A Mouse Model of Tau Pathology in AD & Other Dementias

描述（由申请人提供）：通过在不存在小鼠tau（hTau小鼠）的情况下表达正常人tau基因，开发了人tau病理学的新小鼠模型。这些小鼠显示磷酸化tau蛋白在体树突隔室中的积累，tau蛋白磷酸化的明显年龄相关性增加，tau蛋白的构象变化以及新皮质、海马和其他神经元中丝状tau蛋白聚集体的形成。有证据表明，星形细胞增多症，小胶质细胞增生和神经元死亡的小鼠年龄超过一年。我们的第一个目标将是完成在hTau小鼠整个生命周期中发展的tau病理学的详细表征。这些研究将包括新皮质和海马中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。将检查tau蛋白病理学对胆碱能神经传递的发展的功能后果。tau同种型比率是tau病理和细胞死亡的关键决定因素的假设将通过使hTau小鼠与表达人tau的单一同种型作为转基因的小鼠交配来测试。在具有不同比例的3R和4R tau的hTau小鼠的发育过程中，将产生在空白背景上的3R和4R单一同种型转基因小鼠，并将检查这些小鼠的tau病理学的发展。一个新的基因，saitohin，发现驻留在人类tau基因的内含子内的可能的作用，将检查单，双标记免疫细胞化学，和生物化学技术。GSK3 β，cdk5和其他蛋白激酶在过度磷酸化tau蛋白聚集体形成中的假设作用将使用生物化学，药理学和遗传学策略进行研究。最后，如果证实hTau小鼠中发生神经元死亡，将探索潜在的机制，特别注意涉及细胞凋亡的可能性。

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.