Cellular prion protein exacerbates brain demyelination by activating microglia through the TREM2-TYROBP axis in cuprizone-treated animals

Background The cellular prion protein (PrP^C), widely recognized for its role in prion diseases, is highly expressed in the central nervous system (CNS). While it has been reported to link to demyelination in the peripheral nervous system, the function of PrP^C in CNS demyelination remains unclear. Methods We explored the role of PrP^C in cuprizone-induced demyelination using wild-type and two PrP-deficient mouse models. Results We observed significant upregulation of PrP^C within demyelinating lesions of wild-type mice fed with cuprizone. In contrast, mice lacking PrP^C (Prnp-KO) or with deletion of its octapeptide repeat region (OPR) (Prnp-OPR^de) exhibited markedly reduced myelin loss and oligodendrocyte death, evidenced by luxol fast blue staining, myelin basic protein examination, and detection of OLIG2. RNA sequencing analysis indicated that this protection was associated with attenuated microglial activation and a downregulation of the TREM2-TYROBP signaling pathway. Accordingly, compared to wild-type mice, microglia-mediated neuroinflammatory responses were substantially reduced in Prnp-KO and Prnp-OPR^de mice. Together, these findings demonstrate that PrP^C exacerbates CNS demyelination by promoting microglia activation via the TREM2-TYROBP axis, and further identify OPR as a critical domain responsible for this neurotoxic activity. Conclusions These findings reveal a novel pathogenic mechanism for PrP^C in CNS demyelination and suggest that targeting PrP^C or its OPR may offer new therapeutic opportunities for demyelinating disorders.