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Targeting Caspase-2 in Alzheimer's Disease

靶向 Caspase-2 治疗阿尔茨海默病

基本信息

批准号：
9896064
负责人：
MICHAEL L SHELANSKI
金额：
$ 20.25万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896064
关键词：
Acute Adult Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapy Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Animals Base of the Brain Behavior Brain CASP2 gene Caspase Inhibitor Cell Culture Techniques Cell Death Cell physiology Cells Cessation of life Clinical Trials Cognitive Cultured Cells Defect Development Disease Electrophysiology (science)Enzymes Exposure to Functional disorder Gene Proteins Generations Goals Hippocampus (Brain)Human Human Amyloid Precursor Protein Infusion procedures Injections Intervention Studies Intranasal Administration J20 mouse Knockout Mice Measures Memory Memory impairment Methods Modeling Molecular Morphology Mouse Protein Mus Neurons Parents Patients Peptides Peripheral Permeability Physiological Publishing Reporting Research Research Project Summaries Role Senile Plaques Slice Small Interfering RNA Synapses Testing Therapeutic Transgenes Transgenic Animals Transgenic Mice Vertebral column Wild Type Mouse Work aging brain inhibitor/antagonist knock-down mouse model neuroinflammation novel novel strategies protein aminoacid sequence tau Proteins therapeutic target

项目摘要

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.

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。