Biology of Prion Protein and the TSE Diseases

朊病毒病或传染性海绵状脑病是人类和动物的传染性神经退行性疾病。朊病毒疾病的主要特征是正常宿主蛋白朊病毒蛋白（PrP）重折叠和聚集成疾病相关蛋白酶抗性形式（PrPres），这可能导致脑损伤。 小胶质细胞（MG）在朊病毒感染时对宿主的防御至关重要，但这种神经保护作用的机制尚不清楚。为了更好地研究MG在朊病毒感染期间的影响，我们使用PLX 5622降低了C57 BL/10小鼠大脑中的MG，并使用多种方法评估了朊病毒的清除和复制，包括生物测定，免疫组织化学和实时震动诱导转化（RT-QuIC）。我们还利用间歇性PLX 5622治疗策略来减少MG，并允许MG再增殖，以测试新的MG是否可以改变朊病毒疾病的进展。最后，我们使用tga 20小鼠研究了MG的影响，tga 20小鼠是一种快速朊病毒模型，在受感染的大脑中积累较少的病理特征和较少的PrPres。在C57 BL/10小鼠中，我们发现MG在感染后早期从接种部位被排除，但存在Iba 1阳性浸润单核细胞/巨噬细胞。在朊病毒接种前减少大脑中的MG并不增加朊病毒感染的易感性。在感染朊病毒的C57 BL/10小鼠中，80 dpi后用PLX 5622进行短时间间歇性治疗在改变MG群体、神经胶质增生或存活方面不成功。此外，在tga 20小鼠中使用PLX 5622的MG消耗对朊病毒发病机制仅具有微小影响，表明MG的存在在这种朊病毒蓄积较少的快速模型中可能不太重要。与MG在疾病晚期对抗朊病毒疾病的益处相反，我们目前的实验表明MG在早期朊病毒发病、清除或复制中不起作用。

Prion diseases or transmissible spongiform encephalopathies are infectious neurodegenerative diseases of humans and animals. A major feature of prion diseases is the refolding and aggregation of a normal host protein, prion protein (PrP), into a disease-associated protease-resistant form (PrPres) which may contribute to brain damage. Microglia (MG) are critical to host defense during prion infection, but the mechanism(s) of this neuroprotection are poorly understood. To better examine the influence of MG during prion infection, we reduced MG in the brains of C57BL/10 mice using PLX5622 and assessed prion clearance and replication using multiple approaches that included bioassay, immunohistochemistry, and Real-Time Quaking Inducted Conversion (RT-QuIC). We also utilized a strategy of intermittent PLX5622 treatments to reduce MG and allow MG repopulation to test whether new MG could alter prion disease progress. Lastly, we investigated the influence of MG using tga20 mice, a rapid prion model that accumulates fewer pathological features and less PrPres in the infected brain. In C57BL/10 mice we found that MG were excluded from the inoculation site early after infection, but Iba1 positive infiltrating monocytes/macrophage were present. Reducing MG in the brain prior to prion inoculation did not increase susceptibility to prion infection. Short intermittent treatments with PLX5622 in prion infected C57BL/10 mice after 80 dpi were unsuccessful at altering the MG population, gliosis, or survival. Additionally, MG depletion using PLX5622 in tga20 mice had only a minor impact on prion pathogenesis, indicating that the presence of MG might be less important in this fast model with less prion accumulation. In contrast to the benefits of MG against prion disease in late stages of disease, our current experiments suggest MG do not play a role in early prion pathogenesis, clearance, or replication.