A Mouse Model of Tau Pathology in AD & Other Dementias

描述（由申请人提供）：通过在缺乏小鼠tau的情况下表达正常人类tau基因（hTau小鼠），开发了一种新的人类tau病理小鼠模型。这些小鼠在体突室中显示磷酸化的tau积累，tau磷酸化明显与年龄相关的增加，tau的构象变化以及新皮质，海马和其他神经元中丝状tau聚集体的形成。一岁以上的小鼠有星形细胞增生、小胶质细胞增生和神经元死亡的证据。我们的第一个目标将是完成hTau小鼠在整个生命周期中发展的tau病理的详细表征。这些研究将包括新皮层和海马的神经元和突触密度的定量，以及星形细胞和小胶质细胞反应的检查。对胆碱能神经传递的tau病理发展的功能后果将进行检查。tau亚型比率是tau病理学和细胞死亡的关键决定因素这一假设将通过用表达人类tau单一亚型的转基因小鼠培育hTau小鼠来验证。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基因3R和4R单亚型的小鼠，这些小鼠将被检查tau病理的发展。在人类tau基因的内含子中发现的新基因saiitohin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查。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通过生化、药理学和遗传策略进行检验。最后，如果确认hTau小鼠发生神经元死亡，将探索潜在的机制，特别关注细胞凋亡的可能性。

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.