Characterization of the role of dendritic cells in prion transfer to primary neurons

TSEs (transmissible spongiform encephalopathies) are neuro-degenerative diseases caused by pathogenic isoforms (PrPSc) of the host-encoded PrPc (cellular prion protein). After consumption of contaminated food. PrPSc deposits rapidly accumulate in lymphoid tissues before invasion of the CNS (central nervous system) However, the mechanisms of prion spreading from the periphery to the nervous system are still unclear In the present study. we investigated the role of DCs (dendritic cells) in the spreading of priori infection to neuronal cells. First, we determined that BMDCs (bone-marrow-derived DCs) rapidly uptake PrPSc after exposure to infected brain homogenate Next, we observed a progressive catabolism of the internalized priori aggregates Similar experiments performed with BMDCs isolated from KO (knockout) mice or mice overexpressing PrP (tga20) indicate that both PrPSc uptake and catabolism are independent of PrPc expression in these cells. Finally, using co-cultures of prion-loaded BMDCs and cerebellar neurons, we characterized the transfer of the prion protein and the resulting infection of the neuronal cultures Interestingly. the transfer of PrPSc was triggered by direct cell cell contact As a consequence. BMDCs retained the prion protein when cultured alone, and no transfer to the recipient neurons was observed when a filter separated the two cultures or when neurons were exposed to the BMDC-conditioned medium Additionally. fixed BMDCs also failed to transfer priori infectivity to neurons. suggesting an active transport of prion aggregates. in accordance with a role of TNTs (tunnelling nanotubes) observed in the co-cultures