ROLE OF GLIAL CIRCADIAN CLOCK DYSFUNCTION IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE

项目摘要/摘要 神经胶质生物钟功能障碍在阿尔茨海默病发病机制中的作用 昼夜节律系统的慢性紊乱，表现为睡眠障碍、昼夜混乱和 “日落”是阿尔茨海默氏症的常见症状，使人虚弱。而昼夜节律 长期以来，分裂一直被认为是AD退变过程的结果，积累了人类 老鼠的数据表明，昼夜节律异常可能在明显的认知症状之前就开始了，并且 可能在AD的发病机制中起重要作用。昼夜节律是在细胞中通过 特定的时钟基因，在整个大脑的神经元和神经胶质细胞中表达，并控制24小时 转录中的振荡。我们发现，通过删除来废除生物钟的功能 大脑中主时钟基因BMal1的突变会导致严重的胶质增生、突触丧失、神经炎症和年龄- 相关的神经退行性变。在神经胶质细胞中，生物钟特别强健，调节细胞的激活 星形胶质细胞和小胶质细胞的炎症反应。因此，我们将解决双向 细胞和小鼠昼夜节律紊乱与淀粉样β蛋白(A-β)相关病理的关系 AD模型，重点研究星形胶质细胞和小胶质细胞中时钟基因的功能。使用新方法来 在体内和体外询问细胞类型特异性转录，我们将检验β直接损害的假设 氧化应激依赖的AD模型中星形胶质细胞和小胶质细胞的细胞昼夜节律 机制。然后我们将确定星形胶质细胞和小胶质细胞中是否存在细胞类型特异性的BMal1缺失， 分别会加重AD APP/PS1小鼠模型的神经炎症和突触丢失。我们 在星形胶质细胞和小胶质细胞中发现了特定的昼夜节律控制的通路，这些通路可能介导这些 效果，并将尝试以这些通路为靶点，以减轻神经炎症和突触 老年APP/PS1小鼠的退行性变。

PROJECT SUMMARY/ABSTRACT Role of glial circadian clock dysfunction in the pathogenesis of Alzheimer’s Disease Chronic disruptions of the circadian system, manifesting as sleep disturbances, day-night confusion, and “sundowning”, are well-described and debilitating symptoms of Alzheimer’s Disease. While circadian disruption has long been considered a consequence of the degenerative process in AD, accumulating human and mouse data suggest that circadian rhythm abnormalities may begin before overt cognitive symptoms, and could play an important contributory role in AD pathogenesis. Circadian rhythms are generated in cells by specific clock genes, which are expressed in neurons and glia throughout the brain and control 24-hour oscillations in transcription. We have discovered that abrogating the function of the circadian clock via deletion of the master clock gene Bmal1 in the brain causes severe gliosis, synaptic loss, neuroinflammation, and age- related neurodegeneration. The circadian clock is particularly robust in glial cells, regulating cellular activation and inflammatory responses in both astrocytes and microglia. Thus, we will address the bidirectional relationship between circadian clock disruption and amyloid-beta (Aβ)-related pathology in cellular and mouse models of AD, focusing on the function of clock genes in astrocytes and microglia. Using novel methods to interrogate cell type-specific transcription in vivo and in vitro, we will test the hypothesis that Aβ directly impairs the cellular circadian clocks of astrocytes and microglia in mouse AD models via an oxidative stress-dependent mechanism. We will then determine if cell type-specific Bmal1 deletion in astrocytes and microglia, respectively, will exacerbate neuroinflammation and synapse loss in the APP/PS1 mouse model of AD. We have identified specific circadian-controlled pathways in astrocytes and microglia that may mediate these effects, and will attempt to target these pathways therapeutically to mitigate neuroinflammation and synaptic degeneration in aged APP/PS1 mice.