Presenilins and Cell Adhesion Molecules

早老素和细胞粘附分子

• 批准号: 7540968
• 负责人: ANGELE PARENT
• 金额: $ 33.58万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7540968
• 关键词: Adhesions; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Area; Biochemical; Biological Process; Brain; CD44 gene; Cadherins; Cell Adhesion Molecules; Cell Culture System; Cell Line; Cell physiology; Cells; Coculture Techniques; Complex; Coupled; Cyclic AMP; Cytoplasmic Tail; DCC gene; Development; Disease; Embryo; Embryonic Development; Enzymes; Eph Family Receptors; ErbB4 gene; Functional disorder; Generations; Genes; Glutamates; Hand; Health; Hippocampus (Brain); Image; Impaired cognition; Individual; Investigation; Knock-in Mouse; Length; Ligands; Link; Mediating; Membrane; Membrane Microdomains; Membrane Proteins; Memory; Mutation; N-Cadherin; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurites; Neurons; PVRL1; Pathogenesis; Peptides; Play; Preparation; Presenile Alzheimer Dementia; Process; Production; Property; Proteins; Proteolysis; Receptor Signaling; Reporting; Role; Signal Pathway; Signal Transduction; Synapses; Synaptic Transmission; Synaptic plasticity; System; Testing; Time; Variant; Vertebral column; axon guidance; density; gamma secretase; insight; interest; loss of function; memory process; mutant; nectin; netrin receptor; notch protein; novel; postsynaptic; presenilin; presenilin-1; presynaptic; rac1 GTP-Binding Protein; receptor-mediated signaling; secretase; synaptic function; synaptogenesis; syndecan; trafficking

DESCRIPTION (provided by applicant): Synaptic dysfunction is a critical feature of cognitive decline and neurodegeneration associated with Alzheimer's disease (AD). Autosomal dominant mutations in PSEN genes cause familial early-onset AD. Presenilins (PS) form the catalytic center of gamma-secretase, an enzyme responsible for the generation of beta amyloid peptides, which accumulate in the brains of individuals with AD. In addition to intramembranous cleavage of APP, Notch ligands/Notch receptor, and several cell adhesion molecules (CAMs) including cadherins, protocadherins, DCC, ErbB4, ephrin/Eph receptors, nectin-1alpha and syndecan, are also processed by gamma-secretase. Notably, each of these proteins facilitates diverse neuronal functions during embryonic development such as axon guidance, neuronal outgrowth and synaptogenesis. Recently, we reported that loss of PS expression or function in cultured neurons enhances glutamatergic synaptic transmission, synapse formation, and activation of cAMP-dependent signaling cascades. Interestingly, using PS1 M146V knock-in mice we find that expression of FAD-linked mutant also elevates cAMP-dependent signaling in cultured neurons, and leads to increased spine density in CA1 area of hippocampus. Analysis of DCC (the netrin receptor) processing revealed that lack of gamma-secretase cleavage increases neurite outgrowth and cAMP-dependent signaling, illustrating a novel function for PS wherein cleavage by gamma-secretase terminates intracellular signaling cascades associated with certain CAM substrates. Taken together, we hypothesize that gamma-secretase processing of certain CAMs regulates signaling cascades that play pivotal roles in synapse formation, synaptic transmission and plasticity. We also hypothesize that FAD-linked PS1 variants promote AD pathogenesis by influencing Abeta generation as well as proteolysis of certain CAMs that are important for synaptic function. The specific aims of this investigation are to examine the influence of PS-dependent proteolysis of CAMs: 1) on cellular function, 2) on synapse formation, and 3) on cellular substrates of memory. Using PS1 null embryos, PS1 M146V knock-in mice, and cultured cell systems we propose to perform electrophysiological, biochemical and imaging studies to investigate how PS-dependent proteolysis of CAMs influences synaptic functions. In particular, we will focus our studies on the synaptic influence of APP, DCC and N-cadherin in normal and pathological conditions because of their known association with the pathogenesis of AD, synapse formation and signaling pathways related to synaptic functions. We are extremely confident that our complementary approaches outlined in our proposal will provide important mechanistic insights into the role of PS in health and disease.

描述（由申请人提供）：突触功能障碍是与阿尔茨海默病（AD）相关的认知能力下降和神经变性的一个关键特征。 PSEN 基因的常染色体显性突变导致家族性早发性 AD。早老素 (PS) 形成 γ 分泌酶的催化中心，γ 分泌酶是一种负责生成 β 淀粉样肽的酶，β 淀粉样肽在 AD 患者的大脑中积聚。除了 APP 的膜内裂解外，Notch 配体/Notch 受体以及多种细胞粘附分子 (CAM)（包括钙粘蛋白、原钙粘蛋白、DCC、ErbB4、肝配蛋白/Eph 受体、nectin-1alpha 和 Syndecan）也由 γ-分泌酶加工。值得注意的是，这些蛋白质中的每一种都促进胚胎发育过程中的多种神经元功能，例如轴突引导、神经元生长和突触发生。最近，我们报道了培养神经元中 PS 表达或功能的丧失增强了谷氨酸能突触传递、突触形成和 cAMP 依赖性信号级联的激活。有趣的是，使用 PS1 M146V 敲入小鼠，我们发现 FAD 连接突变体的表达也增强了培养神经元中的 cAMP 依赖性信号传导，并导致海马 CA1 区域的棘密度增加。 DCC（netrin 受体）加工分析表明，缺乏 γ-分泌酶裂解会增加神经突生长和 cAMP 依赖性信号传导，说明 PS 的新功能，其中 γ-分泌酶裂解终止与某些 CAM 底物相关的细胞内信号级联。综上所述，我们假设某些 CAM 的 γ 分泌酶处理调节信号级联，在突触形成、突触传递和可塑性中发挥关键作用。我们还假设 FAD 相关的 PS1 变异通过影响 Abeta 的生成以及某些对突触功能很重要的 CAM 的蛋白水解来促进 AD 发病机制。本研究的具体目的是检查 CAM 的 PS 依赖性蛋白水解作用的影响：1) 对细胞功能，2) 对突触形成，3) 对记忆的细胞底物。我们建议使用 PS1 无效胚胎、PS1 M146V 敲入小鼠和培养细胞系统进行电生理学、生化和成像研究，以研究 CAM 的 PS 依赖性蛋白水解如何影响突触功能。特别是，我们将研究 APP、DCC 和 N-钙粘蛋白在正常和病理条件下对突触的影响，因为已知它们与 AD 的发病机制、突触形成和与突触功能相关的信号通路有关。我们非常有信心，我们提案中概述的补充方法将为 PS 在健康和疾病中的作用提供重要的机制见解。