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: 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
• 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' 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

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（由申请人提供）：阿尔茨海默病（AD）是由淀粉样蛋白- β (asβ)肽在大脑中的渐进性积累引发的，作为淀粉样斑块和可溶性低聚物等有毒结构。β转化为这些有毒物质似乎是浓度依赖性的；因此，确定调节或降低asb水平的机制将为阿尔茨海默病的潜在原因提供基本的理解，并可能导致新的治疗策略。我们小组最近的工作表明，在AD小鼠模型中，5 -羟色胺受体（5HT-Rs）的激活会导致大脑asb水平的急性降低（Cirrito等人，2011）。在阿尔茨海默病小鼠模型中，全身服用SSRI抗抑郁药或直接向海马体输注5-羟色胺可导致脑间质液（ISF） ß水平在几小时内下降25-30%，且单次给药后ß水平在24小时内保持低水平。如果用细胞外调节激酶（ERK）的抑制剂（即典型的MAP激酶）预处理小鼠，则会完全阻断as1的减少。ERK激活似乎增加了APP的α-分泌酶裂解，从而减少了α-分泌酶的生成，并可能降低γ-分泌酶复合物的几种组分的mRNA水平。慢性服用SSRI 4个月可显著降低AD小鼠模型中的斑块负荷和CSF asb水平。本提案的目的是明确ERK信号通路和调控asg生成的相关分子，特别是从5 -羟色胺受体到ERK活化，再到ERK改变APP加工的通路。虽然许多分子可以激活ERK，并且ERK可以有许多下游底物，但其活性受到显著调节，因此每个细胞外受体在细胞内都具有非常特异性的作用，这种特异性部分通过支架蛋白控制，支架蛋白将受体与适当的信号复合物连接起来。并非所有激活ERK的分子都抑制ß的产生；因此，我们将确定支架蛋白和定位蛋白，如ß-arrest和Self，在为这一信号通路提供靶标特异性方面所起的作用。结合遗传学、生物化学和药理学，以及体内微透析技术，我们开发了一种评估大脑ISF ß水平的方法；我们将评估活小鼠中连接5HT-Rs、ERK和ß生成的细胞通路。SSRIs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asb水平方面的有效性，而且还证明了它们起作用的细胞机制，这可能为测试这类化合物在人类受试者中减轻和可能预防AD的能力提供了强大的动力。