Targeting Caspase-2 in Alzheimer's Disease

项目总结： 过去15年发表的研究指出，Caspase 2在 阿尔茨海默病(AD)。携带人淀粉样前体蛋白基因的转基因动物 出现广泛的淀粉样斑块，表现为记忆障碍和突触丧失增加。什么时候 Caspase2从这些动物身上移除后，淀粉样斑块形成，但突触丧失和记忆 不会发生减损。细胞培养实验表明，Caspase2是诱导所必需的 突触功能障碍和细胞死亡。这些结果与观察到的Caspase 2活性结合在一起 提示Caspase2是治疗AD的潜在靶点。Caspase 2 在成人大脑中的水平很低，只有在疾病或AD模型中才会增加，这表明 它的抑制可能不会影响正常的细胞过程。探索这条道路的主要障碍是 治疗一直是半胱氨酸氨基转移酶抑制剂的非特异性治疗。在这里提出的工作中，我们将使用两个高度 抑制Caspase的具体方法2。第一种方法使用一种细胞渗透型的siRNA来减少 而第二种使用了一种新开发的药物RAIDDpep，它可以阻断Caspase 2在大脑中的作用 激活Caspase 2。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向注射急性引入A的小鼠中A的表达。 这项工作的结果有可能为AD的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.