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

独特小鼠模型中睡眠呼吸暂停与阿尔茨海默病之间的关系：小胶质细胞的作用

• 批准号: 10288404
• 负责人: Tracy L Baker
• 金额: $ 38.19万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288404
• 关键词: Adult; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Animal Model; Apnea; Autophagocytosis; Biochemical; Birth; Brain; Cells; Cessation of life; Characteristics; Cognitive; Cognitive deficits; Complex; Dementia; Deposition; Development; Disease; Disease Progression; Economics; Environment; Exhibits; Exposure to; Family; Foundations; Future; Gene Expression; Genetic; Hippocampus (Brain); Histologic; Hypoxia; Immune; Immune response; Immunohistochemistry; Impaired cognition; Individual; Inflammatory; Inflammatory Response; Laboratories; Life; Maternal Exposure; Measures; Metabolic; Microglia; Modeling; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Onset of illness; Parents; Partner in relationship; Pathology; Patients; Peptides; Phagocytes; Population; Pregnancy; Process; Quality of life; Rattus; Research Design; Risk; Senile Plaques; Severities; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Stimulus; Symptoms; Testing; Time; brain tissue; clinically relevant; comorbidity; disease phenotype; early onset; exhaust; exhaustion; immune activation; in utero; macrophage; male; mouse model; neuroinflammation; neurotoxic; new therapeutic target; normoxia; offspring; parent grant; patient population; pregnant; prenatal; recruit; role model; single-cell RNA sequencing; synergism

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.

阿尔茨海默氏病（AD）和睡眠呼吸暂停（SA）之间存在复杂但了解的关系。 确实，大约一半的阿尔茨海默氏病（AD）患有睡眠呼吸暂停（SA）。重要的是，什么时候 两种病理都是合并的，认知能力下降均加剧，这造成了严重的经济损失，并且已有 对患者和家庭生活质量的重大影响。实际上，SA在几乎所有神经退行性中都普遍存在 鉴于引人注目的重叠，可能涉及常见的基本因果机制的疾病可能涉及 在患者人群中，以及症状时间和发作的相似之处。我们建议 AD和SA是由于小胶质细胞的最初参与而导致的，CNS居民巨噬细胞涉及 两种病理的发展。在早期AD病理学中，小胶质细胞被招募到β周围并积聚 淀粉样蛋白（Aβ）斑块，最初隔离并保护周围健康的脑组织免受毒性Aβ的影响 肽。但是，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，复合正在进行的神经元损害。巧合的是，间歇性缺氧和睡眠碎片化， 两者都是SA的标志，可以给小胶质细胞炎症和吞噬活性产生刺激性，也导致 神经炎症，小胶质细胞激活和神经元变性。根据，我们认为在 SA和AD合并，通常受保护的小胶质细胞能够使大脑从神经毒性Aβ中闭合大脑，并且 吞噬细胞碎片碎片，不知所措，有效地“筋疲力尽”，允许持续 神经退行性过程未经检查。在父母的建议中，我们建立了间歇性的建模 妊娠期间大鼠大坝中SA的缺氧方面（GIH），发现她的成年男性后代赞助 成年后发展为睡眠呼吸暂停，这反映为睡眠期间呼吸暂停。此外，小胶质细胞 从男性GIH后代开始对免疫挑战的炎症反应，为他们的舞台奠定了基础 与一致的AD病理学夸张的免疫响应。在这种补充中，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小鼠提高了赞助商 在推定睡眠期间的呼吸暂停，小胶质疲劳增加以及随着年龄的增长而增强的神经退行性。 我们将在成人，WT和5XFAD同窝后代中评估呼吸暂停和认知功能障碍，为 症状发作和严重程度的度量。我们还将评估分子，生化和组织学方面 这些后代中的小胶质功能。如果可以理解对这些疾病的小胶质贡献，则可能 代表一个可以操纵的新型热目标，以减少互惠，协同，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，旨在证明 耗尽的小胶质细胞对存在的机械贡献对SA和AD表型的恶化， 一起。