SYNAPTIC REGULATION OF ERK-MEDIATED AMYLOID-BETA METABOLISM

ERK 介导的淀粉样蛋白代谢的突触调节

• 批准号: 8342633
• 负责人: John R Cirrito
• 金额: $ 31.16万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8342633
• 关键词: Acute; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antidepressive Agents; Arrestins; Attenuated; Behavioral; Binding; Biochemistry; Brain; Brain-Derived Neurotrophic Factor; Cell physiology; Cells; Chronic; Complex; Coupled; Cytoplasm; Data; Disease; Effectiveness; Etiology; Extracellular Signal Regulated Kinases; FDA approved; GTP-Binding Proteins; Generations; Genetic; Golgi Apparatus; Hippocampus (Brain); Hour; Human; Individual; Infusion procedures; Intercellular Fluid; Lead; Life; Link; MAPK1 gene; MAPK3 gene; Mediating; Messenger RNA; Metabolism; Methods; Microdialysis; Mitogen-Activated Protein Kinases; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Norepinephrine; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Play; Process; Production; Protein Isoforms; Proteins; Recording of previous events; Regulation; Risk; Role; Scaffolding Protein; Second Messenger Systems; Selective Serotonin Reuptake Inhibitor; Senile Plaques; Serotonin; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Specificity; Structure; Synapses; Techniques; Testing; Time; Work; aged; amyloid precursor protein processing; arrestin 2; extracellular; human data; human subject; in vivo; inhibitor/antagonist; insight; mouse model; novel therapeutics; postsynaptic; prevent; receptor; scaffold; second messenger; secretase; serotonin receptor; small hairpin RNA; trafficking; Acute; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antidepressive Agents; Arrestins; Attenuated; Behavioral; Binding; Biochemistry; Brain; Brain-Derived Neurotrophic Factor; Cell physiology; Cells; Chronic; Complex; Coupled; Cytoplasm; Data; Disease; Effectiveness; Etiology; Extracellular Signal Regulated Kinases; FDA approved; GTP-Binding Proteins; Generations; Genetic; Golgi Apparatus; Hippocampus (Brain); Hour; Human; Individual; Infusion procedures; Intercellular Fluid; Lead; Life; Link; MAPK1 gene; MAPK3 gene; Mediating; Messenger RNA; Metabolism; Methods; Microdialysis; Mitogen-Activated Protein Kinases; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Norepinephrine; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Play; Process; Production; Protein Isoforms; Proteins; Recording of previous events; Regulation; Risk; Role; Scaffolding Protein; Second Messenger Systems; Selective Serotonin Reuptake Inhibitor; Senile Plaques; Serotonin; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Specificity; Structure; Synapses; Techniques; Testing; Time; Work; aged; amyloid precursor protein processing; arrestin 2; extracellular; human data; human subject; in vivo; inhibitor/antagonist; insight; mouse model; novel therapeutics; postsynaptic; prevent; receptor; scaffold; second messenger; secretase; serotonin receptor; small hairpin RNA; trafficking

