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（由申请人提供）：阿尔茨海默病（AD）是由淀粉样蛋白（A）肽作为毒性结构（如淀粉样蛋白斑块和可溶性寡聚体）在脑中进行性积累引发的。转换A？进入这些有毒物种的药物似乎是浓度依赖性的;因此，确定调节或降低A？水平的机制将提供对AD根本原因的基本理解，并可能导致新的治疗策略。我们小组最近的工作表明，5-羟色胺受体（5 HT-Rs）的激活导致AD小鼠模型中脑A水平的急性降低（Cirrito等人，2011年）。全身给予SSRI抗抑郁药或直接将5-羟色胺输注到 AD小鼠模型的海马体导致脑间质液（ISF）A？水平在几小时内下降25-30%，并且A？水平在单次给药后保持低水平超过24小时。这种减少A？如果用细胞外调节激酶（ERK）（原型MAP激酶）的抑制剂预处理小鼠，则完全阻断。ERK激活似乎增加了APP的α-分泌酶切割，从而减少了A？生成，并可能降低了g-分泌酶复合物几种组分的mRNA水平。长期给予SSRI 4个月显著降低AD小鼠模型中的斑块负荷和CSF A水平。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5-羟色胺受体到ERK激活，然后ERK到APP加工变化的通路。虽然许多分子可以激活ERK，并且ERK可以具有许多下游底物，但其活性受到显著调节，使得每个细胞外受体可以在细胞内产生非常特异性的作用。 信号复合物并非所有激活ERK的分子都抑制A？生成;因此，我们将确定支架和定位蛋白（如？-arrestin和Self）在为该信号通路提供靶特异性方面所起的作用。使用遗传学，生物化学和药理学的组合，以及体内微透析技术，我们开发了评估大脑ISF A？水平随时间的推移，我们将评估细胞通路连接5 HT-Rs，ERK，和A？生成活小鼠。SSRIs是FDA批准的最安全的神经活性药物之一。不仅证明它们在降低A水平方面的有效性，而且证明它们起作用的细胞机制，可能为测试这类化合物在人类受试者中减弱和可能预防AD的能力提供强大的动力。 公共卫生关系：降低淀粉样蛋白水平阿尔茨海默病（AD）是一种常见的老年痴呆症（AD），是阿尔茨海默病（AD）的主要病因。 我们从人类和小鼠AD模型中获得的初步数据强烈表明，5-羟色胺信号通过激活细胞外调节激酶（ERK）信号通路抑制A？生成。选择性5-羟色胺再摄取抑制剂（SSRI）抗抑郁药的长期治疗降低了AD小鼠模型的脑A水平和斑块，并与人类斑块减少有关。这项提议将确定在活小鼠中连接5-羟色胺受体、ERK和A？抑制的细胞通路和分子。