicity in prion diseasesen_US
dc.typeArticleen_US
dc.identifier.doi10.1186/s40478-021-01123-8
dc.identifier.pmid33546775
dc.source.volume9
dc.source.issue1
dc.source.beginpage22
dc.source.endpage
dc.source.countryUnited States
dc.source.countryEngland


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