A Mouse Model of Tau Pathology in AD & Other Dementias

描述(申请人提供)：通过在没有小鼠tau的情况下表达正常的人tau基因(hTau小鼠)，已经开发出一种新的人类tau病理学的小鼠模型。这些小鼠在躯体树突间积聚了磷酸化的tau，随着年龄的增长，tau的磷酸化明显增加，tau的构象发生了变化，在新皮质、海马区和其他神经元中形成了丝状的tau聚集体。有证据表明，一岁以上的小鼠出现星形胶质细胞增多症、小胶质细胞增多症和神经元死亡。我们的第一个目标将是完成在hTau小鼠整个生命周期内形成的tau病理的详细特征。这些研究将包括新皮质和海马区神经元和突触密度的定量，以及星形胶质细胞和小胶质细胞反应的检查。我们将研究tau病理发展对胆碱能神经传递的功能影响。Tau亚型比率是tau病理和细胞死亡的关键决定因素的假设将通过用表达单个人tau亚型的小鼠作为转基因来培育hTau小鼠来检验。在不同比例的3R和4R tau的hTau小鼠的发育过程中，将产生在零背景下转3R和4R单亚型的小鼠，并对这些小鼠进行tau病理检查。一种新基因saitohin的可能作用将通过单标记和双标记免疫细胞化学以及生化技术进行检测，该基因位于人类tau基因的内含子中。GSK3β、CDK5和其他蛋白激酶在形成过度磷酸化的tau聚集体中的假设作用将通过生化、药理学和遗传策略进行研究。最后，如果证实在hTau小鼠中发生神经元死亡，将探索潜在的机制，并特别关注参与细胞凋亡的可能性。

DESCRIPTION (provided by applicant): A new mouse model of human tau pathology has been developed, by expression of the normal human tau gene in the absence of mouse tau (hTau mice). These mice show accumulation of phosphorylated tau in the somatodendritic compartment, a clear age-related increase in tau phosphorylation, conformational changes in tau and the formation of filamentous tau aggregates in neocortical, hippocampal and other neurons. There is evidence of astrocytosis, microgliosis and neuronal death in mice aged over a year. Our first goal will be to complete the detailed characterization of the tau pathology that develops in the hTau mice, over the entire life span. These studies will include quantitation of neuronal and synaptic density in neocortex and hippocampus, and examination of astrocytic and microglial reactions. The functional consequences of the development of tau pathology for cholinergic neurotransmission will be examined. The hypothesis that tau isoform ratios are the critical determinant of tau pathology and cell death will be tested by breeding hTau mice with mice expressing single isoforms of human tau as transgenes. In the course of development of hTau mice with different ratios of 3R and 4R tau, mice transgenic for 3R and 4R single isoforms on a null background will be generated, and these mice will be examined for the development of tau pathology. The possible role of a new gene, saitohin, discovered to reside within an intron of the human tau gene, will be examined by single and double label immunocytochemistry, and by biochemical techniques. The hypothetical roles of GSK3beta, cdk5 and other protein kinases in the formation of hyperphosphorylated tau aggregates will be examined using biochemical, pharmacological and genetic strategies. Finally, if neuronal death is confirmed to occur in the hTau mice, potential mechanisms will be explored, with special attention paid to the possibility that apoptosis is involved.