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.

阿尔茨海默病（AD）和睡眠呼吸暂停（SA）之间存在复杂但鲜为人知的关系。