Neuronal Network Regulation in A-Beta and Tau Conformation and Spreading

A-Beta 和 Tau 构象和扩散的神经网络调节

• 批准号: 10246277
• 负责人: John R Cirrito
• 金额: $ 37.21万
• 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: 2012-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246277
• 关键词: APP-PS1; Abeta synthesis; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Animals; Biology; Brain; Brain region; Cells; Cerebrospinal Fluid; Dendrites; Dependence; Deposition; Disease; Disease Progression; Electric Stimulation; Electrodes; Event; Extracellular Space; Extracellular Structure; Feedback; Frequencies; Generations; Glutamates; Guidelines; Heparan Sulfate Proteoglycan; Hippocampus (Brain); Hour; Human; Intercellular Fluid; Kinetics; Measures; Metabolism; Molecular Conformation; Monitor; Mus; Neurofibrillary Tangles; Neurons; Neurotransmitters; PTPN11 gene; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peptide Conformation; Peptides; Pharmacology; Phosphotransferases; Physiological; Physiological Processes; Play; Population; Production; Proteins; Receptor Signaling; Regulation; Role; Seeds; Senile Plaques; Signal Transduction; Subcellular structure; Synapses; Synaptic Transmission; System; Technology; Temporal Lobe Epilepsy; Time; Transgenic Mice; Viral; Viral Vector; Work; abeta accumulation; aged; awake; cell type; dentate gyrus; designer receptors exclusively activated by designer drugs; entorhinal cortex; extracellular; functional loss; human model; hyperphosphorylated tau; hypocretin; in vivo; insight; monomer; novel; postsynaptic; protein metabolism; receptor; synergism; tau Proteins; tau aggregation; tau conformation; temporal measurement; uptake

Project Summary/Abstract Accumulation of Aβ peptide in the brain appears to initiate Alzheimer’s disease (AD), including tau aggregation which then plays a major role in disease progression. In humans and animal models of AD, brain regions with the highest levels of synaptic activity show the greatest amount of Aβ plaques, suggesting Aβ production is closely related to synaptic transmission. Studies from our lab have demonstrated that direct modulation of synaptic activity dynamically regulates brain Aβ and tau levels in awake animals, with increased synaptic activity rapidly increasing brain interstitial fluid (ISF) Aβ and tau levels and vice versa for suppressed activity. These findings strongly suggest a close temporal relationship between synaptic activity and Aβ and tau levels in the brain ISF. The brain extracellular space plays a particularly important role in AD biology. Aβ plaques are extracellular structures with the majority of Aβ that builds onto an existing plaque coming from the brain ISF. Hyperphosphorylated tau tangles are intracellular structures and were long thought to be independent of the ISF; however, recent studies demonstrate that tau can be secreted from one neuron into the ISF, then internalized into a naïve neuron to corrupt intracellular tau in that neuron and cause aggregation. Understanding mechanisms that regulate Aβ and tau kinetics within the brain ISF should provide valuable insight into disease pathogenesis. We hypothesize that pathological forms of Aβ and tau are spread between brain regions in a synaptic- dependent manner. We propose that neurons function within a network to regulate not only the amount of Aβ and tau released, but also the conformation (monomer, oligomers, etc.) of Aβ and tau that is released. Aim 1 will determine the relationship between synaptic frequency and Aβ/tau levels and species. Aim 2 will determine how glutamatergic and GABAergic neurons independently impact Aβ and tau in the ISF. And Aim 3 will determine how local synaptic activity within target brain region affects tau propagation. While several studies suggest that synaptic activity within the initiating brain region drives Aβ and tau secretion in the target region, how local synaptic activity within the dendritic target region affects tau uptake, propagation and seeding is unknown. We have developed a novel micro-immunoelectrode electrode (MIE) technology that detects Aβ and tau with very high temporal resolution in the brains of living mice (measures Aβ in vivo every 60 seconds over several hours). MIEs are highly selective for either Aβ40, Aβ42, tau, or their aggregates, enabling us to determine how synaptic activity regulates the rapid dynamics of these peptides and conformations in vivo. In this proposal we will utilize MIEs to measure rapid changes in Aβ and tau levels within intact neuronal networks and from specific cell types. Studies will include young APP/PS1 mice and young P301S mice prior to Aβ or tau pathology, as well as aged pathology-bearing mice to determine how pathological events change the relationship between activity and ISF protein metabolism. We will also use the APP/PS1 and P301S mice bred together to determine how synaptic Aβ impacts synaptic tau generation, and vice versa.

项目总结/摘要 Aβ肽在脑中的积累似乎引发阿尔茨海默病（AD），包括tau蛋白 聚集，其在疾病进展中起主要作用。在人类和AD动物模型中， 突触活动水平最高的大脑区域显示出最多的Aβ斑块，这表明 Aβ的产生与突触传递密切相关。我们实验室的研究表明， 突触活动的调节动态调节清醒动物的脑Aβ和tau水平， 突触活动增加，迅速增加脑间质液（ISF）Aβ和tau水平，反之亦然， 抑制活动。这些发现有力地表明，突触活动之间存在密切的时间关系， 以及脑ISF中的Aβ和tau水平。脑细胞外间隙在AD中起着特别重要的作用 生物学Aβ斑块是细胞外结构，大部分Aβ积聚在现有斑块上 来自大脑的ISF。过度磷酸化的tau缠结是细胞内结构， 被认为是独立的ISF;然而，最近的研究表明，tau可以分泌从 一个神经元进入ISF，然后内化到幼稚神经元中，破坏该神经元中的细胞内tau蛋白， 引起聚集。了解脑ISF内调节Aβ和tau动力学的机制， 为疾病的发病机制提供了有价值的见解。 我们假设病理形式的Aβ和tau蛋白以突触形式在大脑区域之间传播， 依赖的方式。我们认为，神经元在网络中的功能不仅是调节Aβ的数量， 和tau释放，而且构象（单体、寡聚体等）Aβ和tau蛋白要求1 将决定突触频率与Aβ/tau水平和物种之间的关系。目标2将 确定多巴胺能和GABA能神经元如何独立影响ISF中的Aβ和tau蛋白。和宗旨 3将确定靶脑区域内的局部突触活动如何影响tau传播。虽然若干 研究表明，启动大脑区域内的突触活动驱动Aβ和tau分泌， 树突状靶区域内的局部突触活动如何影响tau摄取、传播和 种子未知。 我们开发了一种新型的微免疫电极（MIE）技术，可以检测Aβ和tau蛋白 在活体小鼠的大脑中具有非常高的时间分辨率（每60秒测量一次体内Aβ） 几个小时）。MIE对Aβ40、Aβ42、tau或其聚集体具有高度选择性，使我们能够 确定突触活动如何调节这些肽和构象在体内的快速动力学。 在这项提议中，我们将利用MIEs来测量完整神经元内Aβ和tau水平的快速变化， 网络和特定的细胞类型。研究将包括幼年APP/PS1小鼠和幼年P301 S小鼠 在Aβ或tau病理学之前，以及携带病理学的老年小鼠，以确定病理学事件 改变活性与ISF蛋白代谢的关系。我们还将使用APP/PS1， P301 S小鼠一起繁殖，以确定突触Aβ如何影响突触tau的产生，反之亦然。