Dynamic Regulation of Amyloid-^ in the CNS

项目总结(见说明)： 大多数神经退行性疾病，包括阿尔茨海默病(AD)，都是蛋白质聚集的障碍，在这种疾病中，通常可溶的特定蛋白质聚集在大脑的细胞内或细胞外空间。 在AD中，调节一个容易聚集的蛋白质是否会错误折叠的一个关键因素是它的浓度。研究表明，突触前和突触后因素引起的突触活动与神经元释放淀粉样蛋白B(AB)有关。这表明，了解整合的突触和网络活动如何调节AB和潜在的参与神经退行性疾病的其他蛋白质，可能为发病机制提供新的见解。我们发现，在小鼠的脑间质液中 (ISF)，AP水平与每小时醒着的分钟数呈动态正相关。 药理研究表明，外源性和内源性增食欲素都能调节觉醒和AB水平。在APP TG小鼠模型中，慢性睡眠剥夺显著增加，食欲素受体拮抗剂减少AB沉积。我们的初步数据显示，在ISF中，AB水平以及对大脑代谢/突触活动的测量可以预测在特定脑区发生多少AB沉积。基于这些结果，我们假设大脑区域之间的新陈代谢/突触活动的差异 调节ISF AB水平，睡眠/清醒状态通过对突触活动的影响调节可溶性AB水平，并最终调节AB沉积。其具体目的是：1)通过体内微透析，动态测量随年龄增长不同脑区ISF AB、与突触活动有关的分子如乳酸、控制觉醒的分子(食欲素)和睡眠(生长激素释放激素-GHRH)的水平。2)确定增食欲素和促生长激素释放激素的遗传和药理作用 以及内源性NMDA受体激活、ERK信号和LRP1对ISF AB波动和睡眠/觉醒周期的影响。3)在一项正在进行的对45-75岁认知正常人(成年儿童研究)的研究中，确定平均睡眠/醒来时间、其他睡眠特征和AD生物标记物(淀粉样蛋白成像、脑脊液AB和tau)之间的关系。

PROJECT SUMMARY (See insti-uctions): Most neurodegenerative diseases, including Alzheimer's disease (AD), are disorders of protein aggregation in which specific proteins that are normally soluble, aggregate in the intra or extracellular space of the brain. In AD, a key factor that regulates whether an aggregation prone protein goes on to misfold is its concentration. Studies have shown that synaptic activity due to both presynaptic arid postsynaptic factors is coupled with the neuronal release of amyloid-B (AB). This suggests that understanding how integrated synaptic and network activity regulate both AB and potentially other proteins involved in neurodegenerative disease, may provide novel insights into pathogenesis. We found that in the brain interstitial fluid of mice (ISF), AP levels are dynamically and positively associated with the number of minutes awake per hour. Pharmacological studies showed that exogenous and endogenous orexin modulates both wakefulness and AB levels. Chronic sleep deprivation markedly increased and an orexin-receptor antagonist decreased AB deposition in APP Tg mouse models. Our preliminary data show that in ISF AB levels as well as measures of brain metabolic/synaptic activity predict how much AB deposition will occur in specific brain regions. Based on these results, we hypothesize that differences in brain metabolic/synaptic activity between brain regions regulate ISF AB levels and that the sleep/wake state regulates both soluble AB levels and ultimately AB deposition via effects on synaptic activity. The specific aims are: 1) To dynamically measure the levels of ISF AB, molecules linked with synaptic activity such as lactate, molecules controlling wakefulness (orexin), and sleep (growth hormone releasing hormone-GHRH) by in vivo microdialysis in different brain regions with aging. 2) To determine the effects of genetic and pharmacological manipulation of orexin and GHRH signaling as well as effects of endogenous NMDA receptor activation, ERK signaling, and LRP1 on ISF AB fluctuations and the sleep/wake cycle in collaboration with projects 2 and 3. 3) To determine the relationship between mean sleep/wake time, other sleep features, and AD biomarkers (amyloid imaging, CSF AB and tau) in an ongoing study of cognitively normal humans (the adult children study) 45-75 years of age.