The relationship between sleep apnea and Alzheimer's disease in a unique mouse model: role for microglia

阿尔茨海默病（AD）和睡眠呼吸暂停（SA）之间存在复杂但知之甚少的关系。 事实上，大约一半的阿尔茨海默病（AD）患者也患有睡眠呼吸暂停（SA）。重要的是 这两种病理是共病的，认知能力下降加剧，造成严重的经济损失， 对患者和家庭生活质量有显著影响。事实上，SA在几乎所有神经退行性疾病中普遍存在， 这些疾病表明可能涉及共同的潜在因果机制， 在患者人群中，以及症状发生时间和发作的相似性。我们建议， AD和SA是由小胶质细胞、CNS驻留巨噬细胞的初始过度参与引起的， 两种病理的发展。在早期AD病理学中，小胶质细胞被募集到β细胞周围并在β细胞周围积累。 淀粉样蛋白（Aβ）斑块，最初隔离并保护周围健康脑组织免受有毒Aβ的侵害 缩氨酸然而，在AD进展过程中，持续的Aβ暴露诱导小胶质细胞炎性细胞浸润， 活动，加剧正在进行的神经元损伤。巧合的是，间歇性缺氧和睡眠碎片， 两者都是SA的标志，可以引发小胶质细胞的炎症和吞噬活动，也可以引起 神经炎症、小胶质细胞活化和神经元变性。因此，我们认为， 结合SA和AD，小胶质细胞将脑与神经毒性Aβ隔离的正常保护能力，以及 吞噬细胞碎片，变得不堪重负，有效地“耗尽”他们的新陈代谢，使持续的 神经退行性疾病的发展在家长提案中，我们模拟了间歇性的 缺氧方面的SA在大鼠母鼠在怀孕期间（GIH），并发现她的成年雄性后代自发 成年后出现睡眠呼吸暂停，这反映为睡眠期间呼吸暂停的增加。此外，小胶质细胞 来自雄性GIH后代的小鼠对免疫挑战产生了炎症反应，为他们的免疫挑战奠定了基础。 与AD病理学同时发生的过度免疫应答。在本附录中，我们将检验以下假设： 在子宫内暴露于妊娠间歇性缺氧（GIH）的成年5XFAD小鼠表现出自发性增加， 在假定睡眠期间呼吸暂停，增加小胶质细胞耗竭，并随着年龄的增长而增强神经退行性变。 我们将评估成年、WT和5XFAD同窝仔随时间推移的呼吸暂停和认知功能障碍， 症状发作和严重程度的测量。我们还将评估分子，生物化学和组织学方面的 小胶质细胞的功能。如果小胶质细胞在这些疾病中的作用可以被理解， 代表了一种新的治疗靶点，可以被操纵以减少相互的，协同的， SA和AD之间的相互作用。这些研究将为未来的R01研究奠定基础， 耗尽的小胶质细胞对SA和AD表型恶化的机制贡献（当存在时） 一起

There is a complex, but poorly understood relationship between Alzheimer’s disease (AD) and sleep apnea (SA). Indeed, about half of individuals with Alzheimer’s disease (AD) also have sleep apnea (SA). Importantly, when both pathologies are co-morbid, cognitive decline is exacerbated, which takes a severe economic toll and has significant impact on patient and family quality of life. Indeed, SA is prevalent in almost all neurodegenerative disorders suggesting that common underlying causal mechanisms are likely involved, given the striking overlap in patient populations, and the similarities in symptom timing and onset. We propose that the synergy between AD and SA results from initial over engagement of microglia, CNS resident macrophages that are involved in the development of both pathologies. In early AD pathology, microglia are recruited to and accumulate around beta amyloid (Aβ) plaques, initially walling off and protecting the surrounding healthy brain tissue from toxic Aβ peptides. However, over the course of AD progression, sustained Aβ exposure induces microglial inflammatory activities, compounding ongoing neuronal damage. Coincidentally, intermittent hypoxia and sleep fragmentation, both of which are hallmarks of SA, can prime microglial inflammatory and phagocytic activities, also causing neuroinflammation, microglial activation, and neuronal degeneration. Accordingly, we posit that in the context of combined SA and AD, the normally protective capacity of microglia to wall the brain off from neurotoxic Aβ, and phagocytose cell debris, becomes overwhelmed, effectively “exhausting” them metabolically, allowing ongoing neurodegenerative processes to proceed unchecked. In the parent proposal, we modeled the intermittent hypoxia aspect of SA in rat dams during gestation (GIH) and found that her adult male offspring spontaneously developed sleep apnea as adults, which was reflected as an increase in apneas during sleep. Further, microglia from male GIH offspring had primed inflammatory responses to immune challenges, setting the stage for their exaggerated immune response with coincident AD pathology. In this supplement, we will test the hypothesis that adult 5XFAD mice exposed to gestational intermittent hypoxia (GIH) in utero exhibit increased spontaneous apneas during presumptive sleep, increased microglial exhaustion, and enhanced neurodegeneration with age. We will evaluate apneas and cognitive dysfunction over time in adult, WT and 5XFAD littermate offspring, as measures of symptom onset and severity. We will also assess molecular, biochemical and histologic aspects of microglial function in these offspring. If microglial contributions to these disorders can be understood, they may represent a novel therapeutic target that can be manipulated to reduce reciprocal, synergistic, disease interactions between SA and AD. These studies will form the foundation for future R01 studies designed to probe the mechanistic contributions of exhausted microglia to worsened SA and AD phenotypes when present together.