Non-cell autonomous astrocyte-mediated neuronal toxicity in prion diseases
Date
2021-02-05Journal
Acta Neuropathologica CommunicationsPublisher
Springer NatureType
Article
Metadata
Show full item recordAbstract
Under 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).Identifier to cite or link to this item
http://hdl.handle.net/10713/14744ae974a485f413a2113503eed53cd6c53
10.1186/s40478-021-01123-8
Scopus Count
Collections
Related articles
- RNA-seq and network analysis reveal unique glial gene expression signatures during prion infection.
- Authors: Carroll JA, Race B, Williams K, Striebel J, Chesebro B
- Issue date: 2020 May 7
- The degree of astrocyte activation is predictive of the incubation time to prion disease.
- Authors: Makarava N, Mychko O, Chang JC, Molesworth K, Baskakov IV
- Issue date: 2021 May 12
- Phagocytic Activities of Reactive Microglia and Astrocytes Associated with Prion Diseases Are Dysregulated in Opposite Directions.
- Authors: Sinha A, Kushwaha R, Molesworth K, Mychko O, Makarava N, Baskakov IV
- Issue date: 2021 Jul 8
- Complement 3(+)-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia.
- Authors: Hartmann K, Sepulveda-Falla D, Rose IVL, Madore C, Muth C, Matschke J, Butovsky O, Liddelow S, Glatzel M, Krasemann S
- Issue date: 2019 May 22
- Region-specific glial homeostatic signature in prion diseases is replaced by a uniform neuroinflammation signature, common for brain regions and prion strains with different cell tropism.
- Authors: Makarava N, Chang JC, Molesworth K, Baskakov IV
- Issue date: 2020 Apr