Tyrosine Phosphorylation in Alzheimer's Disease

Tau异常是几种与年龄相关的神经退行性疾病的共同特征。阿尔茨海默氏症 Tau病形成神经原纤维缠结，与淀粉样斑块一起构成主要的神经路径- 该病的生物学特征。在一些额颞叶痴呆患者中，tau基因发生了突变。另外，在其他方面- 仅在颞叶痴呆以及进行性核上性瘫痪和皮质基底变性中 神经病理学中有tau的特殊异构体。神经细胞死亡的机制 这些疾病是未知的。我们的研究集中在tau的一种新的相互作用上，它将tau识别为一个信号 转导蛋白。作为src家族酪氨酸激酶SH3结构域的结合伙伴，我们发现 该tau是酪氨酸磷酸化的，能够上调激酶的活性。我们的初步数据也 结果表明，tau中与疾病相关的结构修饰增加了其对Fyn的SH3结构域的亲和力。 因此，我们假设tau和fyn之间的相互作用是神经退行性变中的一个关键事件。 主动过程。这项提案的具体目标将1)使用额颞部痴呆的动物模型和 阿尔茨海默病研究酪氨酸磷酸化tau的时空表现 相对于其他神经病理特征；2)进一步了解作用于tau的酪氨酸激酶； 3)进一步分析了疾病相关的tau亚型与fyn的SH3结构域之间的相互作用； 4)阐明4个重复与3个重复tau的SH3结合能力差异的结构基础； 5)研究src家族酪氨酸激酶活性上调对神经元功能的影响。 细胞，重点研究细胞周期特征和对细胞凋亡的敏感性。我们的工作模式是 磷酸化的4R tau和/或tau FTDP-17错义突变体上调Fyn的能力增强 和/或SRC活动。在神经元中，这种酪氨酸激酶活性的增加将导致信号的激活 转导途径，如那些参与细胞分裂或凋亡的途径，最终导致细胞死亡。 这一模型与tau的毒性功能和FTDP-17的常染色体显性方面是一致的。 突变。Fyn-tau相互作用是神经退行性变过程中的关键事件 将为治疗干预提供新的候选靶点。

Abnormal tau is a common feature of several age related neurodegenerative diseases. In Alzheimer's disease tau forms neurofibrillary tangles, that along with amyloid plaques, comprise the major neuropath- ological features of the disease. In several frontotemporal dementias, tau is mutated. Also, in other fronto- temporal dementias as well as in progressive supranuclear palsy and corticobasal degeneration, only specific isoforms of tau are featured in the neuropathology. The mechanisms by which neuronal cells die in these diseases is unknown. Our research focuses on a new interaction for tau that identifies tau as a signal transduction protein. As a binding partner for the SH3 domain of src family tyrosine kinases, we have found that tau is tyrosine phosphorylated and is capable of up-regulating kinase activity. Our preliminary data also shows that disease related structural modifications in tau increase its affinity for the SH3 domain of fyn. Therefore, we hypothesize that the interaction between tau and fyn is a critical event in the neurodegenera- tive process. The specific aims of this proposal will 1) use animal models for frontotemporal dementia and Alzheimer's disease to investigate the temporal and spatial appearance of tyrosine phosphorylated tau relative to other neuropathological features; 2) further our knowledge of the tyrosine kinases that act on tau; 3) extend our analysis of the interaction between disease related isoforms of tau and the SH3 domain of fyn; 4) elucidate the structural basis for the differential SH3 binding ability of four repeat versus three repeat tau; and 5) investigate the functional consequences of up-regulated src family tyrosine kinase activity in neuronal cells, focusing on cell cycle characteristics and susceptibility to apoptosis. Our working model is that phosphorylated 4R tau and/or tau FTDP-17 missense mutants have an increased ability to up-regulate fyn and/or src activity. In neurons, this increase in tyrosine kinase activity would result in the activation of signal transduction pathways, such as those involved in cell division or apoptosis, that eventually lead to cell death. This model is consistent with a gain of toxic function for tau and the autosomal dominant aspect of FTDP-17 mutations. The identification of the fyn-tau interaction as a critical event in the neurodegenerative process would suggest new candidate targets for therapeutic interventions.