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

描述（由申请人提供）：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）的诊断数量有所增加，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人更容易患上AD？二十多年前，ApoE 4等位基因被确定为晚发型AD的主要遗传风险因素（1，2）。ApoE 4在中枢神经系统（CNS）中的作用之一是降低神经元对reelin信号传导的反应能力（3）。Reelin是一种神经调节剂，随着年龄的增长而减少，尤其是在阿尔茨海默病中减少（4，5）。在体外，reelin促进突触可塑性，心室内注射reelin的小鼠在学习和记忆任务上具有改善的表现（6，7）。重要的是，reelin在体外保护免受由Asians寡聚体诱导的毒性，Asians寡聚体是一种在阿尔茨海默病中逐渐积聚的有毒颗粒（8-10）。此外，A 最近的研究表明，在AD的小鼠模型中，Reelin过表达挽救了认知缺陷并延迟了淀粉样斑块的发展（11）。对小鼠中reelin损失影响的遗传研究受到了reelin在大脑发育中起着重要作用的事实的阻碍（12）。为了避免这个发育问题所带来的问题，我们已经产生了一种条件性reelin基因敲除小鼠，其中reelin基因正常表达，直到小鼠注射他莫昔芬。我将用这只老鼠来研究在衰老过程中， 相关疾病表型。 为了确定reelin减少在AD中的临床相关性，重要的是在正常成人突触可塑性以及阿尔茨海默病病理学的背景下研究这些条件性reelin敲除小鼠。从我的初步数据和文献的初步结果表明，reelin有一个保护作用，对黄芪诱导的神经变性。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AAF毒性的作用。这些目标将通过学习和记忆的行为研究、突触功能的电生理学实验以及生物化学和组织学表征的组合来实现。为了研究reelin对AD的保护作用，我将把条件性基因敲除小鼠与APPSwe小鼠杂交，APPSwe小鼠是一种表达高水平Abluetin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中作用的新模型，并产生新的治疗思路，使用reelin水平的改变作为神经保护剂治疗神经系统疾病。

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.