Mitchell Center for Neurodegenerative Disorders, University of Texas Medical Branch, UTMB, Galveston, Texas, USA.
Department of Neurology, University of Texas Medical Branch, UTMB, Galveston, Texas, USA.
Brain Pathol. 2023 Jan;33(1):e13112. doi: 10.1111/bpa.13112. Epub 2022 Aug 24.
Accumulation of pathological tau aggregates is a prominent feature in tauopathies that leads during the course of the diseases to neuronal dysfunction before and cell death after. Microglia and astrocytes have been described as playing important roles in synaptic spreading of toxic tau in several neurodegenerative diseases (NDs). Here, we have investigated the immunological and biochemical properties of aggregated tau species in different brain cell types in tau-induced neurodegenerative diseases such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). Additionally, we examined nuclear size, nuclear density, and chromatin compaction in neuronal and glial cells from diseased brain tissues. Microscopic-histological examination was performed using in-house mouse monoclonal antibodies for toxic tau conformers (TTC-M1 and TTC-M2) and tau oligomers (TOMA1-4). By immunohistochemistry and co-immunofluorescence assays using TOMA/TTC-Ms and cell-type specific markers for neurons, astrocytes, and microglia, we observed that TOMA/TTC-Ms were immunoreactive to diverse tau species in different cell types. Analysis of colocalization coefficients indicated an increased pathological tau deposition mainly in the neurons. Western blot analysis of brain homogenates using TOMA/TTC-Ms revealed distinct patterns of tau aggregation in each disease, suggesting that TOMA/TTC-Ms can distinguish between different tau aggregates present in different tauopathies. Additionally, using DAPI staining, we observed that neuronal and astrocytic nuclei had significantly greater nuclear area and increased chromatin compaction in AD cortices compared to non-demented controls. In contrast, reduction in nuclear density/area and more relaxed chromatin was noticed in DLB neurons, astrocytes and microglia and PSP astrocytes and microglia. Cell-type specific tropism of toxic tau species in tauopathies will provide a greater understanding of the involvement of different brain cell types in tau pathology. In this study, we observed that each disease presented cell-type specific nuclear phenotype and tau deposition pattern.
病理性 tau 聚集体的积累是 tau 病的一个突出特征，在疾病过程中导致神经元功能障碍先于细胞死亡。小胶质细胞和星形胶质细胞在几种神经退行性疾病（NDs）中被描述为在毒性 tau 的突触扩散中发挥重要作用。在这里，我们研究了在 tau 诱导的神经退行性疾病（如阿尔茨海默病（AD）、进行性核上性麻痹（PSP）和路易体痴呆（DLB））中不同脑细胞类型中聚集的 tau 物种的免疫学和生物化学特性。此外，我们还检查了来自患病脑组织的神经元和神经胶质细胞中的核大小、核密度和染色质紧缩。使用针对毒性 tau 构象体（TTC-M1 和 TTC-M2）和 tau 寡聚物（TOMA1-4）的内部制备的小鼠单克隆抗体进行显微镜组织学检查。通过使用 TOMA/TTC-Ms 和神经元、星形胶质细胞和小胶质细胞的细胞类型特异性标志物进行免疫组织化学和共免疫荧光测定，我们观察到 TOMA/TTC-Ms 对不同细胞类型中的多种 tau 物种具有免疫反应性。共定位系数分析表明，病理性 tau 沉积主要增加神经元。使用 TOMA/TTC-Ms 对脑匀浆进行 Western blot 分析表明，每种疾病中都存在不同的 tau 聚集模式，表明 TOMA/TTC-Ms 可以区分不同 tau 病中存在的不同 tau 聚集体。此外，使用 DAPI 染色，我们观察到 AD 皮质中的神经元和星形胶质细胞核的核面积显著增大，染色质紧缩增加，而在 DLB 神经元、星形胶质细胞和小胶质细胞以及 PSP 星形胶质细胞和小胶质细胞中则减少。tau 病中毒性 tau 物种的细胞类型特异性趋向性将提供对不同脑细胞类型在 tau 病理学中参与的更深入理解。在这项研究中，我们观察到每种疾病都呈现出细胞类型特异性的核表型和 tau 沉积模式。
