Abstract
BackgroundPrion diseases and prion-like disorders, including Alzheimer’s disease and Parkinson’s disease, are characterized by gliosis and accumulation of misfolded aggregated host proteins. Ablating microglia in prion-infected brain by treatment with the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, PLX5622, increased accumulation of misfolded prion protein and decreased survival time.MethodsTo better understand the role of glia during neurodegeneration, we used RNA-seq technology, network analysis, and hierarchical cluster analysis to compare gene expression in brains of prion-infected versus mock-inoculated mice. Comparisons were also made between PLX5622-treated prion-infected mice and untreated prion-infected mice to assess mechanisms involved in disease acceleration in the absence of microglia.ResultsRNA-seq and network analysis suggested that microglia responded to prion infection through activation of integrin CD11c/18 and did not adopt the expression signature associated with other neurodegenerative disease models. Instead, microglia acquired an alternative molecular signature late in the disease process. Furthermore, astrocytes expressed a signature pattern of genes which appeared to be specific for prion diseases. Comparisons were also made with prion-infected mice treated with PLX5622 to assess the impact of microglia ablation on astrocyte gene expression during prion infection. In the presence of microglia, a unique mix of transcripts associated with A1- and A2-reactive astrocytes was increased in brains of prion-infected mice. After ablation of microglia, this reactive astrocyte expression pattern was enhanced. Thus, after prion infection, microglia appeared to decrease the overall A1/A2-astrocyte responses which might contribute to increased survival after infection.ConclusionsRNA-seq analysis indicated dysregulation of over 300 biological processes within the CNS during prion disease. Distinctive microglia- and astrocyte-associated expression signatures were identified during prion infection. Furthermore, astrogliosis and the unique astrocyte-associated expression signature were independent of microglial influences. Astrogliosis and the unique astrocyte-associated gene expression pattern were increased when microglia were ablated. Our findings emphasize the potential existence of alternative pathways for activating the A1/A2 paradigm in astrocytes during neurodegenerative disease.
Highlights
Prion diseases and prion-like disorders, including Alzheimer’s disease and Parkinson’s disease, are characterized by gliosis and accumulation of misfolded aggregated host proteins
Though the specific protein(s) that misfold and aggregate differ depending on the disease, it is theorized that neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and prion disease are propagated in the central nervous system (CNS) by an analogous mechanism known as “seeded polymerization.”
RNA-seq expression data was analyzed by principal component analysis (PCA) (Additional File, Supplementary Dataset 1). Plotting these results indicated two important points: 1) most of the mockinfected mice that were either PLX5622-treated or untreated clustered tightly, indicative of negligible variance in overall gene expression and 2) mice treated with PLX5622 for 161 days segregated outside of this cluster, suggesting long-term PLX5622 treatment alone has a small but observable effect on overall gene expression in mice
Summary
Prion diseases and prion-like disorders, including Alzheimer’s disease and Parkinson’s disease, are characterized by gliosis and accumulation of misfolded aggregated host proteins. Many neurodegenerative diseases are characterized by the accumulation of misfolded host proteins that form aggregates in the central nervous system (CNS) [1]. Though the specific protein(s) that misfold and aggregate differ depending on the disease, it is theorized that neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and prion disease are propagated in the CNS by an analogous mechanism known as “seeded polymerization.”. Because of the similarities in pathology and misfolded protein aggregation among the infectious prion diseases and several non-infectious neurological diseases [3], there has been a renewed interest in studying prion-like effects in many neurodegenerative diseases. Several aspects of prion disease, such as prominent astrogliosis and microgliosis, are shared with many neuroinflammatory and neurodegenerative disorders [8,9,10,11,12]
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