CpG oligodeoxynucleotide reduces PrPSc accumulation and prolongs survival in prion-infected mice

Prion diseases, also known as transmissible spongiform encephalopathies, are characterized by the accumulation of misfolded prion proteins (PrP^Sc), which resists clearance due to impaired removal mechanisms and immune tolerance. Although strategies aimed at enhancing intracellular clearance pathways, including autophagy, have shown promise, effective in vivo interventions remain limited. Innate immune stimulation with CpG oligodeoxynucleotides (CpG ODN), a Toll-like receptor 9 agonist that mimics bacterial DNA containing unmethylated CpG motifs, has been reported to extend survival in prion-infected mice; however, the underlying mechanisms involved remain incompletely defined. In this study, we examined the effects of CpG ODN in both in vitro and in vivo models of prion disease using the 22L scrapie strain. Mice treated with CpG ODN prior to infection exhibited prolonged mean survival compared with vehicle-treated controls and showed reduced PrP^Sc accumulation in spleen and brain tissues at 60 and 170 days post-infection, respectively. These changes were correlated with increased AMPK (Tyr172) phosphorylation and alterations in autophagy-associated signaling markers in the brain tissue. In 22L scrapie-infected neuronal cells, CpG ODN treatment significantly reduced PrP^Sc levels, and this effect was attenuated by pharmacological inhibition of autophagy-associated and lysosomal degradative processes. Collectively, these findings indicate that CpG ODN reduces PrP^Sc accumulation and prolongs survival in prion-infected mice, supporting the involvement of autophagy-associated degradative processes without establishing enhanced autophagic flux.