The Role of Reelin in Adult Neuronal Function and Alzheimer's Disease

Reelin 在成人神经元功能和阿尔茨海默病中的作用

• 批准号: 8955628
• 负责人: Courtney E Lane-Donovan
• 金额: $ 2.85万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8955628
• 关键词: AMPA Receptors; Adult; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Anxiety; Apolipoprotein E; Architecture; Back; Behavioral; Biochemical; Brain; Calcium; Cognition; Cognitive; Cognitive deficits; Data; Dementia; Deposition; Development; Disease; Electrophysiology (science); Emotional; Endocytosis; Genetic study; Goals; Growth; Health; Healthcare Systems; Heterozygote; Hippocampus (Brain); Impaired cognition; In Vitro; Individual; Injection of therapeutic agent; Investigation; Knock-in Mouse; Knock-out; Knockout Mice; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Learning; Ligand Binding; Literature; Long-Term Potentiation; Memory; Memory Loss; Molecular; Motor; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuromodulator; Neuronal Dysfunction; Neurons; Neuroprotective Agents; Onset of illness; Pathogenesis; Pathogenicity; Pathology; Patients; Performance; Phenocopy; Phosphorylation; Play; Population; Presenile Alzheimer Dementia; Protein Isoforms; Proteins; Recycling; Reeler Mouse; Research; Research Personnel; Resistance; Role; Schizophrenia; Senile Plaques; Sensory; Signal Transduction; Surface; Synapses; Synaptic plasticity; Tamoxifen; Toxic effect; Transgenic Mice; Ventricular; Vertebral column; abeta accumulation; age related; apolipoprotein E receptor 2; apolipoprotein E-4; behavioral study; clinically relevant; combat; density; disease diagnosis; disease phenotype; familial Alzheimer disease; genetic risk factor; hyperphosphorylated tau; improved; in vivo; mouse model; nervous system disorder; neurofibrillary tangle formation; novel; novel therapeutics; outcome forecast; overexpression; particle; patch clamp; postsynaptic; prevent; protective effect; reelin receptor; research study; role model; synaptic function; targeted treatment; tau Proteins; tau phosphorylation; tau-1; trafficking

DESCRIPTION (provided by applicant): As our nation ages, the neurological diseases of later adulthood have become more prevalent. The number of Alzheimer's disease (AD) diagnoses has increased in the past decades, taking a large financial and emotional toll on our health care system. What makes some patients more susceptible to AD than others? Over twenty years ago, the ApoE4 allele was identified as a major genetic risk factor for late onset AD (1, 2). One of ApoE4's effects in the central nervous system (CNS) is to reduce the ability of neurons to respond to reelin signaling (3). Reelin is a neuromodulator that decreases with age and is especially reduced in Alzheimer's disease (4, 5). In vitro, reelin promotes synaptic plasticity, an mice injected with reelin intra- ventricularly have improved performance on learning and memory tasks (6, 7). Importantly, reelin protects in vitro against the toxicity induced by Aß oligomers, a toxic particle that builds up gradually in Alzheimer's disease (8-10). Additionally, a recent study demonstrated that Reelin overexpression in a mouse model of AD rescued cognitive defects and delayed amyloid plaque development (11). Genetic studies on the effect of reelin loss in mice have been hindered by the fact that reelin plays a large role in brain development (12). To circumvent the problem presented by this developmental issue, we have generated a conditional reelin knockout mouse in which reelin is expressed normally until the mice are injected with Tamoxifen. I will use this mouse to study the effect of reelin loss in aging related disease phenotypes. To determine the clinical relevance of reelin reduction in AD, it is important to study these conditional reelin knockout mice on a background of normal adult synaptic plasticity as well as Alzheimer's disease pathology. Initial results from my preliminary data and the literature suggest that reelin has a protective effect against Aß-induced neurodegeneration. The primary goals of this research are to 1) elucidate the role reelin has in normal adult synaptic function; 2) determine the role in vivo for reelin to combat Aß toxicity. These goals will be accomplished by a combination of behavioral studies of learning and memory, electrophysiological experiments on synaptic function, and biochemical and histological characterization. To study the protective role of reelin against AD, I will cross the conditional knockout mice with APPSwe mice, an Alzheimer's disease mouse model that expresses high levels of Aß.The data generated by this study can be used to propose new models of the role of reelin in adult neuronal function and AD and generate new therapeutic ideas to use alterations in reelin levels as a neuroprotective agent in neurological diseases of aging.

描述(申请人提供)：随着我们国家的老龄化，成年后的神经系统疾病变得更加普遍。在过去的几十年里，阿尔茨海默病(AD)的诊断人数有所增加，给我们的医疗保健系统带来了巨大的经济和情感损失。是什么让一些患者比其他患者更容易患上AD？20多年前，ApoE4等位基因被认为是晚发性AD(1，2)的主要遗传危险因素。载脂蛋白E4在中枢神经系统的S效应之一是降低神经元对卷轴蛋白信号的反应能力(3)。Reelin是一种神经调节剂，随着年龄的增长而减少，在阿尔茨海默病中尤其减少(4，5)。在体外，reelin促进突触可塑性，脑室内注射reelin的小鼠在学习和记忆任务中的表现有所改善(6，7)。重要的是，在体外，reelin可以防止低聚物引起的毒性，这是一种在阿尔茨海默病中逐渐积累的有毒颗粒(8-10)。此外，一个 最近的研究表明，Reelin在AD小鼠模型中的过度表达可以挽救认知缺陷和延缓淀粉样斑块的发展(11)。由于卷轴蛋白在大脑发育过程中扮演着重要角色的事实，老鼠体内卷轴蛋白丢失的影响的遗传学研究一直受到阻碍。为了绕过这个发育问题带来的问题，我们创造了一个有条件的reelin基因敲除小鼠，在该小鼠中，reelin正常表达，直到注射三苯氧胺。我将用这只老鼠来研究卷轴蛋白在衰老过程中的作用 相关疾病表型。为了确定reelin降低在AD中的临床相关性，重要的是在正常成人突触可塑性和阿尔茨海默病病理背景下研究这些条件性reelin基因敲除小鼠。我的初步数据和文献的初步结果表明，reelin对Aü诱导的神经退行性变具有保护作用。本研究的主要目的是1)阐明reelin在正常成人突触功能中的作用；2)确定reelin在体内对抗A？毒性的作用。这些目标将通过学习和记忆的行为研究、突触功能的电生理实验以及生化和组织学特征的组合来实现。为了研究reelin对AD的保护作用，我将把reelin的条件基因敲除小鼠与APPswe小鼠进行杂交，APPswe小鼠是一种高水平表达Aü的阿尔茨海默病小鼠模型。这项研究产生的数据可以用来提出reelin在成人神经元功能和AD中的作用的新模型，并产生新的治疗思路，将reelin水平的变化用作神经衰老疾病的神经保护剂。