Tyrosine Phosphorylation in Alzheimer's Disease

异常tau蛋白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 疾病tau形成神经元缠结，其沿着淀粉样斑块，构成主要的神经病理- 疾病的病理特征。在几种额颞叶痴呆中，tau蛋白发生了突变。此外，在其他方面- 颞叶痴呆以及进行性核上性麻痹和皮质基底节变性，仅 tau的特定同种型在神经病理学中具有特征。神经细胞死亡的机制 这些疾病是未知的。我们的研究重点是tau蛋白的一种新的相互作用， 转导蛋白作为src家族酪氨酸激酶SH 3结构域的结合伴侣，我们发现 tau是酪氨酸磷酸化的，并且能够上调激酶活性。我们的初步数据还 显示tau中疾病相关的结构修饰增加了其对fyn的SH 3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的关键事件- 的过程。该提案的具体目标是：1）使用额颞叶痴呆的动物模型， 阿尔茨海默病研究酪氨酸磷酸化tau蛋白的时间和空间表现 相对于其他神经病理学特征; 2）进一步我们对作用于tau的酪氨酸激酶的认识; 3)扩展我们对疾病相关的tau亚型和fyn的SH 3结构域之间相互作用的分析; 4)阐明四个重复与三个重复tau的差异SH 3结合能力的结构基础; 和5）研究神经元中src家族酪氨酸激酶活性上调的功能后果。 细胞，侧重于细胞周期特征和细胞凋亡的易感性。我们的工作模式是， 磷酸化的4 R tau和/或tau FTDP-17错义突变体上调fyn的能力增加 和/或SRC活性。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，如参与细胞分裂或凋亡的那些，最终导致细胞死亡。 该模型与tau的毒性功能获得和FTDP-17的常染色体显性方面一致 突变。Fyn-tau相互作用作为神经退行性变过程中的关键事件的鉴定 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.