Discrimination of prion strain targeting in the central nervous system via reactive astrocyte heterogeneity in CD44 expression

Barry Bradford, Christianus Wijaya, Neil Mabbott

Research output: Contribution to journalArticlepeer-review

Abstract

Prion diseases or transmissible spongiform encephalopathies are fatal, infectious neurodegenerative conditions that affect a variety of mammalian species including humans. Prion infections in the CNS cause extensive neuropathology, including abnormal accumulations of misfolded host prion protein, spongiform pathology and neuronal loss as well as reactive glial responses. Many different prion agent strains exist and these can differ based on disease duration, clinical signs and the targeting and distribution of the neuropathology in distinct brain areas. Reactive astrocytes are a prominent feature in the prion disease affected CNS as revealed by distinct morphological changes and upregulation of glial fibrillary acidic protein (GFAP). The CD44 antigen is a transmembrane glycoprotein involved in cell-cell interactions, cell adhesion and migration. Here we show that CD44 is also highly expressed in a subset of reactive astrocytes in regions of the central nervous system (CNS) targeted by prions. Astrocyte heterogeneity revealed by differential CD44 upregulation occurs coincident with the earliest neuropathological changes during the pre-clinical phase of disease, and is not affected by the route of infection. The expression and distribution of CD44 was compared in brains from a large collection of 15 distinct prion agent strains transmitted to mice of different prion protein (Prnp) genotype backgrounds. Our data show that the pattern of CD44 upregulation observed in the hippocampus in each prion agent strain and host Prnp genotype combination was unique. Many mouse-adapted prion strains and hosts have previously been characterized based on the pattern of the distribution of the spongiform pathology or the misfolded PrP deposition within the brain. Our data show that CD44 expression also provides a reliable discriminatory marker of prion infection with a greater dynamic range than misfolded prion protein deposition, aiding strain identification. Together, our data reveal CD44 as a novel marker to detect reactive astrocyte heterogeneity during CNS prion disease and for enhanced identification of distinct prion agent strains.
Original languageEnglish
Article number411
JournalFrontiers in Cellular Neuroscience
Volume13
DOIs
Publication statusPublished - 10 Sep 2019

Keywords

  • Prion
  • transmissable spongiform encephalopathy
  • Neurodegeneration
  • Neuroinflammation
  • Astrocyte
  • CD44

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