Molecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, Rm 3246, 100 Perth Dr, London, ON, N6A 5K8, Canada.
Neuroscience Program, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada.
Acta Neuropathol Commun. 2019 Nov 8;7(1):170. doi: 10.1186/s40478-019-0816-1.
Although it has been suggested that the co-expression of multiple pathological proteins associated with neurodegeneration may act synergistically to induce more widespread neuropathology, experimental evidence of this is sparse. We have previously shown that the expression of ThrAsp-tau (tau) using somatic gene transfer with a stereotaxically-injected recombinant adeno-associated virus (rAAV9) vector induces tau pathology in rat hippocampus. In this study, we have examined whether the co-expression of human tau with mutant human TDP-43 (TDP-43) will act synergistically. Transgenic female Sprague-Dawley rats that inducibly express mutant human TDP-43 using the choline acetyltransferase (ChAT) tetracycline response element (TRE) driver with activity modulating tetracycline-controlled transactivator (tTA) were utilized in these studies. Adult rats were injected with GFP-tagged tau protein constructs in a rAAV9 vector through bilateral stereotaxic injection into the hippocampus. Injected tau constructs were: wild-type GFP-tagged 2N4R human tau (tau; n = 8), GFP-tagged tau 2N4R human tau (tau, pseudophosphorylated, toxic variant, n = 8), and GFP (control, n = 8). Six months post-injection, mutant TDP-43 expression was induced for 30 days. Behaviour testing identified motor deficits within 3 weeks after TDP-43 expression irrespective of tau expression, though social behaviour and sensorimotor gating remained unchanged. Increased tau pathology was observed in the hippocampus of both tau and tau expressing rats and tau pathology was increased in the presence of cholinergic neuronal expression of human TDP-43. These data indicate that co-expression of pathological TDP-43 and tau protein exacerbate the pathology associated with either individual protein.
虽然有人认为与神经退行性变相关的多种病理蛋白的共表达可能协同作用诱导更广泛的神经病理学，但这方面的实验证据很少。我们之前已经表明，使用立体定位注射的重组腺相关病毒（rAAV9）载体表达 ThrAsp-tau（tau）可诱导大鼠海马中的 tau 病理学。在这项研究中，我们检查了人 tau 与突变人 TDP-43（TDP-43）的共表达是否会协同作用。使用带有活性调节四环素控制的转录激活剂（tTA）的胆碱乙酰转移酶（ChAT）四环素反应元件（TRE）驱动子可诱导突变人 TDP-43 表达的转基因雌性 Sprague-Dawley 大鼠用于这些研究。成年大鼠通过双侧立体定位海马内注射 rAAV9 载体中的 GFP 标记 tau 蛋白构建体。注射的 tau 构建体为：野生型 GFP 标记 2N4R 人 tau（tau；n = 8），GFP 标记 tau 2N4R 人 tau（tau，假磷酸化，毒性变体，n = 8）和 GFP（对照，n = 8）。注射后 6 个月，诱导突变 TDP-43 表达 30 天。行为测试表明，TDP-43 表达后 3 周内出现运动缺陷，无论 tau 表达如何，但社会行为和感觉运动门控保持不变。在 tau 和 tau 表达大鼠的海马中观察到 tau 病理学增加，并且在存在人 TDP-43 的胆碱能神经元表达时 tau 病理学增加。这些数据表明，病理 TDP-43 和 tau 蛋白的共表达加剧了与每种蛋白相关的病理学。
