Department of Pharmacology & Therapeutics, McGill University, Montreal H3G 1Y6, Canada.
Department of Cell Anatomy and Cell Biology, McGill University, Montreal H3A 0C7, Canada.
Neurobiol Dis. 2023 Oct 15;187:106317. doi: 10.1016/j.nbd.2023.106317. Epub 2023 Oct 5.
In tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), the microtubule associated protein tau undergoes conformational and posttranslational modifications in a gradual, staged pathological process. While brain atrophy and cognitive decline are well-established in the advanced stages of tauopathy, it is unclear how the early pathological processes manifest prior to extensive neurodegeneration. For these studies we have applied a transgenic rat model of human-like tauopathy in its heterozygous form, named McGill-R955-hTau. The goal of the present study was to investigate whether lifelong accumulation of mutated human tau could reveal the earliest tau pathological processes in a context of advanced aging, and, at stages before the overt aggregated or fibrillary tau deposition. We characterized the phenotype of heterozygous R955-hTau rats at three endpoints, 10, 18 and 24-26 months of age, focusing on markers of cognitive capabilities, progressive tau pathology, neuronal health, neuroinflammation and brain ultrastructural integrity, using immunohistochemistry and electron microscopy. Heterozygous R955-hTau transgenic rats feature a modest, life-long accumulation of mutated human tau that led to tau hyperphosphorylation and produced deficits in learning and memory tasks after 24 months of age. Such impairments coincided with more extensive tau hyperphosphorylation in the brain at residues pThr231 and with evidence of oligomerization. Importantly, aged R955-hTau rats presented evidence of neuroinflammation, detriments to myelin morphology and detectable hippocampal neuronal loss in the absence of overt neurofibrillary lesions and brain atrophy. The slow-progressing tauopathy of R955-hTau rats should allow to better delineate the temporal progression of tau pathological events and therefore to distinguish early indicators of tauopathy as having the capability to induce degenerative events in the aged CNS.
在tau 病中，如阿尔茨海默病（AD）和额颞叶痴呆（FTD），微管相关蛋白 tau 经历构象和翻译后修饰，这是一个逐渐的、分阶段的病理过程。虽然脑萎缩和认知能力下降在 tau 病的晚期是众所周知的，但在广泛的神经退行性变之前，早期病理过程是如何表现的还不清楚。对于这些研究，我们应用了一种异源型人源 tau 病转基因大鼠模型，命名为 McGill-R955-hTau。本研究的目的是研究突变型人 tau 的终身积累是否能够揭示高级衰老背景下 tau 最早的病理过程，以及在明显的聚集或纤维状 tau 沉积之前的阶段。我们在三个终点，即 10、18 和 24-26 个月龄，对杂合型 R955-hTau 大鼠的表型进行了特征描述，重点关注认知能力、进行性 tau 病理、神经元健康、神经炎症和大脑超微结构完整性的标志物，使用免疫组织化学和电子显微镜。杂合型 R955-hTau 转基因大鼠具有适度的、终身积累的突变型人 tau，导致 tau 过度磷酸化，并在 24 个月龄后导致学习和记忆任务的缺陷。这种损伤与大脑中更多的 tau 在残基 pThr231 处过度磷酸化以及寡聚化的证据一致。重要的是，老年 R955-hTau 大鼠表现出神经炎症的证据，对髓鞘形态的损害，以及在没有明显神经纤维病变和脑萎缩的情况下可检测到的海马神经元丢失。R955-hTau 大鼠的缓慢进展性 tau 病应能更好地描绘 tau 病理事件的时间进程，从而区分 tau 病的早期指标，使其具有在衰老中枢神经系统中诱导退行性事件的能力。
