PS1 mediates the neuroprotective functions of the ephrinB/EphB system

PS1 介导 ephrinB/EphB 系统的神经保护功能

• 批准号: 8475506
• 负责人: NIKOLAOS K ROBAKIS
• 金额: $ 35.06万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8475506
• 关键词: Adult; Affect; Alleles; Alzheimer' s Disease; Binding; Brain; Cell Death; Cells; Cessation of life; Data; Development; Eph Family Receptors; Ephrin B Receptor; Ephrins; Excitatory Synapse; Extracellular Domain; Family; Gene Mutation; Glutamate Receptor; Glutamates; Homologous Gene; Hydrogen Peroxide; Knock-in Mouse; Knock-out; Laboratories; Ligands; Mammals; Mediating; Membrane; Memory; Metalloproteases; Molecular; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Nervous system structure; Neuronal Injury; Neurons; Oxidative Stress; Pathogenesis; Pathway interactions; Peptides; Phosphorylation; Presenile Alzheimer Dementia; Process; Proteins; Proteolytic Processing; Receptor Protein-Tyrosine Kinases; Reporting; Role; Signal Transduction; Synaptic plasticity; System; Therapeutic Intervention; Tissues; Transgenic Mice; Vascular System; axon guidance; base; cell motility; excitotoxicity; familial Alzheimer disease; gamma secretase; in vivo; mouse model; mutant; neuroprotection; neurotoxic; novel; public health relevance; receptor; secretase; src-Family Kinases; synaptogenesis

Excitotoxicity, a form of neuronal damage due to excessive activation of glutamate receptors and oxidative stress are mechanisms of neuronal injury implicated in the pathogenesis of Alzheimer's disease (AD). We found that the ephrinB family of ligand proteins protects primary neuronal cultures from both glutamate- and oxidative stress- induced death. The neuroprotective activities of ephrinB ligands (ephrinBLs) are mediated by their receptors (EphB receptors, EphBRs) and depend on PS1, a protein involved in familial AD (FAD). Interestingly, the neuroprotective effect of ephrinB depends on both PS1 alleles because absence of one allele (haploinsufficiency) results in severe reduction of the ephrinB neuroprotection. Furthermore, we obtained preliminary data that FAD mutants of PS1 interfere with the ephrinB-dependent neuroprotection and that -secretase activity may be involved in the neuroprotective functions of the ephrinBL/EphBR system. Here we propose to further investigate the effects of PS1 FAD mutants and -secretase on the neuroprotective function of ephrinBLs and to elucidate molecular mechanisms by which PS1 mediates this function. We will explore whether PS1 regulates the binding of ephrinBLs to EphBRs and the ephrinBL-induced phosphorylation of both EphB and NMDA receptors. To this end we will use cortical primary neuronal cultures from our PS1 knockout and FAD mutant knock-in transgenic mouse colonies as well as EphBR knock-out colonies available in our laboratory. We will also use our mouse models to examine the neuroprotective function of the ephriBL/EphBR system in vivo and to ask whether PS1 FAD mutations affect this function. Finally, we will ask whether PS2, a homologue of PS1 also involved in FAD, may also be involved in the ephrinB neuroprotection.

兴奋性毒性，一种由于谷氨酸过度激活而导致的神经元损伤 受体和氧化应激是神经元损伤的机制， 阿尔茨海默病（AD）的发病机制。我们发现配体ephrinB家族 蛋白质保护原代神经元培养物免受谷氨酸和氧化应激， 诱导死亡。肝配蛋白B配体（肝配蛋白BLs）的神经保护活性是 由其受体（EphB受体，EphBR）介导，并依赖于PS1，一种蛋白质 家族性AD（FAD）有趣的是，ephrinB的神经保护作用 依赖于两个PS1等位基因，因为一个等位基因的缺失（单倍不足）导致 严重降低ephrinB的神经保护作用。此外，我们还获得了初步的 PS1的FAD突变体干扰ephrinB依赖性神经保护的数据， 分泌酶的活性可能与神经保护功能有关。 ephrinBL/EphBR系统。 在这里，我们建议进一步研究PS1 FAD突变体和β-分泌酶的影响， ephrinBLs的神经保护功能，并阐明分子机制， 而PS1介导了这一功能。我们将探讨PS1是否调节 ephrinBL诱导的EphB和EphBR的磷酸化， NMDA受体。为此，我们将使用我们的皮质原代神经元培养物， PS1敲除和FAD突变体敲入转基因小鼠集落以及EphBR 在我们实验室里可以找到的基因敲除菌落。我们还将使用我们的小鼠模型， 检查ephriBL/EphBR系统在体内的神经保护功能，并询问 PS1 FAD突变是否影响该功能。最后，我们会问PS2，一个 PS1的同源物也参与FAD，也可能参与ephrinB 神经保护