Mechanisms of Synaptic Dysfunction by Amyloid Peptides

淀粉样肽导致突触功能障碍的机制

基本信息

批准号：
7871871
负责人：
OTTAVIO ARANCIO
金额：
$ 3.15万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-15 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7871871
关键词：
APP-PS1 Action Potentials Acute Address Affect Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Cell Culture Techniques Characteristics Chemosensitization Complex Cyclic GMP Cyclic GMP-Dependent Protein Kinases Deposition Disease Economics Elements Event Family Fatigue Fright Functional disorder Guanylate Cyclase Hippocampus (Brain)Human Genetics Impairment In Vitro Knowledge Laboratories Learning Long-Term Potentiation Memory Memory impairment Modeling Molecular Mus Neurodegenerative Disorders Neurons Nitric Oxide Nitric Oxide Donors Pathway interactions Peptides Pharmaceutical Preparations Phase Phosphorylation Physiologic pulse Plastics Preparation Process Protein Kinase Proteins Research Personnel Role Short-Term Memory Signal Pathway Site Slice Societies Soluble Guanylate Cyclase Structure Synapses Synaptic Transmission Synaptic plasticity System Temporal Lobe Testing Transgenic Organisms Vesicle amyloid peptide analog base cost design hippocampal pyramidal neuron in vivo interest mutant neurotransmission phosphoric diester hydrolase postsynaptic presenilin presynaptic receptor response social transmission process

项目摘要

DESCRIPTION (provided by applicant): The overall purpose of this project is to explore the molecular basis for amyloid-induced changes in basal neurotransmission and synaptic plasticity at synapses between pyramidal neurons in the hippocampus, a structure within the temporal lobe particularly critical for memory storage and with remarkable plastic characteristics of the kind that are required for learning and memory. Our approach is to combine the use of in vitro hippocampal slices and neuronal cultures with in vivo animals. This strategy offers the advantage of identifying changes of synaptic transmission in a preparation with intact neuronal circuits (slice), of giving depth to the knowledge of these changes in a more simplified system with the unique possibility of having direct access to both the pre- and the post-synaptic site (cell culture), and finally of determining whether it is possible to re-establish normal learning and memory by counteracting the effects of these changes in an in vivo complex neuronal system (the whole animal). The following aims will be addressed: a) to determine changes of synaptic transmission induced by amyloid-beta, b) to search for potential mechanisms that might alter neurotransmission following amyloid-beta increase, c) to determine if changes of synaptic transmission induced by amyloid-beta involve the nitric oxide (NO)/soluble guanylyl-cyclase (sGC)/cGMP/cGMPdependent- protein kinase (cGK)/CREB pathway, d) to determine if the disruption of learning and memory occurring in APP/PS1 mice is rescued by drugs acting through the NO/sGC/cGMP/cGK/CREB pathway. On the completion of these studies we will clarify whether amyloid-beta causes synaptic dysfunction through pre- and/or post-synaptic mechanisms. We will also identify a new signaling pathway inactivated by amyloid peptides during synaptic plasticity and learning. Findings derived from these studies will contribute to the design of researchers and therapies for Alzheimer's Disease and a host of other neurodegenerative disorders with staggering social, economic and personal costs to the sufferers, their families and all of society.

描述（由申请人提供）：该项目的总体目的是探索淀粉样蛋白诱导的海马锥体神经元之间突触的基础神经传递和突触可塑性变化的分子基础，海马是颞叶内对记忆存储特别重要的结构并具有学习和记忆所需的显着可塑性。我们的方法是将体外海马切片和神经元培养物与体内动物结合起来。该策略具有以下优点：在具有完整神经元回路（切片）的制剂中识别突触传递的变化，在更简化的系统中深入了解这些变化，并具有直接访问前和前的独特可能性。突触后位点（细胞培养），最后确定是否可以通过抵消体内复杂神经元系统（整个动物）中这些变化的影响来重新建立正常的学习和记忆。将解决以下目标：a）确定β-淀粉样蛋白诱导的突触传递的变化，b）寻找β-淀粉样蛋白增加后可能改变神经传递的潜在机制，c）确定β-淀粉样蛋白是否诱导突触传递的变化-beta涉及一氧化氮（NO）/可溶性鸟苷酸环化酶（sGC）/cGMP/cGMP依赖性蛋白激酶（cGK）/CREB途径，d）确定学习和记忆是否受到干扰通过 NO/sGC/cGMP/cGK/CREB 途径起作用的药物可挽救 APP/PS1 小鼠中发生的疾病。这些研究完成后，我们将阐明β淀粉样蛋白是否通过突触前和/或突触后机制导致突触功能障碍。我们还将确定在突触可塑性和学习过程中淀粉样肽失活的新信号传导途径。这些研究的结果将有助于针对阿尔茨海默病和许多其他神经退行性疾病的研究人员和疗法的设计，这些疾病给患者、他们的家人和整个社会带来了惊人的社会、经济和个人成本。