Goldansaz Seyed Ali, Hailemariam Dagnachew, Dervishi Elda, Zwierzchowski Grzegorz, Wójcik Roman, Wishart David S, Ametaj Burim N
Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada.
Sustainable Livestock Systems Branch, Sustainable Agri-Food Sciences Division, Agri-Food & Biosciences Institute, Hillsborough BT26 6DR, UK.
Int J Mol Sci. 2025 Jun 28;26(13):6245. doi: 10.3390/ijms26136245.
Prion diseases are classically attributed to the accumulation of protease-resistant prion protein (PrP); however, recent evidence suggests that alternative misfolded prion conformers and systemic inflammatory factors may also contribute to neurodegeneration. This study investigated whether recombinant moPrP, generated by incubating wild-type mouse PrP with bacterial lipopolysaccharide (LPS), can induce prion-like disease in FVB/N female mice, whether LPS alone causes neurodegeneration, and how LPS modulates disease progression in mice inoculated with the Rocky Mountain Laboratory (RML) strain of prions. Wild-type female FVB/N mice were randomized into six subcutaneous treatment groups: saline, LPS, moPrP, moPrP + LPS, RML, and RML + LPS. Animals were monitored longitudinally for survival, body weight, and clinical signs. Brain tissues were analyzed histologically and immunohistochemically for vacuolar degeneration, PrP accumulation, reactive astrogliosis, and amyloid-β plaque deposition. Recombinant moPrP induced a progressive spongiform encephalopathy characterized by widespread vacuolation and astrogliosis, yet with no detectable PrP by Western blot or immunohistochemistry. LPS alone triggered a distinct neurodegenerative phenotype, including cerebellar amyloid-β plaque accumulation and terminal-stage spongiosis, with approximately 40% mortality by the end of the study. Co-administration of moPrP and LPS resulted in variable regional pathology and intermediate survival (50% at 750 days post-inoculation). Interestingly, RML + LPS co-treatment led to earlier clinical onset and mortality compared to RML alone; however, vacuolation levels were not significantly elevated and, in some brain regions, were reduced. These results demonstrate that chronic endotoxemia and non-infectious misfolded PrP conformers can independently or synergistically induce key neuropathological hallmarks of prion disease, even in the absence of classical PrP. Targeting inflammatory signaling and toxic prion intermediates may offer novel therapeutic strategies for prion and prion-like disorders.
传统上，朊病毒疾病被认为是由抗蛋白酶的朊病毒蛋白（PrP）积累所致；然而，最近的证据表明，替代性错误折叠的朊病毒构象异构体和全身炎症因子也可能导致神经退行性变。本研究调查了通过将野生型小鼠PrP与细菌脂多糖（LPS）孵育产生的重组小鼠PrP（moPrP）是否能在FVB/N雌性小鼠中诱发朊病毒样疾病，LPS单独是否会导致神经退行性变，以及LPS如何调节接种落基山实验室（RML）株朊病毒的小鼠的疾病进展。野生型雌性FVB/N小鼠被随机分为六个皮下治疗组：生理盐水组、LPS组、moPrP组、moPrP + LPS组、RML组和RML + LPS组。对动物进行纵向监测，观察其存活情况、体重和临床症状。对脑组织进行组织学和免疫组织化学分析，以检测空泡变性、PrP积累、反应性星形胶质细胞增生和淀粉样β斑块沉积。重组moPrP诱发了一种进行性海绵状脑病，其特征为广泛的空泡化和星形胶质细胞增生，但通过蛋白质印迹法或免疫组织化学未检测到PrP。单独使用LPS引发了一种独特的神经退行性表型，包括小脑淀粉样β斑块积累和终末期海绵样变，到研究结束时死亡率约为40%。moPrP和LPS联合给药导致不同区域的病理变化和中等生存率（接种后750天为50%）。有趣的是，与单独使用RML相比，RML + LPS联合治疗导致更早的临床发病和死亡；然而，空泡化水平没有显著升高，并且在某些脑区有所降低。这些结果表明，慢性内毒素血症和非感染性错误折叠的PrP构象异构体即使在没有经典PrP的情况下也能独立或协同诱导朊病毒疾病的关键神经病理学特征。针对炎症信号和有毒朊病毒中间体可能为朊病毒和朊病毒样疾病提供新的治疗策略。
