A novel developmental pathway for genes involved in Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种破坏性疾病，侵蚀心灵，逐步导致失能性痴呆，最终死亡。该疾病的病因和进展尚不清楚，目前还没有已知的治疗方法。脑中AD病理学的一个标志是淀粉样蛋白β肽（A <$42）的积累和聚集，淀粉样蛋白β肽（A <$42）是APP蛋白被<$-分泌酶跨膜蛋白酶裂解的产物，其进入细胞外淀粉样蛋白斑块。这些被认为有助于突触变性，破坏钙稳态和神经元死亡。我们已经确定了一种新的发育途径，促进树突状细胞的生长响应神经元的活动，这涉及到分泌酶。我们的目标是阐明这一通路，其发展的重要性，并在成人的潜在失调，提供新的治疗目标和干预工具，治疗AD。在神经发育过程中，轴突和树突在伸展和收缩的动态过程中生长和连接，其中最终连接基于显著的活动模式选择。在成人中，活动依赖性结构重排被认为是感觉地图可塑性和学习过程中新连接形成的基础。神经元结构和功能的这些变化是由对突触活动有反应的特定基因的转录激活介导的。我们的实验室之前已经发现了一个大的 这些候选可塑性基因（CPG）的数量，其表达是上调的活动。我们已经确定了两个CPG，tspan 5和ptprm，它们影响抑制性神经元的结构重塑，并且这两个基因都被证明与β-分泌酶相互作用。我们建议，tspan 5和ptprm的表达在树突状生长和结构重塑在发展过程中起着重要的作用，他们后来有助于成人活动依赖性可塑性，他们在成人的失调可能有助于AD我们建议研究这一途径，使用生物化学和细胞生物学技术来测试Tspan 5，Ptprm，和<$-分泌酶的相互作用在体外和体内。通过改变tspan 5和ptprm的表达水平，我们将确定它们对结构重塑的影响。我们还将使用阿尔茨海默病的小鼠模型来确定改变tspan 5或ptprm表达水平是否可以挽救AD的细胞异常和/或认知缺陷特征。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating illness that erodes the mind, progressively leading to incapacitating dementia and eventually death. The cause and progression of the disease are not well understood, and there is currently no known cure. One hallmark of AD pathology in the brain is the accumulation and aggregation of amyloid beta peptide (A¿42), a cleavage product of the APP protein by the ¿- secretase transmembrane protease, into extracellular amyloid plaques. These are thought to contribute to synapse degeneration, disrupted calcium homeostasis, and neuronal death. We have identified a novel developmental pathway promoting dendritic growth in response to neuronal activity, which involves ¿-secretase. Our goal is to elucidate this pathway, its developmental importance, and potential dysregulation in the adult to provide new therapeutic targets and interventional tools fo treatment of AD. During neural development, axons and dendrites grow and connect in a dynamic process of extension and retraction, where final connections are selected based on salient activity pattern. In the adult, activity- dependent structural rearrangements are thought t underlie sensory map plasticity and the formation of novel connections during learning. These changes in neuronal structure and function are mediated by the transcriptional activation of specific genes which are responsive to synaptic activity. Our lab has previously identified a large number of these candidate plasticity genes (CPGs), whose expression is up-regulated in response to activity. We have identified two CPGs, tspan5 and ptprm, which affect structural remodeling of inhibitory neurons, and both of these genes have both been shown to interact with ¿-secretase. We propose that the expression of tspan5 and ptprm plays an important role in dendritic outgrowth and structural remodeling during development, that they later contribute to adult activity-dependant plasticity, and that their dysregulation in the adult may contribute to AD We propose to study this pathway using biochemical and cell biological techniques to test the interaction of Tspan5, Ptprm, and ¿-secretase both in vitro and in vivo. By altering the expression levels of tspan5 and ptprm we will determine their effects on structural remodeling. We will also use a mouse model of Alzheimer's disease to determine if changing tspan5 or ptprm expression levels can rescue cellular abnormalities and/or cognitive defects characteristic of AD.