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，成年后期的神经系统疾病变得越来越普遍。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阿尔茨海默病？二十多年前，ApoE4等位基因被确定为迟发性AD的主要遗传危险因素（1,2）。ApoE4在中枢神经系统（CNS）中的作用之一是降低神经元对reelin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，尤其是在阿尔茨海默病中减少（4,5）。在体外实验中，reelin促进突触可塑性，在脑室内注射reelin的小鼠在学习和记忆任务上的表现有所改善（6,7）。重要的是，鱼尾酰胺在体外保护机体免受寡聚物引起的毒性，寡聚物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

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 Aoligomers, 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 A�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 A�oxicity. 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 A�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.