Abstract
Prion diseases are rare transmissible neurodegenerative disorders caused by the accumulation of a misfolded isoform (PrPSc) of the cellular prion protein (PrPC) in the central nervous system (CNS). Neuropathological hallmarks of prion diseases are neuronal loss, astrogliosis, and enhanced microglial proliferation and activation. As immune cells of the CNS, microglia participate both in the maintenance of the normal brain physiology and in driving the neuroinflammatory response to acute or chronic (e.g., neurodegenerative disorders) insults. Microglia involvement in prion diseases, however, is far from being clearly understood. During this review, we summarize and discuss controversial findings, both in patient and animal models, suggesting a neuroprotective role of microglia in prion disease pathogenesis and progression, or—conversely—a microglia-mediated exacerbation of neurotoxicity in later stages of disease. We also will consider the active participation of PrPC in microglial functions, by discussing previous reports, but also by presenting unpublished results that support a role for PrPC in cytokine secretion by activated primary microglia.
Highlights
The Prion Protein, Prions and Prion DiseasesThe cellular prion protein, PrPC, is a glycosylphosphatidylinositol (GPI)-anchored protein, residing in the outer leaflet of the plasma membrane (PM), expressed in several cell types and abundant in the central nervous system (CNS) and immune cells [1].PrPC is primarily renowned for being the precursor of prions, the proteinaceous infectious agents lacking nucleic acids that cause invariably fatal neurodegenerative disorders named transmissible spongiform encephalopathies (TSEs) or prion diseases in humans and other mammalian species [2,3,4]
The great majority of human prion diseases arise sporadically (e.g., sporadic Creutzfeldt–Jakob disease (CJD)), but a significant percentage (~10%) is of genetic origin, due to the autosomal dominant transmission of inherited mutations in the PrPC-coding gene and about 5% of all cases develop on infectious grounds (e.g., Kuru, iatrogenic CJD and a new variant form of CJD that was transmitted to humans through the consumption of meat from bovine spongiform encephalopathy-affected cattle) [5]
PrPSc-infected CD14 knock-out (KO) mice survived longer and expressed more anti-inflammatory cytokines and less pro-inflammatory IL-1β than PrPSc-infected wild-type (WT) mice [54], suggesting a harmful role for CD14-mediated signalling in prion pathogenesis (Figure 1). Another key issue is the involvement of astroglial cells in prion replication, and propagation to neighboring cells and throughout the CNS, which has been proposed to occur in prion diseases [34,61] and other neurodegenerative disorders associated with prion-like proteins [62]
Summary
Recent studies confirmed the prediction of the founder of the microglia field, Pio del Rio–Hortega [16], indicating that microglial cells are derived from c-Kit+ erythromyeloid precursors in the yolk sac that seed the CNS rudiment from the cephalic mesenchyme very early during embryogenesis and continuing until the blood–brain barrier is formed, following a gradual process of differentiation into highly specialized immune cells in the brain [17,18] After such a developmental origin, self-renewal is the only source of new microglial cells in the healthy brain, which is regulated by astrocytes and neurons through the activation of the microglial colony-stimulating factor (CSF)-1 tyrosine kinase receptor (CSF-1R) by its ligands CSF-1 and interleukin (IL)-34 [19]. Key surface receptors (i.e., cluster of differentiation (CD) 45, CD14, and CD11b/CD18 (Macrophage-1 antigen)) maintain microglial cells in a resting but highly dynamic state [23] that is favored by the interaction with neurons, for example through the formation of a molecular complex between the neuronal transmembrane glycoprotein CD200 and its receptor CD200R present in the plasma membrane of microglial cells [24], or between the neuronal chemokine C-X3-C motif chemokine (CX3C) ligand 1 (CX3CL1, named Fractalkine) and its receptor CX3CR1, expressed solely by microglial cells [25]
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