Neuroinflammation in Prion Disease

Abstract

Neuroinflammation, typically manifest as microglial activation and astrogliosis accompanied by transcriptomic alterations, represents a common hallmark of various neurodegenerative conditions including prion diseases. Microglia play an overall neuroprotective role in prion disease, whereas reactive astrocytes with aberrant phenotypes propagate prions and contribute to prion-induced neurodegeneration. The existence of heterogeneous subpopulations and dual functions of microglia and astrocytes in prion disease make them potential targets for therapeutic intervention. A variety of neuroinflammation-related molecules are involved in prion pathogenesis. Therapeutics targeting neuroinflammation represents a novel approach to combat prion disease. Deciphering neuroinflammation in prion disease will deepen our understanding of pathogenesis of other neurodegenerative disorders.

microRNA-146a-5p, Neurotropic Viral Infection and Prion Disease (PrD)

“…Shortly after the first reports of a significantly upregulated miRNA-146a in AD-affected brain and IL-1β-, TNFα-and/or Aβ42 peptide-stressed human neuronal-glial (HNG) cells (transplantation grade) in primary co-culture, the increased abundance of this same proinflammatory sncRNA was reported by multiple groups in animal and human nervous tissues affected with PrD [10,54,55,63,75,101]. As a pro-inflammatory sncRNA, over the last 15 years, miRNA-146a has been repeatedly shown to participate in the regulation of adaptive and innate-immune systems and cytokine-mediated pro-inflammatory responses that potentially culminate in uncontrolled neural tissue damage [24,33,67,69,102,103]. miRNA-146a upregulation in transfected co-cultures of neuronal-glial cells can downregulate both CFH mRNA and protein levels via miRNA-146a pairing with 3 -UTR of human CFH, a finding also observed in multiple murine transgenic models for neural degeneration and in human AD, AMD, MS and TLE [10,22,24,104].…”

“…It was subsequently found that the induction of this endotoxin-responsive microRNA is under transcriptional control by NF-kB (p50/p65); shortly thereafter, this inducible, pro-inflammatory miRNA-146a was found to be upregulated by metal sulfate-generated reactive oxygen species (ROS); by pro-inflammatory cytokines, such as IL-1β and TNFα; by bacterial endotoxins, such as LPS and fragilysin; by Aβ42 peptides; by inflammatory cocktails containing IL-1β and Aβ42 peptides together, in stressed human primary neuronal-glial (HNG) cells in primary culture, in stressed human brain-derived microglial (HMG) cells; and by many different strains of prions and neurotropic viruses [7,16,21,40,53,63,66] (see Table 1). Importantly, miRNA-146a is also found to be moderately abundant in the aging human brain and CNS and the immune cells of mice and humans where its over-expression during neurodegenerative disease contributes to astroglial proliferation and astrogliosis, cytokine overexpression, deficits in the innate-immune response and the initiation of inflammatory events leading to dysfunctional neurons, synaptic deficits and eventually neuronal cell atrophy and brain cell death [13,21,40,55,67].…”

“…Typically, activated microglia accumulate within the immediate vicinity of abnormal PrPsc aggregates, and they release cytokines such as IL-1β that play important roles in the inflammatory pathogenesis of PrD, including the upregulation of genes that promote pro-inflammatory signaling and innate-immune system deficits [86,90]. As PrPsc aggregates progressively form over time, they further induce inevitably fatal neurodegenerative disease conditions, including neuroinflammation, which is typically discernable by massive microglial activation and proliferation and the subsequent and self-reinforcing upregulation of cytokines, such as TNF-alpha (TNFα), interleukin 1 alpha (IL-1α) and glial fibrillary acidic protein (GFAP) as well as astrogliosis accompanied by multiple additional pathogenic alterations in the neuronal transcriptome [25,59,67,85,86,96].…”

“…Human prion diseases currently include Creutzfeldt-Jacob disease (CJD), stratified into sporadic CJD (sCJD) and variant CJD (vCJD) clinical subtypes, Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru, a fatal neurological disease found among natives from New Guinea who practiced a form of ritual cannibalism in which they consumed the brains of their predecessors [56][57][58][59][60]97]. Animal prion diseases include scrapie in sheep and goats (Ruminants of the order Artiodactyla, family Bovidae, subfamily Caprinae), bovine spongiform encephalopathy (BSE, also known as mad cow disease) in cattle (also of the family Bovidae), chronic wasting disease (CWD) in cervids (family Cervidae), transmissible mink encephalopathy (TME) in mink (family Mustelidae) and feline spongiform encephalopathy (FSE) in cats (family Felidae; [56,67,75]). Atypical and novel human prion diseases in Chordata continue to emerge, such as the recently identified camel prion disease (CPD) in dromedary camels observed for the first time in Algeria (order Artiodactyla, family Camelidae) [100]).…”

“…Atypical and novel human prion diseases in Chordata continue to emerge, such as the recently identified camel prion disease (CPD) in dromedary camels observed for the first time in Algeria (order Artiodactyla, family Camelidae) [100]). Prion diseases can also be experimentally studied via the inoculation of brain and other PrPsc-containing extracts into laboratory animals such as mice, voles, gerbils and hamsters, causing a recapitulation of the PrD and TLE in sensitive animals that can be further studied, analyzed and carefully investigated in a biohazard safety level 2 or 3 (BSL-2 or BSL-3) laboratory (see Handling Prions-Environmental Health and Safety, Michigan State University (msu.edu); www.ehs.msu.edu/lab-clinic/bio/handling-prions.html; last accessed on 23 August 2021; [25,67,[82][83][84]90]; (Table 1).…”