Neurobiology Centre, Nencki Institute of Experimental Biology, Warsaw, Poland.
Neurobiology Centre, Nencki Institute of Experimental Biology, Warsaw, Poland; Department of Applied Physiology, Mossakowski Medical Research Centre, Warsaw, Poland.
J Neurosci Methods. 2019 May 1;319:47-59. doi: 10.1016/j.jneumeth.2018.11.009. Epub 2018 Nov 16.
Background Tauopathies, including Alzheimer's disease (AD), are multifactorial diseases with strong phenotypic and genetic heterogeneity. Recent evidence revealed that mechanisms of pathogenesis of early (hereditary) and late (sporadic) forms of AD are different. This is not properly reflected in current experimental models, especially when it comes to sporadic forms of AD. Here, we present novel seeding based model and explore its suitability for therapeutic intervention. New method We validate novel region specific approach to modelling Tau pathology reported by Koss and co-authors (2015). Wistar rats 3, 9 and 15 month-old were surgically prepared for hippocampal loading with pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) and recombinant human tau including pharmacological inhibition of phosphatase activity by okadaic acid co-administration. We explored whether tau seeding caused molecular and behavioural traits reminiscent of AD and explored their reversibility/prevention by administration of either memantine or lithium. Results The presented model emulates several changes observed in progressive dementia such as: heightened levels of tau and its hyperphosphorylation, changes in tau compartmentalization, breakdown of the cytoskeleton, cognitive impairments, and sensitivity for anti-dementia treatment. Comparison with existing methods Seeding has been achieved in transgenic mouse models, but this is the first rat model significantly mimicking cognitive and neuronal changes akin to tauopathies. Moreover, we have successfully included the factor age in our model and can show sensitivity to drug treatment. Conclusions These data validate a novel model of locally infused recombinant human Tau as an inducer of tauopathy in rats and holds the potential for development of novel therapies.
包括阿尔茨海默病（AD）在内的 Tau 病是一种多因素疾病，具有很强的表型和遗传异质性。最近的证据表明，早发性（遗传性）和晚发性（散发性）AD 形式的发病机制不同。这在当前的实验模型中没有得到很好的反映，尤其是在涉及散发性 AD 时。在这里，我们提出了一种新的基于接种的模型，并探讨了其用于治疗干预的适用性。
我们验证了 Koss 及其同事（2015 年）报道的新型区域特异性 Tau 病理学建模方法。3、9 和 15 月龄的 Wistar 大鼠接受了海马加载带有孔形成聚合 1,3-烷基吡啶鎓盐（Poly-APS）和重组人 Tau 的手术准备，同时进行了磷酸酶活性的药理学抑制，通过添加 okadaic 酸共同给药。我们探讨了 Tau 接种是否会导致类似于 AD 的分子和行为特征，并探讨了通过给予美金刚或锂来预防或逆转这些特征的可能性。
所提出的模型模拟了进行性痴呆中观察到的几种变化，例如：tau 及其过度磷酸化水平升高、tau 区室化变化、细胞骨架破裂、认知障碍以及对抗痴呆治疗的敏感性。
在转基因小鼠模型中已经实现了接种，但这是第一个在大鼠模型中显著模拟类似于 Tau 病的认知和神经元变化的模型。此外，我们已经成功地将年龄因素纳入我们的模型中，并能够显示对药物治疗的敏感性。
这些数据验证了局部输注重组人 Tau 作为 Tau 病诱导剂的新型大鼠模型，并具有开发新型治疗方法的潜力。
