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

描述(申请人提供)：阿尔茨海默病(AD)是一种毁灭性的疾病，侵蚀大脑，逐渐导致丧失工作能力的痴呆症，最终导致死亡。这种疾病的病因和发展还不是很清楚，目前也没有已知的治疗方法。脑内AD病理的一个特征是淀粉样β蛋白(A？42)的积聚和聚集，A？42是APP蛋白被？分泌酶跨膜蛋白酶切割的产物，形成细胞外淀粉样斑块。这些都被认为是导致突触退化、破坏钙稳态和神经元死亡的原因。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，以响应神经元的活动，其中涉及分泌酶。我们的目标是阐明这一途径，它在成人中的发育重要性和潜在的失调，为AD的治疗提供新的治疗靶点和干预工具。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，其中最终的连接是根据显著的活动模式选择的。在成人中，依赖活动的结构重排被认为是学习过程中感觉图可塑性和新连接形成的基础。神经元结构和功能的这些变化是由特定基因的转录激活所介导的，这些基因对突触活动做出反应。我们的实验室此前发现了一种大型 这些候选可塑性基因(CPGs)的数量，其表达随着活性的上调而上调。我们已经确定了两个Cpg，tspan5和ptprm，它们影响抑制性神经元的结构重构，并且这两个基因都被证明与分泌酶相互作用。我们认为，tspan5和ptprm的表达在树突状突起的生长和发育过程中的结构重建中起着重要的作用，它们后来促进了成人的活动依赖性可塑性，并且它们在成人中的失调可能有助于AD的发生。我们建议使用生化和细胞生物学技术来研究这一途径，以检验Tspan5、Ptprm和分泌酶在体外和体内的相互作用。通过改变tspan5和ptprm的表达水平，我们将确定它们在结构重塑中的作用。我们还将使用阿尔茨海默病的小鼠模型来确定改变tspan5或ptprm的表达水平是否可以挽救阿尔茨海默病特有的细胞异常和/或认知缺陷。

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.