Department of Medicine, The University of Melbourne, 30 Royal Parade, Parkville, VIC, Australia.
Florey Department of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, Australia.
Neurobiol Dis. 2023 May;180:106075. doi: 10.1016/j.nbd.2023.106075. Epub 2023 Mar 11.
Prion diseases are pathogenically linked to the normal cellular prion protein (PrP) misfolding into abnormal conformers (PrP), with PrP accumulation underpinning both transmission and neurotoxicity. Despite achieving this canonical understanding, however fundamental questions remain incompletely resolved, including the level of pathophysiological overlap between neurotoxic and transmitting species of PrP and the temporal profiles of their propagation. To further investigate the likely time of occurrence of significant levels of neurotoxic species during prion disease development, the well characterised in vivo M1000 murine model was employed. Following intracerebral inoculation, detailed serial cognitive and ethological testing at specified time points suggested subtle transition to early symptomatic disease from ∼50% of the overall disease course. In addition to observing a chronological order for impaired behaviours, different behavioural tests also showed distinctive profiles of evolving cognitive impairments with the Barnes maze demonstrating a relatively simple linear worsening of spatial learning and memory over an extended period while in contrast a conditioned fear memory paradigm previously untested in murine prion disease demonstrated more complex alterations during disease progression. These observations support the likely production of neurotoxic PrPSc from at least just prior to the mid-point of murine M1000 prion disease and illustrate the likely need to tailor the types of behavioural testing across the time course of disease progression for optimal detection of cognitive deficits.
朊病毒病与正常细胞朊蛋白（PrP）错误折叠成异常构象（PrP）有关，PrP 的积累是两者传播和神经毒性的基础。然而，尽管已经达成了这一经典的认识，但仍有一些基本问题尚未得到完全解决，包括神经毒性和传播性 PrP 物种之间的病理生理学重叠程度，以及它们传播的时间特征。为了进一步研究朊病毒病发展过程中神经毒性物种出现显著水平的可能时间，采用了特征明确的体内 M1000 鼠模型。在大脑内接种后，在特定时间点进行详细的连续认知和行为测试表明，从整个疾病过程的约 50%开始，出现了向早期症状疾病的微妙转变。除了观察到行为障碍的时间顺序外，不同的行为测试还显示出认知障碍逐渐演变的不同特征，Barnes 迷宫显示出在较长时间内空间学习和记忆的相对简单线性恶化，而在对比中，以前在鼠朊病毒病中未测试过的条件性恐惧记忆范式在疾病进展过程中显示出更复杂的改变。这些观察结果支持至少在 M1000 鼠朊病毒病的中点之前就产生了神经毒性 PrPSc，并说明了可能需要根据疾病进展的时间过程调整行为测试的类型，以最佳检测认知缺陷。
