Astroglial mechanisms in sleep homeostasis

星形胶质细胞睡眠稳态机制

基本信息

批准号：
10283928
负责人：
MARCOS G FRANK
金额：
$ 38.25万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-06-30
项目状态：
未结题

项目摘要

Summary Our parent grant NS114780 will determine cellular and molecular signaling pathways in astrocytes important in mammalian sleep regulation. We now extend our approach to neurodegenerative diseases, with a focus on mouse models of Alzheimer’s. Sleep may play an important role in the etiology and progression of neurodegenerative disease. Abnormal sleep is a common symptom of many neurodegenerative diseases including Alzheimer’s. Sleep also influences several neurological processes that if perturbed may contribute to cognitive decline and dementia. Among these are synaptic morphology/plasticity, immune response/neuroinflammation, brain metabolism and protein clearance. Therefore, understanding how sleep and sleep loss impact the diseased brain may provide new insights into Alzheimer’s and related diseases. This requires an understanding of how different classes of brain cells operate during sleep. The glial cells known as astrocytes are particularly important to examine in this context. Astrocytes mediate several processes dysregulated in Alzheimer’s (e.g. synaptic pruning, neuronal metabolism and removal of plaque proteins and are abnormally hyper-reactive in neurodegenerative disease (as measured by increased intracellular Ca2+. Astrocyte hyper-reactivity may in turn disrupt these normal processes vital to brain function. We have shown that astrocytes play central roles in mammalian sleep regulation. We have also recently demonstrated that sleep normally reduces (clears) astrocyte intracellular Ca2+ concentrations that accumulate during wakefulness [18]. We hypothesize that in Alzheimer’s the regulation of intracellular Ca2+ in astrocytes during sleep is abnormal leading to astrocytic hyper-reactivity. We will test this hypothesis by Impact: Sleep and astrocytes are implicated in neurodegenerative diseases like Alzheimer’s. Recent findings from our laboratory indicate that astrocytes influence sleep. This indicates that astrocytes may mediate important sleep functions that are relevant to neurodegenerative diseases. The requisite step to exploring this possibility is to examine the activity of these glial cells during sleep in mouse models of neurodegenerative disease. Our hypothesis is that sleep loss results in a persistent activation of astrocytes in neurodegenerative disease, which in turn could lead to neuronal cell death. If true, our findings will be impactful because they will identify a heretofore poorly understood interaction between sleep and glia that can be leveraged for new therapeutic approaches to Alzheimer’s.

概括我们的母基金 NS114780 将确定星形胶质细胞中重要的细胞和分子信号通路我们现在将我们的方法扩展到神经退行性疾病，重点是哺乳动物的睡眠调节。阿尔茨海默病小鼠模型。睡眠可能在神经退行性疾病的病因和进展中发挥重要作用。睡眠是包括阿尔茨海默病在内的许多神经退行性疾病的常见症状。一些神经系统过程如果受到干扰可能会导致认知能力下降和痴呆。这些是突触形态/可塑性、免疫反应/神经炎症、脑代谢和蛋白质因此，了解睡眠和睡眠不足如何影响患病的大脑可能会提供新的信息。了解阿尔茨海默氏症和相关疾病需要了解不同类别的大脑如何运作。细胞在睡眠期间运作。在这种情况下，被称为星形胶质细胞的神经胶质细胞的检查尤其重要。阿尔茨海默病中的几个过程失调（例如突触修剪、神经元代谢和去除斑块蛋白在神经退行性疾病中异常过度反应（通过增加来测量）细胞内 Ca2+ 的过度反应可能反过来破坏这些对大脑功能至关重要的正常过程。我们最近也发现星形胶质细胞在哺乳动物睡眠调节中发挥着核心作用。睡眠通常会降低（清除）星形胶质细胞细胞内累积的 Ca2+ 浓度我们在阿尔茨海默病中发现了星形胶质细胞内 Ca2+ 的调节。睡眠期间的异常会导致星形细胞过度反应，我们将通过以下方式检验这一假设。影响：睡眠和星形胶质细胞与阿尔茨海默病等神经退行性疾病有关。我们实验室的研究表明星形胶质细胞影响睡眠，这表明星形胶质细胞可能介导。与神经退行性疾病相关的重要睡眠功能是探索这一点的必要步骤。可能性是在神经退行性疾病小鼠模型中检查这些神经胶质细胞在睡眠期间的活动我们的假设是，睡眠不足会导致神经退行性疾病中星形胶质细胞的持续激活。如果这是真的，我们的发现将具有影响力，因为它们会导致神经细胞死亡。确定迄今为止人们对睡眠和神经胶质细胞之间的相互作用了解甚少，该相互作用可用于新的研究阿尔茨海默病的治疗方法。