Role of reactive astrocytes in prion diseases

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Summary Prion diseases are a family of transmissible neurodegenerative maladies that have no treatment and are 100% lethal. Transformation of astrocytes and microglia into reactive states is recognized as one of the major hallmarks of neurodegenerative disease including prion, Alzheimer’s, and Parkinson’s diseases. The vast majority of previous work on neuroinflammation associated with prion diseases has focused on reactive microglia, whereas very little is known about the role of reactive astrocytes in disease pathogenesis. Recent years witnessed a growing appreciation of the view that, like microglia, reactive astrocytes are intimately involved in chronic neurodegeneration. However, whether the reactive astrocytes associated with prion diseases are beneficial or detrimental is not known. The current project is designed to fill this gap and is the first to critically examine the role of reactive astrocytes in prion disease. Our preliminary studies in animals infected with prions reveal global dysregulation across multiple physiological functions including the loss of neuronal support function in reactive astrocytes. Moreover, reactive astrocytes isolated from prion-infected mice were found to exhibit deleterious effects on primary neurons. The degree of astrocyte reactivity was found to be predictive of the incubation time to prion disease, suggesting that phenotypic changes in astrocytes contribute to faster disease progression. Consistent with current knowledge that astrocyte reactivity is driven by the Stat3 transcription factor, we observed activation of Stat3 in reactive astrocytes in prion-infected animals. The current application will employ a novel mouse model, Aldh1l1-CreERT-Stat3-floxP, for conditional knockout of Stat3 in astrocytes to examine the role of reactive astrocytes in prion disease. Specific Aim 1 will examine the effects of conditional knockout of the Stat3 transcription factor in astrocytes on the pathogenesis of prion disease in mice. Specific Aim 2 will employ astrocytes and microglia acutely isolated from prion-infected animals to test the extent to which Stat3 knockout in astrocytes rescues their homeostatic functions; and impacts the reactive state of microglia. Specific Aim 3 will employ single-nuclei RNAseq to characterize the phenotypic heterogeneity of reactive astrocytes associated with prion disease. Upon completion of the proposal we expect to learn whether reactive astrocytes drive disease pathogenesis, and whether conditional knockout of Stat3 rescues important homeostatic functions of astrocytes and/or delays or ameliorates the disease. Thus, the results of this study will provide critical information as to whether astrocyte reactivity should be targeted as a potential therapeutic strategy for treating prion disease.