Humanized MAPT knockin mouse models for frontotemporal dementia

项目总结/摘要 额颞叶痴呆（Frontotemporal dementia，FTD）是一种常见的神经退行性疾病， 老年组存在认知功能障碍和功能障碍。微管相关蛋白tau 在家族性FTD患者中的致病性突变突出了这一点。此外， 神经元缠结中的tau蛋白是阿尔茨海默病大脑中的关键病理霍尔标志物 (AD)FTD患者。为了了解tau蛋白介导的脑梗死的分子致病机制， 神经变性疾病和痴呆的动物模型已经产生并表征。然而，在这方面， 这些动物模型没有概括出分子、细胞、病理学 在AD和FTD患者中观察到的行为和认知特征，部分原因是 过表达人MAPT的cDNA或BAC片段并不代表人MAPT的所有分子特征， 小鼠大脑中的MAPT。在本申请中，我们将产生和表征人源化敲入（KI）小鼠 在FTD中观察到MAPT的致病性变体（P301 L），以概括人 老鼠大脑中的病人。为了实现这一目标，首先，我们将产生新的人源化KI小鼠，其中， 插入MAPT的野生型人基因组区域或具有P301 L突变的野生型人基因组区域作为正向同源序列的替换 小鼠基因组中的Mapt基因座。这种小鼠基因组区域与人类基因组区域的KI置换， 基因组区域将表达人野生型突变tau的所有替代mRNA和蛋白质同种型， 内源性小鼠Mapt启动子。其次，我们将对hMAPT-P301 L KI进行分子表征 小鼠以检查人tau蛋白在脑中的空间和时间表达谱。我们还将表演 hMAPT-P301 L KI中神经元存活的神经病理学分析、tau病理学和行为分析 小鼠这些研究的完成将为研究分子疾病提供宝贵的工具 MAPT在AD和FTD中的作用机制。

PROJECT SUMMARY/ABSTRACT Frontotemporal dementia (FTD) is a common neurodegenerative disorder characterized by progressive cognitive impairment and functional disability in the elderly group. MAPT (microtubule-associated protein tau) has been highlighted by its pathogenic mutations in familial FTD patients. In addition, insoluble aggregates of the tau protein in neurofibrillary tangles are a key pathological hall marker in the brains of Alzheimer’s Disease (AD) and FTD patients. In order to understand the tau mediated molecular pathogenic mechanisms of neurodegenerative diseases and dementias, animal models have been generated and characterized. However, these animal models do not recapitulate the full spectrum and complexity of molecular, cellular, pathological, behavior, and cognitive features observed in AD and FTD patients, in part because the transgenic mice which overexpress cDNA or BAC fragments of human MAPT do not represent all molecular features of the human MAPT in the mouse brain. In this application, we will generate and characterize humanized knockin (KI) mice with a pathogenic variant of MAPT (P301L) seen in FTD to recapitulate the respective pathophysiology of human patients in the mouse brain. To achieve this goal, first, we will generate novel humanized KI mice in which the wild-type human genomic region of MAPT or with P301L mutation is inserted as a replacement of an orthologous gene in the mouse genome of Mapt locus. This KI replacement of the mouse genomic region with the human genomic region will express all alternative mRNA and protein isoforms of human wild-type mutant tau under the endogenous mouse Mapt promoters. Second, we will conduct molecular characterization of hMAPT-P301L KI mice to examine the spatial and temporal expression profile of human tau in the brains. We will also perform neuropathological analyses of neuronal survival, tau pathology, and behavioral analyses in hMAPT-P301L KI mice. The completion of these studies will provide an invaluable tool to investigate the molecular disease mechanism of MAPT in AD and FTD.