The amyloid cascade in a novel mouse model of Alzheimer's disease

新型阿尔茨海默病小鼠模型中的淀粉样蛋白级联反应

基本信息

批准号：
8240480
负责人：
CAROL Anne COLTON
金额：
$ 30.43万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8240480
关键词：
Age Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Asses Behavior Behavioral Binding Proteins Brain Brain region Caspase Characteristics Chronic Chronic Disease Data Deltastab Dementia Deposition Disease Disease Progression Environment Gene Delivery Generations Goals Hippocampus (Brain)Human Immunization Inflammation Injection of therapeutic agent Knock-out Learning Measures Mediating Memory Methods Microtubules Modeling Mus Mutate Nerve Degeneration Neurodegenerative Disorders Neurons Nitric Oxide Nitric Oxide Synthase Nitric Oxide Synthase Type I Outcome Oxidation-Reduction Passive Immunization Pathology Pattern Peptides Pharmacologic Substance Phenotype Prevention Process Production Proteins Public Health Recovery Regulation Reporting Role Small Interfering RNA Source Staging Subfamily lentivirinae Testing Therapeutic Tissues Transgenes Transgenic Mice Vaccination amyloid peptide caspase-3 cognitive function design disorder prevention in vivo insight mouse model neuron loss neuronal cell body neuropathology novel pre-clinical small hairpin RNA tau Proteins tau aggregation tool vector control

项目摘要

The neuropathological features of Alzheimer's disease are characterized by the presence of insoluble amyloid deposits in the brain and cerebrovasculature, the intra-neuronal accumulation of abnormally phosphorylated and aggregated forms of tau, a microtubule binding protein and neuronal loss. Although the exact mechanisms producing these pathological changes remain unknown, the amyloid cascade hypothesis states that the peptides (Ass) that make up amyloid deposits are the cause of the disease process. Despite numerous supportive studies, discrepancies between animal models of AD and humans with AD remain an obstacle for full acceptance of Ass as the primary causal agent for AD. By altering the nitric oxide in mouse brain, we have generated a novel mouse model that provides unique insights into mouse-human differences. Our bigenic mouse models of AD increase the expression of human Ass on a murine nitric oxide synthase 2 (NOS2) knockout background. The resulting phenotype is highly reminiscent of the pathology observed in humans with AD including high levels of Ass peptides, tau hyperphosphorylation, tau redistribution and tau aggregation, neuronal loss and behavioral deficits. A primary advantage of the APPSw/NOS2-/- mouse is the formation of tau pathology from normal, not mutated tau AND the presence of significant neuronal loss. Thus, our model provides a unique opportunity to fully test the amyloid cascade hypothesis in vivo under conditions of chronic disease. The first aim will confirm a pathological cascade in the APPSw/NOS2-/- mouse brain by measuring Ass, tau pathology, neuronal loss and memory and learning in the APPSw/NOS2-/- mice brains at specific ages. To establish a direct, causal role for Ass peptides in the cascade, we propose a) to reduce Ass levels in the brains of APPSw/NOS2-/- mice by passive immunization and b) to increase Ass levels in the brains of NOS2-/- mice using intrahippocampal injection of Ass peptide mixtures. The second aim will examine the role of NOS2. We propose a) to reduce brain iNOS protein using lentivirus delivery of small interfering RNA (shNOS2 lentivirus) b) to test the ability of NOS2 and NO replacement to alter the pathological cascade mediated by Ass. The third aim will examine a likely mechanism of NO's action, the regulation of caspase activity.

阿尔茨海默病的神经病理学特征是不溶性淀粉样蛋白的存在大脑和脑血管系统中的沉积物，异常磷酸化的神经元内积聚以及聚集形式的 tau（一种微管结合蛋白）和神经元损失。虽然确切的机制产生这些病理变化的情况仍然未知，淀粉样蛋白级联假说指出构成淀粉样沉积物的肽（Ass）是疾病过程的原因。尽管有无数支持性研究表明，AD 动物模型和 AD 人类之间的差异仍然是研究的障碍完全接受 Ass 是 AD 的主要致病因素。通过改变小鼠大脑中的一氧化氮，我们产生了一种新颖的小鼠模型，为小鼠与人类的差异提供了独特的见解。我们的双基因 AD 小鼠模型增加了鼠类一氧化氮合酶 2 (NOS2) 上人 Ass 的表达淘汰赛背景。由此产生的表型非常让人想起在患有该病的人类中观察到的病理学 AD 包括高水平的 Ass 肽、tau 过度磷酸化、tau 重新分布和 tau 聚集，神经元损失和行为缺陷。 APPSw/NOS2-/- 小鼠的主要优点是形成 tau 病理学不同于正常的、未突变的 tau 蛋白，并且存在显着的神经元损失。因此，我们的模型提供了在慢性条件下体内充分测试淀粉样蛋白级联假说的独特机会疾病。第一个目标是通过测量确定 APPSw/NOS2-/- 小鼠大脑中的病理级联反应特定年龄的 APPSw/NOS2-/- 小鼠大脑中的 Ass、tau 病理学、神经元损失以及记忆和学习。为了确定 Ass 肽在级联中的直接因果作用，我们建议 a) 降低 Ass 水平 b) 通过被动免疫增加 APPSw/NOS2-/- 小鼠大脑中的 Ass 水平小鼠海马内注射 Ass 肽混合物。第二个目标是研究 NOS2 的作用。我们建议 a) 使用慢病毒递送小干扰 RNA (shNOS2) 来减少脑 iNOS 蛋白慢病毒）b）测试NOS2和NO替代改变Ass介导的病理级联的能力。第三个目标是研究 NO 作用的可能机制，即 caspase 活性的调节。