Regional, Synpatic, Cellular Modulation of Abeta Metabolism

Abeta 代谢的区域、突触、细胞调节

基本信息

批准号：
9044827
负责人：
DAVID M. HOLTZMAN
金额：
$ 111.99万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-15 至 2017-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9044827
关键词：
Abeta clearance Abeta synthesis Adult Children Age Age-Years Aging Alzheimer&apos s Disease Amino Acids Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Biological Markers Brain Brain region Cell Death Cellular biology Chronic Collaborations Coupled Coupling Data Dementia Deposition Development Disease Electroencephalography Endocytosis Event Extracellular Space Frequencies Gene Delivery Generations Genetic Genotype Glucose Hippocampus (Brain)Hour Human Impaired cognition In Vitro Individual Individual Differences Intercellular Fluid LDL-Receptor Related Protein 1 Label Lead Life Link Location Mass Spectrum Analysis Measures Mediating Metabolic Metabolism Microdialysis Molecular Mus Mutation N-Methyl-D-Aspartate Receptors Neurodegenerative Disorders Neuronal Dysfunction Neurons Neuropeptides Neurotransmitter Receptor Neurotransmitters Oxygen Pathogenesis Pathology Peptides Physiologic pulse Play Probability Process Production Proteins Public Health Receptor Activation Regulation Research Personnel Role Senile Plaques Signal Transduction Sleep Sleep Deprivation Sleep Wake Cycle Slow-Wave Sleep Somatotropin-Releasing Hormone Stroke Synapses Synaptic Transmission Synaptic Vesicles System Techniques Testing Time Toxic effect Transgenic Mice Universities Viral Wakefulness Washington abeta deposition aerobic glycolysis amyloid imaging awake base cognitive task effective therapy genetic risk factor hypocretin in vivo insight mouse model neurotoxicity novel protein aggregate protein aggregation receptor synaptic function tau Proteins vesicular release

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia. There is compelling data that the amyloid- beta (Abeta) peptide plays a key early role in initiating disease pathogenesis. The progressive buildup of toxic forms of Abeta in the brain appears to ultimately lead to downstream events culminating in dementia. Since the concentration of soluble Abeta peptide is directly related to the probability that it will aggregate, determining what normally regulates Abeta levels in the brain will likely provide critical insights ino factors that initiate the AD pathological cascade. The investigators on this PPG proposal have found that synaptic activity is dynamically coupled with the release of the Abeta peptide in the extracellular space of the brain. Our labs have utilized mouse models of AD to discover some of the cellular mechanisms that link synaptic transmission and dynamic changes in Abeta levels in awake, behaving mice with confirmation in human studies. Abeta is dynamically regulated by the sleep-wake cycle and this regulation appears important in determining Abeta deposition later in life. The regulation of Abeta by the sleep-wake cycle may be tied to synaptic activity as brain interstitial fluid (ISF) levels of Abeta are directly coupled with synaptic activity both pre- and post-synapticall. A molecule likely involved in this coupling is LRP1, since APP endocytosis is required for a large component of Abeta generation and LRP1 influences APP endocytosis and Abeta generation. Our hypothesis is that synaptic activity influences both Abeta production and clearance in the brain and that over time this activity influences whether, where, and when Abeta aggregates into toxic species in the brain. In addition, we hypothesize that synaptic activity-mediated Abeta generation and release 1) is influenced by the sleep/wake cycle and molecules that regulate that cycle; 2) occurs in part via post-synaptic stimulation of NMDA receptors via ERK signaling; and 3) is influenced by the LDL-receptor related protein-1 (LRP1) via its interactions with APP. We will combine unique techniques including in vivo protein microdialysis, 13C-labeled amino acid pulse chase labeling combined with mass spectrometry, and focal viral-mediated gene delivery with approaches that assess systems level network function, synaptic and molecular signaling, and cell biology.

描述（由申请人提供）：阿尔茨海默氏病（AD）是痴呆症的最常见原因。有令人信服的数据表明，β 淀粉样蛋白 (Abeta) 肽在疾病发病机制的启动中发挥着关键的早期作用。大脑中有毒形式的 Abeta 的逐渐积累似乎最终会导致下游事件，最终导致痴呆。由于可溶性 Abeta 肽的浓度与其聚集的可能性直接相关，因此确定大脑中 Abeta 水平的正常调节因素可能会为引发 AD 病理级联的因素提供重要的见解。这项 PPG 提案的研究人员发现，突触活动与大脑细胞外空间中 Abeta 肽的释放动态耦合。我们的实验室利用 AD 小鼠模型，发现了一些将突触传递与清醒、行为小鼠 Abeta 水平动态变化联系起来的细胞机制，并在人类研究中得到证实。 Abeta 受到睡眠-觉醒周期的动态调节，这种调节对于确定晚年 Abeta 沉积似乎很重要。睡眠-觉醒周期对 Abeta 的调节可能与突触活动有关，因为 Abeta 的脑间质液 (ISF) 水平与突触前和突触后的突触活动直接相关。可能参与这种偶联的分子是 LRP1，因为 Abeta 生成的大部分需要 APP 内吞作用，并且 LRP1 影响 APP 内吞作用和 Abeta 生成。我们的假设是，突触活动会影响大脑中 Abeta 的产生和清除，并且随着时间的推移，这种活动会影响 Abeta 是否、在何处以及何时在大脑中聚集成有毒物质。此外，我们假设突触活动介导的 Abeta 生成和释放 1) 受到睡眠/觉醒周期和调节该周期的分子的影响； 2) 部分通过 ERK 信号传导对 NMDA 受体进行突触后刺激而发生； 3) 通过与 APP 的相互作用而受到 LDL 受体相关蛋白 1 (LRP1) 的影响。我们将结合独特的技术，包括体内蛋白质微透析、13C 标记的氨基酸脉冲追踪标记与质谱分析、焦点病毒介导的基因传递以及评估系统级网络功能、突触和分子信号传导以及细胞生物学的方法。