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，它会侵蚀大脑，逐渐导致失智并最终死亡。这种疾病的病因和进展尚不清楚，目前也没有已知的治疗方法。大脑AD病理的一个标志是淀粉样蛋白β肽（A¿42）的积累和聚集，A¿42是APP蛋白被分泌酶跨膜蛋白酶裂解成细胞外淀粉样斑块的产物。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，促进树突生长，以响应神经元活动，其中包括-分泌酶。我们的目标是阐明这一通路、其在成人中的发育重要性和潜在的失调，为治疗AD提供新的治疗靶点和介入工具。在神经发育过程中，轴突和树突的生长和连接是一个动态的伸展和收缩过程，最终的连接是根据显著的活动模式来选择的。在成人中，活动依赖的结构重排被认为是学习过程中感觉地图可塑性和新连接形成的基础。这些神经元结构和功能的变化是由特定基因的转录激活介导的，这些基因对突触活动有反应。我们实验室之前发现了一个很大的

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.