Developing new conditional models to study tauopathy, amyloidosis, and their interaction

这项提案的MPI独立地共同开发并彻底描述了一些最 用于研究阿尔茨海默病和相关疾病(ADRD)的常用小鼠模型；然而，所有 现有的tau和/或淀粉样蛋白小鼠模型仍然存在缺陷，限制了它们的实用性，并且存在以下问题 它们可以用来回答问题。例如，表达人P301L tau的rTg4510模型通过 多西环素可阻抑系统是该领域的黄金标准模型之一，但rTg4510存在局限性， 由于它对两个互不相连的转基因的依赖，提早发病的紧张症和认知功能障碍，以及 Tau表达的泄漏性。这项提案的总体目标是为 阿尔茨海默病领域克服了现有模型的缺点，最终提供了一种 创新的平台，其中淀粉样变性和直立性疾病的顺序性质和分子 它们相互作用的基础路径可以以简化、成本效益高的方式进行检查。在……下面 目的1.我们建立了CaMKII-四环素转基因和tau的转基因模型。 条件表达tau所需的应答转基因(WT或P301L)将被共注射并 从而共同整合到小鼠基因组中，随后可以作为单个等位基因传播。我们将努力 建立P301L tau/TTA模型，在12-15个月时出现缠结前病变，在18个月时出现缠结 年纪大了。这一新模型随后将在生化、病理学、认知学和 在结构上使用核磁共振。一旦建立，这些新颖的，有条件的tau转基因将提供一种更便宜的， 更易接近的模型，在中老年发展成牵张症；使这两项研究都旨在加速 以及减缓/废除牛顿反转。我们还预计，这款车型，如JNPL3和rTg4510 tau 模型，会发展成神经炎和继发性TDP-43蛋白病变。在目标2下，我们建议 通过共注入/共整合创建一种新的条件APP转基因模型 控制APPswe/ind表达的系统。没有一种小鼠模型利用大脑中的累积物抑制系统 简单地让应用程序在这种可选的有条件的系统下进行转基因，就可以将该模型用于 研究以确定APP与tau、？-突触核蛋白或其他潜在的相互作用因子之间的相互作用。最后，在 目的3，我们将新的、单等位基因、四环素抗性tau模型与单等位基因Cumate-Tau杂交。 可抑制的APP允许解剖tau(牛磺酸病)和APP(淀粉样变性)之间的相互作用 循序渐进、系统化的时尚。这种创新的模式，需要具有成本效益的单一繁殖，允许 独立控制tau和app转基因，并将定位该领域以填补知识的关键空白 目前AD领域现有的动物模型都不允许这种情况发生。

The MPIs for this proposal independently co-developed and thoroughly characterized some of the most commonly used mouse models for research on Alzheimer’s disease and related disorders (ADRD); however, all existing tau and/or amyloid mouse models still have shortcomings which limit their utility and the questions that they can be used to answer. For example, the rTg4510 model which expresses human P301L tau through a doxycline-repressible system is one of the gold standard models in the field; however, rTg4510 is limited, in part, by its dependence on two unlinked transgenes, the early onset of tauopathy and cognitive dysfunction, and the leakiness of the tau expression. The overall goal of this proposal is to develop new models for the Alzheimer’s Disease field that overcome the shortcomings of existing models, ultimately providing an innovative platform in which the sequential nature of amyloidosis and tauopathy and the molecular pathways underlying their interaction can be examined in a streamlined, cost-effective manner. Under Aim 1, we propose to generate a model in which the CamKII-tetracycline transactivator transgene and the tau responder transgene (either WT or P301L) required for the conditional expression of tau will be co-injected and thus co-integrated into the murine genome which can subsequently transmit as a single allele. We will strive to develop a P301L tau/tTA model that will develop pre-tangle pathology at 12-15 months and tangles at 18 months of age. This new model will subsequently be fully characterized biochemically, pathologically, cognitively and structurally using MRI. Once established, these novel, conditional tau transgenics will provide a less expensive, more accessible model that develops tauopathy in mid to late life; enabling both studies aimed at accelerating and at slowing/abrogating the tauopathy. We also anticipate that this model, like the JNPL3 and rTg4510 tau models, will develop neuroinflammation and secondary TDP-43 proteinopathy. Under Aim 2, we propose to create a new conditional APP transgenic model through co-injection/co-integration using the cumate-repressible system to control APPswe/ind expression. No mouse model utilizes the cumate-repressible system in the brain and simply having the APP transgene under this alternatively conditional system positions this model for use in studies to identify interactions between APP and tau, ?-synuclein or other potential interactors. Finally, under Aim 3, we will crossbreed the new, single allele, tetracycline-repressible tau model with the single allele, cumate- repressible APP to allow the dissection of the interaction between tau (tauopathy) and APP (amyloidosis) in a sequential and systematic fashion. This innovative model, requiring a cost-effective, single breeding, permits independent control of both the tau and APP transgenes and will position the field to fill critical gaps in knowledge that no existing animal model in the AD arena currently allows.