Lipopolysaccharide and Recombinant Prion Protein Induce Distinct Neurodegenerative Pathologies in FVB/N Mice

Prion diseases are typically attributed to the accumulation of protease-resistant prion protein (PrPSc), yet growing evidence indicates that alternative misfolded PrP conformers and inflammatory factors may also drive neurodegeneration. Whether bac-terial lipopolysaccharide (LPS) can independently generate or exacerbate prion-like pathology in the absence of classical PrPSc remains unclear. This study aimed to determine if recombinant moPrPRes, produced by incubating normal mouse PrPC with LPS, induces prion-like disease in wild-type FVB/N mice, whether LPS alone triggers neurodegen-eration, and how co-administration of LPS influences moPrPRes and RML prion pathology. FVB/N mice were randomized into six subcutaneous treatment groups: saline, LPS, moPrPRes, moPrPRes+LPS, RML, or RML+LPS. Animals were monitored for survival, clinical signs, and body weight. Brains were assessed histologically and biochemically for spongiform changes, astrogliosis, and protease-resistant PrP. Subcutaneous moPrPRes induced a distinctive encephalopathy, with 20% mortality by 200 days post-inoculation (dpi), rising to 60% by study’s end, despite undetectable PrPSc. Chronic LPS infusion alone caused an Alzheimer’s-like pathology (~40% mortality). Co-administration of moPrPRes with LPS resulted in 30% mortality by 200 dpi and 50% survival at 750 dpi. Keywords: keyword 1; keyword 2; keyword 3 (List three to ten pertinent keywords specific to the article yet reasonably common within the subject discipline.) Notably, LPS strongly synergized with RML, accelerating disease onset, intensifying PrP deposition, and ex-acerbating spongiform changes compared to RML alone. Instead, misfolded prion con-formers and endotoxin-driven inflammation can independently or synergistically pro-mote neuropathology. Targeting inflammatory pathways and subclinical prion con-formers may thus provide new therapeutic avenues for prion-like disorders.