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

项目总结/摘要 胶质细胞生物钟功能紊乱在阿尔茨海默病发病机制中的作用 昼夜节律系统的慢性破坏，表现为睡眠障碍，昼夜混淆， “日落”，是阿尔茨海默病的描述充分和衰弱的症状。虽然昼夜节律 长期以来，破坏一直被认为是AD中退行性过程的结果，积累了人类 小鼠数据表明，昼夜节律异常可能在明显的认知症状之前开始， 可能在AD发病机制中起重要作用。昼夜节律在细胞中产生， 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 转录中的振荡我们已经发现，通过基因删除来消除生物钟的功能， 大脑中主时钟基因Bmal 1的缺失会导致严重的神经胶质增生、突触丢失、神经炎症和衰老， 相关的神经变性生物钟在神经胶质细胞中特别强大，调节细胞活化 以及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 细胞和小鼠生物钟紊乱与β淀粉样蛋白（Aβ）相关病理的关系 AD模型，重点关注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， 通过在体内和体外研究细胞类型特异性转录，我们将检验Aβ直接损害 小鼠AD模型中星形胶质细胞和小胶质细胞的细胞生物钟通过氧化应激依赖 机制然后我们将确定星形胶质细胞和小胶质细胞中细胞类型特异性Bmal 1缺失， 将加剧AD的APP/PS1小鼠模型中的神经炎症和突触损失。我们 已经确定了星形胶质细胞和小胶质细胞中特定的昼夜节律控制通路， 影响，并将试图在治疗上靶向这些通路，以减轻神经炎症和突触 老年APP/PS1小鼠的退化。

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.