SYNAPTIC REGULATION OF ERK-MEDIATED AMYLOID-BETA METABOLISM

ERK 介导的淀粉样蛋白代谢的突触调节

基本信息

批准号：
9064726
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
项目类别：
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/9064726
关键词：
Abeta synthesis Acute Alzheimer&apos 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 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 abeta accumulation aged alpha secretase amyloid precursor protein processing arrestin 2 beta-arrestin extracellular gamma secretase human data human subject in vivo inhibitor/antagonist insight mouse model novel therapeutic intervention postsynaptic prevent receptor scaffold second messenger serotonin receptor small hairpin RNA trafficking

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is initiated by the progressive accumulation of amyloid-ß (Aß) peptide in the brain as toxic structures such as amyloid plaques and soluble oligomers. Conversion of Aß into these toxic species appears to be concentration-dependent; therefore identifying mechanisms that regulate or lower Aß 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 Aß 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) Aß levels to decline by 25-30% within a few hours and with Aß levels remaining low for over 24 hours after a single administration. This reduction in Aß is completely blocked if mice are pretreated with inhibitors of the extracellular regulated kinase (ERK), the prototypical MAP kinase. ERK activation appears to increase α-secretase cleavage of APP, thus reducing Aß generation as well as may reduce mRNA levels of several components of the γ-secretase complex. Chronic administration of a SSRI for 4 months dramatically reduces plaque load and CSF Aß levels in a mouse model of AD. The objective of this proposal is to define the ERK signaling pathways and related molecules that regulate Aß 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 Aß generation; therefore we will determine the role that scaffold and localization proteins, such as ß-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 Aß levels over time; we will assess the cellular pathways linking 5HT-Rs, ERK, and Aß 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 Aß 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.

描述（由适用提供）：阿尔茨海默氏病（AD）是由淀粉样蛋白 - 肽（Aß）肽在大脑中的逐渐积累引发的，因为淀粉样蛋白斑块和固体寡聚物等有毒结构。将Aß转化为这些有毒物种似乎是浓度依赖性的。因此，确定调节或较低Aß水平的机制将提供对AD的根本原因的基本理解，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小鼠模型中脑Aß水平的急性降低（Cirrito等，2011）。 SSRI抗抑郁药的全身施用或直接输注AD小鼠模型的海马，导致脑间隙液（ISF）Aß水平在几个小时内下降了25-30％，并且在一次给药后24小时以上的Aß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）的抑制剂预处理小鼠，则Aß中的这种降低将完全阻止。 ERK激活似乎增加了APP的α-分泌酶裂解，从而降低了Aß产生，并可以降低γ-分泌酶复合物的几个成分的mRNA水平。长期给予SSRI 4个月大幅度降低了鼠标的斑块负荷和CSFAß水平，该提案的目的是定义ERK信号通路和相关分子，这些分子和相关分子调节Aß产生，尤其是从血清素受体到ERK激活的途径到ERK的激活，然后在应用程序处理中变化。尽管许多分子可以激活ERK和ERK可以具有许多下游底物，但其活性受到明显调节，因此每个细胞外受体可以在细胞内非常特异性的效果，这种特异性通过脚手架蛋白将接收器与适当的信号传导复合物联系起来部分控制。并非所有激活ERK抑制Aß产生的分子；因此，我们将确定脚手架和定位蛋白（例如ß-arrestin和self）的作用，为此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组合，我们开发了用于评估脑ISFAß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Aß产生的细胞途径。 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Aß水平的有效性，而且还表明其作用的细胞机制可能会为测试这类化合物的强大动力，以使其在人类受试者中减弱和预防AD的能力。