Interactions between metabolism and sleep in Alzheimer's disease pathogenesis

项目摘要/摘要 阿尔茨海默病是痴呆症最常见的形式，全世界有超过4500万人受到影响， 花费了超过8000亿美元的医疗费用。它的特征是细胞外淀粉样β蛋白的积聚。 (aβ)斑块和细胞内神经原纤维tau缠结，发生在症状出现前5至15年。 代谢紊乱和睡眠障碍是阿尔茨海默病的主要特征，它们代表了两者 疾病病理生理学的原因和后果。两者之间存在双向关系，其中 睡眠受损和新陈代谢单独导致阿尔茨海默病的发展，而睡眠和新陈代谢的存在 病理改变会导致大脑新陈代谢下降，外周葡萄糖耐量降低，睡眠中断。 此外，患有2型糖尿病(T2D)的人患阿尔茨海默病的风险增加2-4倍， 暗示了一种潜在的共同机制。慢性高血糖，T2D的一个决定性特征，导致 导致海马区神经元活动和Aβ水平增加，这种影响因 一种β病理，表明外周代谢、神经元活动和β产生之间的关系 会受到斑块病理的影响。这些指标都有由睡眠/觉醒维持的昼夜节律 因此，外周血糖水平或血糖变异性的急性变化可能足以 通过改变睡眠和外周代谢障碍之间的关系来驱动睡眠中断和进一步的外周代谢功能障碍 大脑葡萄糖代谢和神经元活动。培训补助金的目的是确定有多严重 血糖变异性在T2D的发展和治疗中都很常见，与阿尔茨海默病有协同作用 影响大脑新陈代谢、神经元活动和睡眠/清醒周期的病理。我们将直接评估 用植入小鼠海马区的生物传感器测量外周血糖挑战的影响 间质液(ISF)中葡萄糖和乳酸水平的变化、脑代谢和神经元的测定 活动分别为。我们将通过以下步骤确定血糖变化对睡眠/清醒周期的影响 同步脑电/肌电记录，评估每种状态和睡眠的总持续时间 碎片化。最后，我们将表征遗传模型小鼠的基线外周新陈代谢和 确定睡眠剥夺和睡眠挽救对外周糖耐量的影响。总而言之，这 一项提案将建立血糖变异性作为导致睡眠减少、大脑增加的机制 新陈代谢和神经元活动，以及进一步的外周糖耐量异常，所有这些都是确定的 阿尔茨海默病发病的危险因素。定义这些关系将提供更有效的 针对T2D和阿尔茨海默病之间相互作用的方法。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease is the most common form of dementia, affecting over 45 million people worldwide and costing over $800 billion in medical care. It is characterized by the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tau tangles, which occur 5 to 15 years before symptom onset. Metabolic perturbation and sleep disturbance are key features of Alzheimer’s disease, where they represent both cause and consequence of disease pathophysiology. A bidirectional relationship exists between the two where impaired sleep and metabolism individually contribute to Alzheimer’s disease development while the presence of pathology leads to decreased cerebral metabolism, peripheral glucose intolerance, and disrupted sleep. Further, individuals with type-2-diabetes (T2D) have a 2-4-fold increased risk of developing Alzheimer’s disease, suggesting an underlying common mechanism. Chronic hyperglycemia, a defining characteristic of T2D, leads to increased neuronal activity and Aβ levels within the hippocampus, an effect exacerbated by the presence of Aβ pathology, indicating a relationship between peripheral metabolism, neuronal activity, and Aβ production that is compromised by plaque pathology. These metrics all have diurnal rhythms maintained by the sleep/wake cycle; therefore, acute changes in peripheral blood glucose levels, or glycemic variability, may be sufficient to drive sleep disruptions and further peripheral metabolic dysfunction by modifying the relationship between cerebral glucose metabolism and neuronal activity. The purpose of the training grant is to determine how acute glycemic variability, common in both the development and treatment of T2D, synergizes with Alzheimer’s disease pathology to affect cerebral metabolism, neuronal activity, and sleep/wake cycles. We will directly evaluate the impact of peripheral glycemic challenges using biosensors implanted into the hippocampus of mice measuring changes in interstitial fluid (ISF) glucose and lactate levels, measures of cerebral metabolism and neuronal activity, respectively. We will determine the impact of glycemic variability on sleep/wake cycles through simultaneous EEG/EMG recordings, evaluating both the total duration in each state as well as sleep fragmentation. Finally, we will characterize baseline peripheral metabolism of the genetic model mice and determine the effect of sleep deprivation and sleep rescue on peripheral glucose tolerance. Together, this proposal will establish glycemic variability as mechanism driving decreased sleep, increased cerebral metabolism and neuronal activity, and further peripheral glucose intolerance, all of which are well established risk-factors in the development of Alzheimer’s disease. Defining these relationships will offer a more efficacious approach to targeting the interactions between T2D and Alzheimer’s disease.