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Abstract
Prion diseases or prionoses are a group of rapidly progressing and invariably fatal neurodegenerative diseases. The pathogenesis of prionoses is associated with self-replication and connectomal spread of PrPSc, a disease specific conformer of the prion protein. Microglia undergo activation early in the course of prion pathogenesis and exert opposing roles in PrPSc mediated neurodegeneration. While clearance of PrPSc and apoptotic neurons have disease-limiting effect, microglia-driven neuroinflammation bears deleterious consequences to neuronal networks. Apolipoprotein (apo) E is a lipid transporting protein with pleiotropic functions, which include controlling of the phagocytic and inflammatory characteristics of activated microglia in neurodegenerative diseases. Despite the significance of microglia in prion pathogenesis, the role of apoE in prionoses has not been established. We showed here that infection of wild type mice with 22L mouse adapted scrapie strain is associated with significant increase in the total brain apoE protein and mRNA levels and also with a conspicuous cell-type shift in the apoE expression. There is reduced expression of apoE in activated astrocytes and marked upregulation of apoE expression by activated microglia. We also showed apoE ablation exaggerates PrPSc mediated neurodegeneration. Apoe−/− mice have shorter disease incubation period, increased load of spongiform lesion, pronounced neuronal loss, and exaggerated astro and microgliosis. Astrocytes of Apoe−/− mice display salient upregulation of transcriptomic markers defining A1 neurotoxic astrocytes while microglia show upregulation of transcriptomic markers characteristic for microglial neurodegenerative phenotype. There is impaired clearance of PrPSc and dying neurons by microglia in Apoe−/− mice along with increased level of proinflammatory cytokines. Our work indicates that apoE absence renders clearance of PrPSc and dying neurons by microglia inefficient, while the excess of neuronal debris promotes microglial neurodegenerative phenotype aggravating the vicious cycle of neuronal death and neuroinflammation.
Highlights
Prion disease are a group of fatal neurodegenerative diseases affecting humans and certain mammalian species
Prion infection increases brain Apolipoprotein E (apoE) level and causes cell‐type shift in the apoE expression We first compared the total brain apoE level and its expression by astrocytes and microglia in wild-type (WT) C57BL/6 mouse strain (B6) mice, which were intraperitoneally inoculated with 22L mouse adapted scrapie strain or normal brain homogenate (NBH). 22L inoculated B6 mice were killed at 15 and 23 week post inoculation, when animals remain neurologically asymptomatic or show overt clinical symptoms of prion disease, respectively
Cell-type specific determination of apoE expression was performed in the brain cortex by apoE corrected total cell fluorescence (CTCF) analysis in apoE/ Glial fibrillary acidic protein (GFAP) and apoE/Ionized calcium binding adaptor molecule (Iba1) double immunostained astrocytes and microglia, respectively
Summary
Prion disease (or prionoses) are a group of fatal neurodegenerative diseases affecting humans and certain mammalian species. Human prionoses include Creutzfeldt-Jakob disease (CJD), Gerstmann Sträussler Scheinker syndrome, fatal familial insomnia, variably. Like Alzheimer’s disease (AD), prionoses belong to neurodegenerative conformational disorders, where the pathogenesis is driven by the accumulation of β-sheet misfolded proteins, which triggers activation of astrocytes and microglia. P rPSc (Sc-scrapie) is a toxic, proteolysis-resistant, and oligomerization-prone conformer of the cellular prion protein (PrPC) typical to all prionoses. Microglia display prominent inflammatory phenotype and secrete numerous cytokines and chemokines, which exert toxic effect on neurons either directly or indirectly by recruiting A1 neurotoxic astrocytes [3, 10]. The net contribution of microglia proinflammatory vs phagocytic effect to prion pathogenesis remains actively debated [3, 12]
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