Astroglial mechanisms in sleep homeostasis

摘要 我们的父母资助NS114780将确定星形胶质细胞中重要的细胞和分子信号通路 哺乳动物的睡眠调节。我们现在将我们的方法扩展到神经退行性疾病，重点是 阿尔茨海默病的小鼠模型。 睡眠可能在神经退行性疾病的病因和进展中起重要作用。异常 睡眠是包括阿尔茨海默氏症在内的许多神经退行性疾病的常见症状。 一些神经过程如果受到干扰，可能会导致认知能力下降和痴呆症。其中 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 通行证。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 对阿尔茨海默氏症和相关疾病的洞察。这需要了解不同类别的大脑是如何 细胞在睡眠中运作。 在这种背景下，被称为星形胶质细胞的胶质细胞尤其重要。星形胶质细胞在 阿尔茨海默病的几个过程调节失调(例如，突触修剪、神经元新陈代谢和 斑块蛋白和异常高反应性在神经退行性疾病中(通过增加 细胞内钙离子。星形胶质细胞的高反应性可能会反过来扰乱这些对大脑功能至关重要的正常过程。 我们已经证明，星形胶质细胞在哺乳动物的睡眠调节中起着核心作用。我们最近也有 证明睡眠通常会降低(清除)星形胶质细胞内积累的钙离子浓度 在清醒时[18]。我们假设阿尔茨海默病患者星形胶质细胞内钙离子的调节 睡眠异常导致星形胶质细胞高反应性。我们将通过以下方式验证这一假设 影响：睡眠和星形胶质细胞与阿尔茨海默氏症等神经退行性疾病有关。最新发现 来自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在 与神经退行性疾病相关的重要睡眠功能。探索这一点的必要步骤 有可能在神经退行性变的小鼠模型中检查这些神经胶质细胞在睡眠期间的活动 疾病。我们的假设是，睡眠不足会导致神经退行性变中星形胶质细胞的持续激活 疾病，进而可能导致神经细胞死亡。如果是真的，我们的发现将是有影响的，因为它们将 找出迄今知之甚少的睡眠和神经胶质细胞之间的相互作用，这些相互作用可以用于新的 阿尔茨海默氏症的治疗方法。

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.