Deteriming the Role of Caspase Cleaved Tau in Alzheimer’s Disease

项目总结/摘要 阿尔茨海默病（AD）是一种严重的健康威胁，是世界上增长最快的十大死亡原因。 美国的AD目前每年花费美国人2800亿美元的直接医疗费用。AD是 其特征在于聚集的微管相关蛋白tau的原纤维。Tau在这些纤维中 在几个方面是独特的，包括被半胱天冬酶截短。半胱天冬酶和切割的tau蛋白在AD中的作用还没有被证实。 已经明确定义，并提出了两个不相互排斥的假设。第一个假设是 半胱天冬酶在AD早期被上调并将tau切割成有毒物质。第二种可能的解释是 半胱天冬酶响应于tau上调而过表达，并且在AD后发生tau裂解 进展已经开始。 该提案的总体目标是了解胱天蛋白酶切割的tau蛋白在tau蛋白病理学中的作用。到 迄今为止，已经在体内观察到几种截短的tau产物，但是大多数努力都是为了了解这些产物的作用。 产品都围绕着半胱天冬酶的遗传或化学抑制。在所有半胱天冬酶中， 半胱天冬酶-3和半胱天冬酶-6已显示在细胞和动物模型中减轻tau病理和细胞死亡。 敲除caspase-3在小鼠中是致命的，但caspase-6可以在小鼠中敲除而没有任何不良影响。 这就引出了一个问题，半胱天冬酶-6是否是治疗AD的潜在治疗靶点？的答案 这个问题是肯定的，它必须表明为什么阻断半胱天冬酶-6会使tau病理学恶化。 我们的中心假设是tau蛋白的半胱天冬酶切割导致蛋白毒性物质， tau蛋白病和细胞死亡。为了证明这一点，我们将首先表征半胱天冬酶可以切割tau蛋白的位置， 重组系统。接下来，我们将描述稳定性、接种倾向、细胞半衰期和毒性 这些切割的tau蛋白。最后，我们将证明表达不可切割tau蛋白的细胞对毒性具有抵抗力。 与半胱天冬酶诱导有关。这些实验将证明tau切割对于 半胱天冬酶诱导引起的神经元细胞死亡。当结合以前的观察结果时，1） 切割的tau与AD进展相关，2）半胱天冬酶活性的阻断使tau病理学和细胞凋亡恶化。 死亡，拟议的研究将提供一个强有力的情况下，半胱天冬酶作为治疗目标的AD。

Project Summary/Abstract Alzheimer’s disease (AD) is significant health threat that is the fastest growing top 10 cause of death in the United States. AD currently costs Americans $280 billion dollars in direct health care costs annually. AD is characterized by, among other things, fibrils of aggregated microtubule associated protein tau. Tau in these fibrils is unique in several ways including truncation by caspases. The role of caspases and cleaved tau in AD has not been clearly defined, and two non-mutually exclusive hypotheses have been proposed. The first hypothesis is that caspases are being upregulated early in AD and cleave tau to a toxic species. A second possible explanation is that caspases are overexpressed in response to tau upregulation and cleavage of tau occurs after AD progression has been initiated. The overall goal of this proposal is understanding the role caspase cleaved tau plays in tau pathology. To date, several truncated tau products have been observed in vivo, but most efforts to understand the role of these products has revolved around genetic or chemical inhibition of caspases. Among all caspases, inhibition of caspase-3 and capase-6 have shown to alleviate tau pathology and cell death in cell and animal models. Knockout of caspase-3 is lethal in mice, but caspase-6 can be knocked out of mice without any adverse effects. This begs the question, is caspases-6 a potential therapeutic target for the treatment of AD? For the answer to this question to be yes, it must be shown why blocking caspase-6 alleviates tau pathology. Our central hypothesis is that caspase cleavage of tau results in a proteotoxic species that promotes tauopathy and cell death in AD. To demonstrate this, we will first characterize where caspases can cleave tau in a recombinant system. Next, we will characterize the stability, seeding propensity, cellular half-life, and toxicity of these cleaved tau proteins. Finally, we will show that cells expressing uncleavable tau are resistant to toxicity associated with caspase induction. These experiments will demonstrate that tau cleavage is necessary for neuronal cell death induced by caspase induction. When combined with previous the observations that 1) cleaved tau correlates with AD progression and 2) blockage of caspase activity alleviates tau pathology and cell death, the proposed research will provide a strong case for caspases as therapeutic targets in AD.