Department of Clinical Neurosciences, UK Dementia Research Institute at the University of Cambridge, Cambridge, UK.
John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
Acta Neuropathol Commun. 2021 Mar 12;9(1):41. doi: 10.1186/s40478-021-01141-6.
A fundamental property of infectious agents is their particulate nature: infectivity arises from independently-acting particles rather than as a result of collective action. Assemblies of the protein tau can exhibit seeding behaviour, potentially underlying the apparent spread of tau aggregation in many neurodegenerative diseases. Here we ask whether tau assemblies share with classical pathogens the characteristic of particulate behaviour. We used organotypic hippocampal slice cultures from P301S tau transgenic mice in order to precisely control the concentration of extracellular tau assemblies in neural tissue. Whilst untreated slices displayed no overt signs of pathology, exposure to recombinant tau assemblies could result in the formation of intraneuronal, hyperphosphorylated tau structures. However, seeding ability of tau assemblies did not titrate in a one-hit manner in neural tissue. The results suggest that seeding behaviour of tau arises at high concentrations, with implications for the interpretation of high-dose intracranial challenge experiments and the possible contribution of seeded aggregation to human disease.
感染性源自独立作用的颗粒，而不是集体作用的结果。tau 蛋白的聚集物可以表现出成核行为，这可能是许多神经退行性疾病中 tau 聚集物明显扩散的基础。在这里，我们想知道 tau 聚集物是否与经典病原体具有颗粒状行为的特征。我们使用来自 P301S tau 转基因小鼠的 P30 海马脑片培养物，以便精确控制神经组织中细胞外 tau 聚集物的浓度。虽然未经处理的脑片没有明显的病理迹象，但暴露于重组 tau 聚集物会导致神经元内过度磷酸化的 tau 结构的形成。然而，tau 聚集物的成核能力在神经组织中不能以一击的方式滴定。结果表明，tau 的成核行为发生在高浓度下，这对高剂量颅内挑战实验的解释以及接种聚集物对人类疾病的可能贡献有影响。