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is initiated by the progressive accumulation of amyloid-¿ (A¿) peptide in the brain as toxic structures such as amyloid plaques and soluble oligomers. Conversion of A¿ into these toxic species appears to be concentration-dependent; therefore identifying mechanisms that regulate or lower A¿ levels will provide a fundamental understanding of the underlying causes of AD and may lead to new therapeutic strategies. Recent work by our group demonstrates that activation of serotonin receptors (5HT-Rs) cause an acute reduction in brain A¿ levels in mouse models of AD (Cirrito et al., 2011). Systemic administration of SSRI antidepressants or direct infusion of serotonin into the hippocampus of a mouse model of AD causes brain interstitial fluid (ISF) A¿ levels to decline by 25-30% within a few hours and with A¿ levels remaining low for over 24 hours after a single administration. This reduction in A¿ is completely blocked if mice are pretreated with inhibitors of the extracellular regulated kinase (ERK), the prototypical MAP kinase. ERK activation appears to increase a-secretase cleavage of APP, thus reducing A¿ generation as well as may reduce mRNA levels of several components of the g-secretase complex. Chronic administration of a SSRI for 4 months dramatically reduces plaque load and CSF A¿ levels in a mouse model of AD. The objective of this proposal is to define the ERK signaling pathways and related molecules that regulate A¿ generation, in particular the pathways that lead from serotonin receptor to activation of ERK and then ERK to changes in APP processing. While many molecules can activate ERK and ERK can have many downstream substrates, its activity is remarkably regulated so that each extracellular receptor can very specific effects within a cell This specificity is partially controlled via scaffold proteins that link receptors with appropriate signaling complexes. Not all molecules that activate ERK suppress A¿ generation; therefore we will determine the role that scaffold and localization proteins, such as ¿-arrestin and Self, play n providing target specificity for this signaling pathway. Using a combination of genetics, biochemistry, and pharmacology, as well as an in vivo microdialysis technique we developed to assess brain ISF A¿ levels over time; we will assess the cellular pathways linking 5HT-Rs, ERK, and A¿ generation in living mice. SSRIs are one of the safest neuroactive drugs approved by the FDA. A demonstration not only of their effectiveness in lowering A¿ levels, but also the cellular mechanisms by which they act, may provide a strong impetus for testing this class of compounds for their ability to attenuate, and possibly prevent, AD in human subjects. PUBLIC HEALTH RELEVANCE: Reducing levels of amyloid-¿, the peptide that accumulates and initiates Alzheimer's disease (AD), is the most likely method to treat or prevent this disease. Our preliminary data from humans and mouse models of AD strongly suggest the serotonin signaling suppresses A¿ generation by activating the extracellular regulated kinase (ERK) signaling pathway. Chronic treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants reduces brain A¿ levels and plaques in mouse models of AD and is associated with less plaques humans. This proposal will determine the cellular pathways and molecules that link serotonin receptors, ERK, and A¿ suppression in living mice.

描述（由适用提供）：阿尔茨海默氏病（AD）是由淀粉样蛋白（A¿）肽在大脑中的逐渐积累而引发的，因为淀粉样蛋白斑块和固体寡聚物等有毒结构。将a的转化为这些有毒物种似乎是浓度依赖性的。因此，确定调节或降低A级别的机制将提供对AD基本原因的基本理解，并可能导致新的治疗策略。我们小组的最新工作表明，血清素受体（5HT-RS）的激活导致AD小鼠模型中的大脑A水平急性降低（Cirrito等，2011）。 SSRI抗抑郁药的系统性给药或直接输注5-羟色胺 小鼠AD模型的海马导致脑间隙液（ISF）A水平在几个小时内下降25-30％，并且在一次给药后24小时以上24小时，A水平保持较低。如果将小鼠用细胞外调节激酶（ERK）（原型MAP激酶）的抑制剂预处理，则A域的这种降低将完全阻止。 ERK激活似乎增加了APP的A-分泌酶裂解，从而降低了A的生成，并可以降低G-分泌酶复合物的几个成分的mRNA水平。长期对SSRI的施用4个月大大降低了AD小鼠模型中的斑块载荷和CSF A级。该提案的目的是定义ERK信号通路和调节A生成的相关分子，特别是从血清素受体到ERK激活，然后再进行ERK到应用程序处理的变化的途径。虽然许多分子可以激活ERK和ERK可以具有许多下游底物，但其活性受到了明显的调节，因此每个细胞外受体可以在细胞中非常特异 信号复合物。并非所有激活ERK抑制A的分子都会抑制A的一代；因此，我们将确定脚手架和定位蛋白（例如 - arrestin和self）的作用，为该信号通路提供目标特异性。我们开发了遗传学，生物化学和药理学以及一种体内微透析技术的结合，我们开发了用于评估脑ISF A水平随着时间的流逝而开发的；我们将评估在活小鼠中连接5HT-RS，ERK和A生成的细胞途径。 SSRI是FDA批准的最安全的神经活性药物之一。不仅证明了它们在降低A水平的有效性，而且还可以证明其作用的细胞机制，还可以为测试这类化合物的强大动力，以使其在人类受试者中衰减和预防AD的能力。 公共卫生相关性：降低淀粉样蛋白的水平，淀粉样蛋白的水平是累积和启动阿尔茨海默氏病（AD）的胡椒，是治疗或预防这种疾病的最可能方法。 我们来自人类的初步数据和AD的小鼠模型强烈表明5-羟色胺信号传导通过激活细胞外调节激酶（ERK）信号通路来抑制A的产生。选择性5-羟色胺再摄取抑制剂（SSRI）抗抑郁药的慢性治疗可降低AD小鼠模型中的脑A水平和斑块，并且与较少的斑块人相关。该建议将确定在活小鼠中连接血清素受体，ERK和A抑制的细胞途径和分子。