Targeting Caspase-2 in Alzheimer's Disease

项目摘要： 过去15年发表的研究指出，胱天蛋白酶2在 阿尔茨海默病（AD）。携带人淀粉样前体蛋白（APP）基因的转基因动物 出现广泛的淀粉样斑块，并表现出记忆障碍和突触丧失。当 从这些动物中去除半胱天冬酶2，淀粉样斑块发展，但突触丢失和记忆 不会发生损害。细胞培养工作已经证明Caspase 2是A β诱导凋亡所必需的 突触功能障碍和细胞死亡。这些结果与Caspase 2活性 提示Caspase 2是AD治疗的潜在治疗靶点。半胱天冬酶2 在成人大脑中的水平非常低，仅在疾病或AD模型中增加，这表明 它的抑制可能不会影响正常的细胞过程。探索这一途径的主要障碍是 治疗是半胱天冬酶抑制剂的非特异性。在这里提出的工作中，我们将使用两个高度 抑制Caspase 2的具体方法。第一种方法使用可渗透细胞的siRNA形式， 而第二种方法使用一种新开发的药物RAIDDpep， Caspase 2的激活。这些药物将被测试其阻断认知和突触效应的能力 在J20 APP转基因小鼠和通过立体定位注射急性引入A β的小鼠中， 这项工作的结果有可能为AD治疗开辟一条新的途径。

Project Summary: Research published over the past 15 years has pointed to a critical role of the enzyme Caspase 2 in Alzheimer's disease (AD). Transgenic animals carrying human Amyloid Precursor Protein (APP) genes develop extensive amyloid plaques and show increasing memory impairment and synaptic loss. When Caspase 2 is removed from these animals, the amyloid plaques develop but the synaptic loss and memory impairment do not occur. Cell culture work has demonstrated that Caspase 2 is necessary of A induced synaptic dysfunction and cell death. These results taken together with the observation that Caspase 2 activity is increased in human AD suggest that Caspase 2 is a potential therapeutic target for AD treatment. Caspase 2 is present at very low levels in the adult brain and increases only in disease or in the AD models suggesting that its inhibition might not affect normal cellular processes. The major obstacle to exploring this avenue of treatment has been the non-specificity of caspase inhibitors. In the work proposed here we will use two highly specific methods of inhibiting Caspase 2. The first uses a cell permeable form of siRNA to diminish the amount of Caspase 2 in the brain while the second uses a newly developed agent, RAIDDpep, which blocks the activation of Caspase 2. These agents will be tested for their ability to block the cognitive and synaptic effects of A in the J20 APP transgenic mouse and in mice where A is introduced acutely by stereotaxic injection. The results of this work have the potential to open a new avenue for AD therapy.