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

阿尔茨海默病相关基因的新发育途径

• 批准号: 8706757
• 负责人: Katherine Villa
• 金额: $ 4.27万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-14 至 2015-09-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706757
• 关键词: Adhesions; Adult; Affect; Age; Age-Months; Alzheimer' s Disease; Amyloid beta-Protein; Asses; Axon; Behavioral; Biochemical; Biological; Biological Assay; Brain; Calcium; Cell Adhesion; Cell Adhesion Molecules; Cell Aggregation; Cell membrane; Cells; Cerebral cortex; Cessation of life; Characteristics; Cleaved cell; Co-Immunoprecipitations; Cognitive; DNA Sequence Rearrangement; Defect; Dementia; Dendrites; Development; Disease; Disease Progression; Enzymes; Exhibits; Extracellular Matrix; Family; Genes; Goals; Growth; Homeostasis; Human; In Vitro; Individual; Interneurons; Learning; Maps; Mediating; Membrane Microdomains; Membrane Proteins; Memory impairment; Messenger RNA; Microscopy; Mind; Mus; Mutation; Neurites; Neurons; Pathology; Pathway interactions; Pattern; Peptide Hydrolases; Phosphoric Monoester Hydrolases; Play; Process; Protein Family; Proteins; Quantitative Reverse Transcriptase PCR; Recruitment Activity; Resolution; Role; Seizures; Senile Plaques; Sensory; Structure; Synapses; Techniques; Testing; Transcriptional Activation; Visual; Western Blotting; base; brain tissue; cellular imaging; early onset; extracellular; human PHEMX protein; human PTPRT protein; immunocytochemistry; in vivo; inhibitory neuron; knock-down; member; mouse model; neurodevelopment; new therapeutic target; notch protein; novel; overexpression; peptide A; public health relevance; receptor; research study; response; secretase; small hairpin RNA; therapeutic development; tool; two-photon

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.

描述（由申请人提供）：阿尔茨海默氏病（AD）是一种破坏性的疾病，会侵蚀大脑，逐渐导致丧失能力的痴呆症并最终导致死亡。该疾病的病因和进展尚不清楚，目前尚无已知的治疗方法。大脑中 AD 病理学的一个标志是淀粉样β肽 (A¿42)（一种 APP 蛋白被 ¿-分泌酶跨膜蛋白酶裂解的产物）在细胞外淀粉样斑块中的积累和聚集。这些被认为会导致突触退化、钙稳态破坏和神经元死亡。我们已经确定了一种响应神经元活动而促进树突生长的新发育途径，其中涉及 ¿-分泌酶。我们的目标是阐明这一途径、其发育重要性以及成人中潜在的失调，为 AD 治疗提供新的治疗靶点和介入工具。在神经发育过程中，轴突和树突在延伸和收缩的动态过程中生长和连接，其中最终连接是根据显着的活动模式选择的。在成人中，活动依赖性结构重排被认为是感觉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作出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 这些候选可塑性基因（CPG）的数量，其表达随着活动而上调。我们已经鉴定了两个 CPG，tspan5 和 ptprm，它们影响抑制性神经元的结构重塑，并且这两个基因都已被证明与 ¿-分泌酶相互作用。我们认为 tspan5 和 ptprm 的表达在发育过程中的树突生长和结构重塑中发挥重要作用，它们后来有助于成体活动依赖性可塑性，并且它们在成体中的失调可能导致 AD。我们建议使用生化和细胞生物学技术来研究该途径，以在体外测试 Tspan5、Ptprm 和 ¿-分泌酶的相互作用 和体内。通过改变 tspan5 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小鼠模型来确定改变 tspan5 或 ptprm 表达水平是否可以挽救 AD 特征的细胞异常和/或认知缺陷。