Differential astrocyte and oligodendrocyte vulnerability in murine Creutzfeldt-Jakob disease

Abstract

Glial vulnerability to prions is assessed in murine Creutzfeldt-Jakob disease (CJD) using the tg340 mouse line expressing four-fold human PrP M129 levels on a mouse PrP null background at different days following intracerebral inoculation of sCJD MM1 brain tissues homogenates. The mRNA expression of several astrocyte markers, including glial fibrillary acidic protein (gfap), aquaporin-4 (aqp4), solute carrier family 16, member 4 (mct4), mitochondrial pyruvate carrier 1 (mpc1) and solute carrier family 1, member 2 (glial high-affinity glutamate transporter, slc1a2) increases at 120 and 180 dpi. In contrast, the mRNA expression of oligodendrocyte and myelin markers oligodendrocyte transcription factor 1 (olig1), olig2, neural/glial antigen 2 (cspg), solute carrier family 16, member 1 (mct1), myelin basic protein (mbp), myelin oligodendrocyte glycoprotein (mog) and proteolipid protein 1 (plp1) is preserved. Yet, myelin regulatory factor (myrf) mRNA is increased at 180 dpi. In the striatum, a non-significant increase in the number of GFAP-positive astrocytes and Iba1-immunoreactive microglia occurs at 160 dpi; a significant increase in the number of astrocytes and microglia, and a significant reduction in the number of Olig2immunoreactive oligodendrocytes occur at 180 dpi. A decrease of MBP, but not PLP1, immunoreactivity is also observed in the striatal fascicles. These observations confirm the vulnerability and the reactive responses of astrocytes, together with the microgliosis at middle stages of prion diseases. More importantly, these findings show oligodendrocyte vulnerability and myelin alterations at advanced stages of murine CJD. They confirm oligodendrocyte involvement in the pathogenesis of CJD.

Histotype-Dependent Oligodendroglial PrP Pathology in Sporadic CJD: A Frequent Feature of the M2C “Strain”

“…Moreover, Andres Benito et al [28] reported an altered gene expression profile specific to astrocytes, oligodendrocytes and myelin in the frontal cortex of sCJD (7 MM1, 10 VV2), supporting the notion that molecular deficits linked to energy metabolism and solute transport in astrocytes and oligodendrocytes, in addition to neurons, may be relevant in the pathogenesis of cortical lesions in CJD. The authors also made similar observations in a murine CJD model [29].…”

“…In animals, a ramified astroglial PrP pattern is described for BSE and scrapie [20][21][22][23][24][25][26][27][28][29][30][31][32]. Particularly, in experimental TSE, the H-type BSE cases have been reported to show widespread glial labelling throughout the white matter of the spinal cord and the cerebellum [33].…”

Dysregulation of neuroprotective astrocytes, a spectrum of microglial activation states, and altered hippocampal neurogenesis are revealed by single-cell RNA sequencing in prion disease

“…Transcriptional alterations to oligodendrocytes are rarely the focus of investigations into prion pathogenesis because mature oligodendrocytes are considered relatively resistant to prion replication [ 66 ]. However, mature Olig2 + oligodendrocytes were recently shown to decrease at the advanced stages of disease in a murine model of Creutzfeldt-Jakob disease [ 3 ], implying a role in pathogenesis. In our dataset, populations of oligodendrocyte progenitors were increased in relative frequency during RML disease, particularly in the hippocampus (Fig.…”

Unexpected decrease of full-length prion protein in macaques inoculated with prion-contaminated blood products

“…However, cases of the "panencephalopathic" type of CJD initially reported in Japan (Mizutani et al, 1981) suggested the possibility of primary involvement of white matter, at least with some prion strains, and the description of oligodendrocytes engulfed within the cytoplasm of hypertrophic astrocytes (emperipolesis) was later reported to be common in the cerebral white matter of sporadic CJD patients (Shintaku and Yutani, 2004). More recently, oligodendrocyte vulnerability and myelin alterations were reported in the advanced stages of murine CJD (Andrés-Benito et al, 2021). Our data suggest that PrP c would also play a key role in the maintenance of myelin in the central nervous system, and its loss of function would be involved in the myelopathic lesions observed in the spinal cord with demyelination of the posterior tracts, which is coherent with the loss of sensitivity that we observed in our primates.…”