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：
8838268
负责人：
DAVID M. HOLTZMAN
金额：
$ 112.94万
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8838268
关键词：
Abeta clearance 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 Relative (related person)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 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，淀粉样蛋白β（ABETA）肽在启动疾病发病机理中起关键的早期作用。大脑中有毒Abeta的有毒形式的逐步积累似乎最终导致下游事件最终导致痴呆症。由于可溶性ABETA肽的浓度与汇总的概率直接相关，因此确定通常调节大脑中Abeta水平的方法可能会提供启动AD病理级联的关键见解因素。该PPG提案的研究者发现，突触活动与大脑细胞外空间中Abeta肽的释放动态结合。我们的实验室利用了AD的小鼠模型来发现一些细胞机制，这些机制将突触传播和ABETA水平的动态变化联系起来，在人类研究中表现出了小鼠的证实。 ABETA受睡眠效果周期动态调节，该调节对于确定后来的ABETA沉积似乎很重要。由于脑间隙液（ISF）ABETA水平直接与突触前和突触后的突触后直接耦合，因此通过睡眠效益周期调节ABETA可能与突触活动有关。可能涉及此耦合的分子是LRP1，因为ABTA生成的大部分需要APP内吞作用，而LRP1会影响App内吞作用和Abeta的产生。我们的假设是，突触活动会影响大脑中Abeta的产生和清除率，并且随着时间的流逝，这种活动会影响Abeta是否汇集到大脑中的有毒物种。此外，我们假设突触活动介导的Abeta的产生和释放1）受到调节该周期的睡眠/唤醒周期和分子的影响； 2）部分通过突触后通过ERK信号传导刺激NMDA受体； 3）受LDL受体相关蛋白-1（LRP1）的影响，其与APP的相互作用。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逐标记与质谱结合，以及局灶性病毒介导的基因递送以及评估系统水平网络功能，突触启动和分子信号传导以及细胞生物学的方法。