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

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（通过应用程序证明）：阿尔茨海默氏病（AD）是由淀粉样蛋白的进行性积累引发的（a。）大脑中的肽作为淀粉样蛋白斑和Soligomers等有毒结构。进入这些有毒物种似乎是浓度依赖性的。级别将为AD的根本原因提供一些导致新的治疗策略的基础。 AD的小鼠模型中的水平（Cirrito等，2011）。 AD小鼠模型的海马导致脑间质液（ISF）a¿在几个小时的时间里，iThin的水平下降了25-30％。单个管理后的水平持续24小时以上。如果用细胞外典型激酶（ERK）的抑制剂预处理小鼠，ERK似乎会增加APP的A-分泌酶裂解，从而降低A e emk，从而完全阻塞。 G-分泌酶复合物的产生和mRNA水平。 AD的小鼠模型中的水平定义ERK信号通路和相关分子产生，特别是从血清素到ERK激活到App过程的变化的途径。是通过将受体与适当的脚手架蛋白进行的部分控制的 信号复合物并非所有激活ERK的分子一代-arrestin和自我，播放n为信号通路提供目标规范，以及我们开发的体内微透析技术随着时间的流逝，我们将评估连接5HT-R，ERK和A的细胞途径SSRIS的生成是FDA批准的最安全的神经活性药物之一。水平，其作用的细胞机制，可以为其性能测试化合物的扁桃体，并在人类受试者中预防AD。 公共卫生相关性：降低淀粉样蛋白的水平，积累厌食的阿尔茨海默氏病（AD）的肽是信任或证明这种疾病的最可能的方法。 我们来自人类和AD小鼠模型的初步数据强烈表明5-羟色胺信号抑制了a。通过细胞外调节激酶（ERK）信号通路产生。与人类斑块相关的小鼠模型中的水平和斑块。活着的老鼠的ins。