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In neurodegenerative diseases including Alzheimer’s, Parkinson’s and prion diseases, astrocytes acquire disease-associated reactive phenotypes. With growing appreciation of their role in chronic neurodegeneration, the questions whether astrocytes lose their ability to perform homeostatic functions in the reactive states and whether the reactive phenotypes are neurotoxic or neuroprotective remain unsettled. The current work examined region-specific changes in expression of genes, which report on astrocyte physiological functions and their reactive states, in C57Black/6J mice challenged with four prion strains via two inoculation routes. Unexpectedly, strong reverse correlation between the incubation time to the diseases and the degree of astrocyte activation along with disturbance in functional pathways was observed. The animal groups with the most severe astrocyte response and degree of activation showed the most rapid disease progression. The degree of activation tightly intertwined with the global transformation of the homeostatic state, characterized by disturbances in multiple gene sets responsible for normal physiological functions producing a neurotoxic, reactive phenotype as a net result. The neurotoxic reactive phenotype exhibited a universal gene signature regardless of the prion strain. The current work suggests that the degree of astrocyte activation along with the disturbance in their physiological pathways contribute to the faster progression of disease and perhaps even drive prion pathogenesis.

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.

Alzheimer’s disease (AD) is a devastating fatal neurodegenerative disease. An alternative to the amyloid cascade hypothesis is that a viral infection is key to the etiology of late-onset AD, with β-amyloid (Aβ) peptides playing a protective role. In the current study, young 5XFAD mice that overexpress mutant human amyloid precursor protein with the Swedish, Florida, and London familial AD mutations were infected with one of two strains of herpes simplex virus 1 (HSV-1), 17syn+ and McKrae, at three different doses. Contrary to previous work, 5XFAD genotype failed to protect mice against HSV-1 infection. The region- and cell-specific tropisms of HSV-1 were not affected by the 5XFAD genotype, indicating that host–pathogen interactions were not altered. Seven- to ten-month-old 5XFAD animals in which extracellular Aβ aggregates were abundant showed slightly better survival rate relative to their wild-type (WT) littermates, although the difference was not statistically significant. In these 5XFAD mice, HSV-1 replication centers were partially excluded from the brain areas with high densities of Aβ aggregates. Aβ aggregates were free of HSV-1 viral particles, and the limited viral invasion to areas with a high density of Aβ aggregates was attributed to phagocytic activity of reactive microglia. In the oldest mice (12–15 months old), the survival rate did not differ between 5XFAD and WT littermates. While the current study questions the antiviral role of Aβ, it neither supports nor refutes the viral etiology hypothesis of late-onset AD.