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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.

项目概要：过去 15 年发表的研究指出 Caspase 2 在阿尔茨海默病（AD）。携带人类淀粉样前体蛋白（APP）基因的转基因动物形成广泛的淀粉样蛋白斑块，并表现出日益严重的记忆障碍和突触丧失。什么时候 Caspase 2 从这些动物身上被去除，淀粉样蛋白斑块形成，但突触丧失和记忆不会发生损害。细胞培养工作已证明 Caspase 2 是 A 诱导的必要条件突触功能障碍和细胞死亡。这些结果与 Caspase 2 活性的观察结果结合在一起人类 AD 中 Caspase 2 的增加表明 Caspase 2 是 AD 治疗的潜在治疗靶点。半胱天冬酶2 成人大脑中的水平非常低，仅在疾病或 AD 模型中增加，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 Caspase抑制剂的治疗一直存在非特异性。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。第一种使用细胞可渗透形式的 siRNA 来减少 Caspase 2 的量大脑中的 Caspase 2，而第二个使用新开发的药物 RAIDDpep，它可以阻止 Caspase 2 的激活。将测试这些药物阻断认知和突触效应的能力 J20 APP 转基因小鼠和通过立体定位注射急性引入 A 的小鼠中 A 的存在。这项工作的结果有可能为 AD 治疗开辟一条新途径。