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)之间有一种复杂但鲜为人知的关系。 事实上，大约一半的阿尔茨海默病(AD)患者也有睡眠呼吸暂停(SA)。重要的是，当 这两种疾病都是并存的，认知能力下降加剧，这会造成严重的经济损失，并 对患者和家庭的生活质量有重大影响。事实上，SA在几乎所有的神经退行性变中都很普遍 疾病表明，鉴于惊人的重叠，可能涉及共同的潜在因果机制 在患者群体中，以及症状时间和发病时间上的相似性。我们认为两者之间的协同作用 AD和SA是由小胶质细胞、中枢神经系统驻留的巨噬细胞最初过度参与导致的 两种疾病的发展。在AD早期病理中，小胶质细胞被招募到并积聚在β细胞周围 淀粉样蛋白(Aβ)斑块，最初隔开并保护周围健康的脑组织免受有毒Aβ的伤害 多肽。然而，在AD进展过程中，持续的Aβ暴露会诱导小胶质细胞炎症 活动，加剧了持续的神经元损伤。巧合的是，间歇性低氧和睡眠碎片， 这两者都是SA的特征，可以启动小胶质细胞的炎症和吞噬活动，也会导致 神经炎症、小胶质细胞活化和神经元变性。因此，我们假设，在 结合SA和AD，小胶质细胞正常保护大脑免受神经毒性Aβ的能力，以及 吞噬细胞碎片变得不堪重负，有效地在新陈代谢中耗尽它们，使正在进行的 神经退行性变过程不受控制地进行。在父提案中，我们模拟了间歇性 大鼠怀孕期间SA的缺氧方面(GIH)，并发现她的成年雄性后代自发地 成年后出现睡眠呼吸暂停，这反映为睡眠中呼吸暂停的增加。此外，小胶质细胞 从雄性GIH后代启动了对免疫挑战的炎症反应，为他们的 夸大的免疫反应与AD的病理一致。在本补充中，我们将检验假设 子宫内暴露于妊娠间歇性低氧(GIH)的成年5XFAD小鼠自发性增加 假定睡眠期间会出现呼吸暂停，增加小胶质细胞的耗竭，并随着年龄的增长而加剧神经变性。 我们将随着时间的推移评估成年、WT和5XFAD仔鼠的呼吸暂停和认知功能障碍，如 症状发作和严重程度的测量。我们还将评估分子、生化和组织学方面的 这些后代的小胶质细胞功能。如果可以理解小胶质细胞在这些疾病中的作用，它们可能 代表了一种新的治疗目标，可以通过操纵来减少相互作用、协同作用的疾病 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，旨在探索 耗尽的小胶质细胞在SA和AD表型恶化中的作用 在一起。

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.