Presenilins and Cell Adhesion Molecules

早老素和细胞粘附分子

• 批准号: 7742630
• 负责人: ANGELE PARENT
• 金额: $ 33.24万
• 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/7742630
• 关键词: Acute; Address; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Area; Biochemical; Biological Assay; Bite; Brain; Cadherins; Cell Adhesion Molecules; Cell Culture System; Cell Death; Cell physiology; Critiques; Cyclic AMP; Development; Disease; Embryo; Embryonic Development; Environment; Enzymes; Eph Family Receptors; Equilibrium; ErbB4 gene; Event; Functional disorder; Generations; Genes; Glutamates; Grant; Health; Hippocampus (Brain); Image; Impaired cognition; Individual; Investigation; Knock-in Mouse; Knock-out; Life; Ligands; Link; Longevity; Measures; Membrane Lipids; Membrane Microdomains; Memory; Minor; Mutation; N-Cadherin; Nerve Degeneration; Neurites; Neurons; Parents; Pathogenesis; Patients; Physiological; Play; Policies; Presenile Alzheimer Dementia; Process; Proteins; Proteolysis; Published Comment; Reporting; Research Personnel; Role; Shotguns; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Suggestion; Synapses; Synaptic Transmission; Text; Time; United States National Institutes of Health; Variant; Vertebral column; age related; axon guidance; cholinergic; cognitive function; critical period; density; follow-up; gamma secretase; insight; mutant; nectin; netrin receptor; notch protein; novel; presenilin; response; secretase; synaptic function; synaptogenesis; syndecan

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氏病（AD）相关的认知下降和神经变性的关键特征。 PSEN基因中的常染色体显性突变引起家族性早发AD。 Presenilins（PS）形成了伽马分泌酶的催化中心，伽马分泌酶是一种负责产生β淀粉样蛋白肽的酶，该酶积聚在AD患者的大脑中。除了APP的膜内切割外，Notch配体/Notch受体以及几个细胞粘附分子（CAM），包括钙粘蛋白，原钙粘着蛋白，DCC，ERBB4，Ephrin/Eph受体，Nectin-1Alpha和Syndecan，也通过胶质酶进行处理。值得注意的是，这些蛋白质中的每一个都促进了胚胎发育期间的多种神经元功能，例如轴突引导，神经元出生和突触发生。最近，我们报告说，培养神经元中PS表达或功能的丧失会增强谷氨酸能突触传播，突触形成以及依赖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连接突变体的表达还可以提高培养神经元中cAMP依赖性信号传导，并导致海马CA1区域的脊柱密度增加。 DCC（Netrin受体）加工的分析表明，缺乏γ-分泌酶的裂解增加了神经突产物的生长和cAMP依赖性信号传导，这说明了PS的新功能，其中γ-分泌酶的裂解终止了与某些CAMSTRATES相关的细胞内信号级联。综上所述，我们假设某些CAM的伽马分泌酶处理调节信号级联，这些级联在突触形成，突触传播和可塑性中起关键作用。我们还假设，通过影响ABETA的产生以及对突触功能很重要的某些CAM的蛋白水解来促进AD发病机理的FAD连接PS1变体。这项研究的具体目的是检查cam的PS依赖性蛋白水解的影响：1）对细胞功能，2）对突触形成的影响，以及3）对记忆的细胞底物的影响。使用PS1无效胚胎，PS1 M146V敲入小鼠以及培养的细胞系统，我们建议进行电生理，生化和成像研究，以研究CAMS的PS依赖性蛋白水解如何影响突触功能。特别是，由于已知与AD的发病机理，突触形成和与突触功能相关的信号通路，我们将在正常和病理条件下将研究重点放在APP，DCC和N-钙黏着蛋白的突触影响上。我们非常有信心，我们的提案中概述的互补方法将为PS在健康和疾病中的作用提供重要的机理见解。