Center for Alzheimer's and Neurodegenerative Diseases, Peter O'Donnell Jr. Brain Institute, NL10.120, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX, 75390, USA.
Clinical Neuroanatomy Section/Department of Neurology, Center for Biomedical Research, University of Ulm, Ulm, Germany.
Acta Neuropathol Commun. 2021 Oct 11;9(1):164. doi: 10.1186/s40478-021-01255-x.
Tauopathies are heterogeneous neurodegenerative diseases defined by progressive brain accumulation of tau aggregates. The most common tauopathy, sporadic Alzheimer's disease (AD), involves progressive tau deposition that can be divided into specific stages of neurofibrillary tangle pathology. This classification is consistent with experimental data which suggests that network-based propagation is mediated by cell-cell transfer of tau "seeds", or assemblies, that serve as templates for their own replication. Until now, seeding assays of AD brain have largely been limited to areas previously defined by NFT pathology. We now expand this work to additional regions. We selected 20 individuals with AD pathology of NFT stages I, III, and V. We stained and classified 25 brain regions in each using the anti-phospho-tau monoclonal antibody AT8. We measured tau seeding in each of the 500 samples using a cell-based tau "biosensor" assay in which induction of intracellular tau aggregation is mediated by exogenous tau assemblies. We observed a progressive increase in tau seeding according to NFT stage. Seeding frequently preceded NFT pathology, e.g., in the basolateral subnucleus of the amygdala and the substantia nigra, pars compacta. We observed seeding in brain regions not previously known to develop tau pathology, e.g., the globus pallidus and internal capsule, where AT8 staining revealed mainly axonal accumulation of tau. AT8 staining in brain regions identified because of tau seeding also revealed pathology in a previously undescribed cell type: Bergmann glia of the cerebellar cortex. We also detected tau seeding in brain regions not previously examined, e.g., the intermediate reticular zone, dorsal raphe nucleus, amygdala, basal nucleus of Meynert, and olfactory bulb. In conclusion, tau histopathology and seeding are complementary analytical tools. Tau seeding assays reveal pathology in the absence of AT8 signal in some instances, and previously unrecognized sites of tau deposition. The variation in sites of seeding between individuals could underlie differences in the clinical presentation and course of AD.
tau 病是由 tau 聚集物在大脑中进行性积累定义的异质性神经退行性疾病。最常见的 tau 病，散发性阿尔茨海默病（AD），涉及渐进性 tau 沉积，可分为神经原纤维缠结病理学的特定阶段。这种分类与实验数据一致，实验数据表明，基于网络的传播是由 tau“种子”或组装体的细胞间转移介导的，这些组装体充当自身复制的模板。到目前为止，AD 大脑的接种测定在很大程度上仅限于以前由 NFT 病理学定义的区域。我们现在将这项工作扩展到其他区域。我们选择了 20 名具有 NFT 阶段 I、III 和 V 的 AD 病理学患者。我们使用抗磷酸化 tau 单克隆抗体 AT8 对每个患者的 25 个大脑区域进行染色和分类。我们使用基于细胞的 tau“生物传感器”测定法测量每个样本中的 tau 接种，该测定法通过外源性 tau 组装体介导细胞内 tau 聚集的诱导。我们观察到根据 NFT 阶段，tau 接种呈进行性增加。接种通常先于 NFT 病理学，例如在杏仁核的基底亚核和黑质致密部。我们观察到以前未知发生 tau 病理学的大脑区域存在接种，例如苍白球和内囊，在那里 AT8 染色主要显示 tau 的轴突积累。由于 tau 接种而确定的大脑区域的 AT8 染色也揭示了以前未描述的细胞类型的病理学：小脑皮质的 Bergmann 神经胶质。我们还在以前未检查过的大脑区域检测到 tau 接种，例如中间网状区、中缝背核、杏仁核、梅内尔特基底核和嗅球。总之，tau 组织病理学和接种是互补的分析工具。tau 接种测定在某些情况下揭示了 AT8 信号缺失时的病理学，以及以前未被识别的 tau 沉积部位。个体之间接种部位的差异可能是 AD 临床表现和病程差异的基础。
