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(申请人提供)：阿尔茨海默病(AD)是由淀粉样蛋白(A)肽在大脑中逐渐积累而成的有毒结构，如淀粉样斑块和可溶性寡聚体。A？向这些有毒物种的转化似乎是浓度依赖的；因此，识别调节或降低A？水平的机制将有助于从根本上理解AD的潜在原因，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(5HT-Rs)的激活导致阿尔茨海默病(AD)小鼠模型脑Aβ水平的急剧下降(Cirrito等人，2011年)。全身应用SSRI抗抑郁药或直接注射5-羟色胺 AD小鼠模型的海马体可导致脑间质液(ISF)A？水平在几小时内下降25%-30%，并在单次给药后24小时以上保持低水平。如果用细胞外调节激酶(ERK)的抑制剂(典型的MAP激酶)对小鼠进行预处理，则A？的这种减少完全被阻断。ERK的激活似乎增加了APP的α-分泌酶的裂解，从而减少了A？的生成，并可能降低了g-分泌酶复合体的几个组分的mRNA水平。在AD小鼠模型中，长期服用SSRI 4个月可显著降低斑块负荷和脑脊液A？水平。本研究的目的是明确ERK信号转导通路和调节A？生成的相关分子，特别是从5-羟色胺受体到ERK激活再到APP处理变化的信号转导通路。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可以在细胞内产生非常特异的作用。这种特异性部分是通过连接受体和适当受体的支架蛋白来控制的 信号复合体。并不是所有激活ERK的分子都抑制A？的生成；因此，我们将确定支架和定位蛋白，如？-arrestin和self，在为这一信号通路提供靶标特异性方面所起的作用。利用遗传学、生物化学和药理学的结合，以及我们开发的体内微透析技术，我们开发了一种随着时间的推移来评估大脑ISF A？水平的技术；我们将在活着的小鼠中评估连接5HT-Rs、ERK和A？代的细胞通路。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A水平方面的有效性，而且还证明了它们的细胞机制，这可能为测试这类化合物在人类受试者中减弱并可能预防阿尔茨海默病的能力提供强大的动力。 公共卫生相关性：降低淀粉样蛋白的水平是治疗或预防这种疾病的最有可能的方法。淀粉样蛋白是积累和引发阿尔茨海默病(AD)的多肽。 我们来自人类和小鼠AD模型的初步数据有力地表明，5-羟色胺信号通过激活细胞外调节激酶(ERK)信号通路来抑制A？的生成。选择性5-羟色胺再摄取抑制剂(SSRI)抗抑郁药的慢性治疗降低了AD小鼠模型的脑A？水平和斑块，并与较少的人类斑块有关。这一提议将确定将5-羟色胺受体、ERK和A？抑制联系在一起的细胞通路和分子。