TEMPORAL RELATIONSHIP BETWEEN SYNAPTIC ACTIVITY AND ABETA AGGREGATION

突触活动与 ABETA 聚合之间的时间关系

• 批准号: 8699656
• 负责人: John R Cirrito
• 金额: $ 19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699656
• 关键词: APP-PS1; Affect; Age-Years; Alzheimer' s Disease; Amino Acids; Amyloid; Animal Model; Animals; Antibodies; Area; Behavioral Symptoms; Biological Markers; Brain; Brain region; Coupled; Data; Detection; Development; Disease Progression; Electrochemistry; Electrodes; Electrons; Endocytosis; Endosomes; Event; Exclusion; Extracellular Space; Frequencies; Generations; Goals; Hippocampus (Brain); Human; In Vitro; Individual; Intercellular Fluid; Kinetics; Lead; Length; Life; Link; Location; Measures; Methodology; Methods; Microdialysis; Molecular Conformation; Mus; Neurobehavioral Manifestations; Neurons; Onset of illness; Pathogenesis; Peptides; Positioning Attribute; Presynaptic Terminals; Production; Proteins; Proton Pump Inhibitors; Publications; Publishing; Resolution; Sampling; Specificity; Structure; Surface; Synapses; Synaptic Transmission; Techniques; Technology; Temporal Lobe Epilepsy; Testing; Time; Transgenic Mice; Tyrosine; abeta accumulation; awake; carbon fiber; improved; in vivo; monomer; novel; oxidation; peptide A; public health relevance; transmission process; voltage

DESCRIPTION (provided by applicant): Accumulation of A¿ plaque in the brain is a hallmark feature of Alzheimer's disease and a biomarker of disease progression. Observations in humans show that plaques are found in regions of the brain that display high levels of neuronal activity, sometimes referred to as the default mode network. Similarly, about 10% of individuals with temporal lobe epilepsy develop plaques within affected areas as early as 30 years of age. Studies from our lab have demonstrated that direct modulation of synaptic activity dynamically regulates brain A¿ levels in awake animals, with increased synaptic activity rapidly increases brain interstitial fluid (ISF) A¿ levels and vice versa for suppressed activity. These findings strongly suggest a close temporal relationship between synaptic activity and A¿ generation. Determining the mechanisms that underlie this link remains important for understanding the pathological development of AD. We have developed novel micro- immunoelectrode electrodes (MIEs) that detect A¿ with very high temporal resolution (measures A¿ in vivo every minute). This approach enables us to study the rapid kinetics and dynamics of A¿ in vivo. In our published studies (Prabhulkar et al. 2012), and in preliminary data we show that these MIEs can specifically measure ISF A¿1-40, A¿1-42 or aggregates, depending on the antibody attached to the electrode surface. Our in vivo MIE studies demonstrate brain interstitial fluid (ISF) A¿ levels change from minute-to-minute in APP/PS1 transgenic mice. Previous publications from our group and others demonstrate that ISF A¿ levels are closely linked to synaptic transmission. In vitro data suggest that high concentration and low pH facilitate conversion of A¿ into toxic aggregates. Synaptic activity increases A¿ generation within endosomes, a confined location where the pH is low, and the concentration of A¿ can potentially be elevated. We propose that there is a rapid link between synaptic transmission and A¿ generation, with higher frequencies of synaptic transmission causing more A¿ to be formed. In addition, elevated synaptic A¿ generation in low-pH endosomes will convert A¿ into aggregated species (either oligomers or fibrils). The goal of this proposal is to use this new MIE technology in combination with pharmacological manipulation to block or enhance specific aspects of synaptic activity to elucidate the cellular mechanisms that regulate A¿ generation and aggregation on a short time-scale. The results of these studies will improve our understanding of the temporal relationship between synaptic activity and A¿ generation/species and uncover mechanisms involved in the progression of AD.

描述（由申请人提供）： A¿ 的积累大脑中的斑块是阿尔茨海默病的一个标志性特征，也是疾病进展的生物标志物。对人类的观察表明，在大脑中表现出高水平神经元活动的区域中发现了斑块，有时被称为默认模式网络。早在 30 岁时，就有 % 的颞叶癫痫患者在受影响区域出现斑块。我们实验室的研究表明，直接调节突触活动可以动态调节大脑 A¿清醒动物中的水平，随着突触活动的增加，脑间质液 (ISF) A 迅速增加这些发现强烈表明突触活动与 A¿ 之间存在密切的时间关系。确定这种联系背后的机制对于理解 AD 的病理发展仍然很重要，我们开发了检测 A¿ 的新型微免疫电极电极 (MIE)。具有非常高的时间分辨率（每分钟在体内测量 A¿），这种方法使我们能够研究 A¿ 的快速动力学和动力学。在我们发表的研究（Prabhulkar 等人，2012）中，以及在初步数据中，我们表明这些 MIE 可以专门测量 ISF A¿ 1-40，A¿ 1-42 或聚集体，具体取决于附着在电极表面的抗体我们的体内 MIE 研究证明脑间质液 (ISF) A¿级别 APP/PS1 转基因小鼠中的变化每分钟都在变化，我们小组和其他人之前的出版物表明 ISF A¿体外数据表明，高浓度和低 pH 值有利于 A¿ 的转化。进入有毒聚集体。内体中的生成，pH值较低的有限位置，以及A¿我们认为突触传递和 A¿ 之间存在快速联系。的产生，更高频率的突触传递导致更多 A¿此外，突触 A 升高。低 pH 内体中的生成将转化 A¿该提案的目标是使用这种新的 MIE 技术与药理学操作相结合来阻断或增强突触活性的特定方面，以阐明调节 A¿的细胞机制。这些研究的结果将提高我们对突触活动和 A¿ 之间的时间关系的理解。世代/物种并揭示 AD 进展中涉及的机制。