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）：阿尔茨海默氏病（AD）是由淀粉样蛋白-K（AK）肽在大脑中逐渐积累为有毒结构（例如淀粉样斑块和可溶性寡聚体）引发的。 A¿ 转化为这些有毒物质似乎与浓度有关；因此，确定调节或降低 A¿ 水平的机制将为 AD 的根本原因提供基本的了解，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，血清素受体 (5HT-R) 的激活会导致大脑 A 水平急剧下降（Cirrito 等，2011）。全身给予 SSRI 抗抑郁药或直接输注血清素 AD 小鼠模型的海马导致脑间质液 (ISF) A¿ 水平在几小时内下降 25-30%，并且单次给药后 A 水平在 24 小时以上仍保持较低水平。如果用细胞外调节激酶（ERK）（典型的 MAP 激酶）的抑制剂预处理小鼠，则 A¿ 的减少会被完全阻止。 ERK 激活似乎会增加 APP 的α-分泌酶裂解，从而减少 A¿ 的产生，并可能降低 g-分泌酶复合物的几种成分的 mRNA 水平。长期服用 SSRI 4 个月可显着降低 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 信号传导途径和调节 A 生成的相关分子，特别是从血清素受体到 ERK 激活，然后 ERK 导致 APP 处理变化的途径。虽然许多分子可以激活 ERK，并且 ERK 可以有许多下游底物，但其活性受到显着调节，因此每个细胞外受体都可以在细胞内产生非常特异性的作用。这种特异性部分是通过支架蛋白控制的，支架蛋白将受体与适当的受体连接起来。 信号复合物。并非所有激活 ERK 的分子都会抑制 A 的产生；因此，我们将确定支架和定位蛋白（例如 ¿-arrestin 和 Self）在为该信号通路提供靶点特异性方面所发挥的作用。结合遗传学、生物化学和药理学以及我们开发的体内微透析技术来评估大脑 ISF A 水平随时间的变化；我们将评估活体小鼠中连接 5HT-R、ERK 和 A 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 A 水平方面的有效性，而且还证明了它们作用的细胞机制，可以为测试此类化合物在人类受试者中减轻甚至可能预防 AD 的能力提供强大的动力。 公共健康相关性：降低淀粉样蛋白（一种积累并引发阿尔茨海默病 (AD) 的肽）的水平，是治疗或预防这种疾病的最有可能的方法。 我们从人类和小鼠 AD 模型中获得的初步数据强烈表明，血清素信号通过激活细胞外调节激酶 (ERK) 信号通路来抑制 A¿ 的产生。使用选择性血清素再摄取抑制剂 (SSRI) 抗抑郁药进行长期治疗可降低 AD 小鼠模型中的脑 A 水平和斑块，并且与人类斑块减少相关。该提案将确定活体小鼠中连接血清素受体、ERK 和 A¿ 抑制的细胞途径和分子。