Mechanisms of Obstructive Sleep Apnea in Tau Pathophysiology, Risk and Progression of Alzheimer's Disease

阻塞性睡眠呼吸暂停在 Tau 病理生理学、阿尔茨海默病风险和进展中的机制

• 批准号: 10408756
• 负责人: Ana C. Pereira
• 金额: $ 58.48万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408756
• 关键词: Affinity Chromatography; Alzheimer' s Disease; Alzheimer' s disease model; Anatomy; Animal Model; Apnea; Bicuculline; Cerebrum; Chronic; Clinical; Cognition; Cognitive deficits; Data; Deposition; Development; Disease; Elderly; Epidemiology; Frequencies; Functional disorder; Future; Genetic Transcription; Goals; Healthcare; High Prevalence; Hippocampal Formation; Hippocampus (Brain); Human; Hypoxia; Impaired cognition; Impairment; Injections; Intervention Studies; Investigation; Kainic Acid; Long-Term Depression; Long-Term Potentiation; Measures; Memory impairment; Messenger RNA; Methodology; Molecular; Molecular Disease; Molecular Profiling; Mus; Nature; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Obstructive Sleep Apnea; Oxygen; Pathogenesis; Pathologic; Pathology; Phenotype; Physiologic pulse; Physiological; Play; Population; Predisposition; Prefrontal Cortex; Preventive; Proteins; Resistance; Ribosomes; Risk; Risk Factors; Role; Seizures; Senile Plaques; Sleep Apnea Syndromes; Sleep Fragmentations; Slice; Synapses; Synaptic plasticity; Tauopathies; Testing; Therapeutic; Time; Transgenic Mice; Translating; Translations; Wild Type Mouse; abnormally phosphorylated tau; age related; antagonist; care burden; cell type; effective therapy; human tissue; hyperphosphorylated tau; in vitro Model; indexing; innovative technologies; mild cognitive impairment; mouse model; multimodality; network dysfunction; neural circuit; neural network; neuron loss; neurophysiology; new therapeutic target; novel; public health relevance; tau Proteins; tau aggregation; tau mutation; tau phosphorylation; tau-1; transcriptome sequencing; transgene expression

PROJECT SUMMARY: Accumulating evidence suggests that obstructive sleep apnea (OSA), the most common form of sleep-disordered breathing (SDB), is an important risk factor in the development and progression of Alzheimer's disease (AD). OSA has a higher prevalence in the elderly population, and it is thought to cause its deleterious effects through sleep fragmentation and chronic intermittent hypoxia (CIH). Recent epidemiological evidence suggests CIH as the best predictor of cognitive decline in the elderly with OSA. Elderly subjects with higher oxygen desaturation index (ODI) and percent time in apnea or hypopnea have increased risk of developing mild cognitive impairment (MCI) and AD dementia. However, the mechanism(s) by which CIH impacts cognition, and risk and progression of AD remain(s) largely unknown. There is a critical need for investigations in animal models in which causal relationships can be established to understand the exact role(s) CIH play in AD pathophysiology. Neurofibrillary tangles (NFTs), a major neuropathological hallmark of AD, formed of abnormally hyperphosphorylated tau, are well-known to be better correlated with cognitive decline than amyloid β plaques in AD. We have strong preliminary data showing that CIH induces cognitive deficits both in wild-type mice and P301S human tau mouse model of AD and related tauopathies and it promotes tau propagation through connected anatomical neural circuits. The primary goal of this proposal is to elucidate the causal relationship between CIH and exacerbation and progression of tau pathology that increases risk of development and progression of AD. Our central hypothesis is that CIH plays a role in abnormally hyperphosphorylated tau accumulation and spread and cerebral network dysfunction, contributing to AD's molecular and cognitive dysfunctions. We will utilize a multi-modal and integrative approach evaluating in the setting of CIH in P301S human tau transgenic mice, first, trans-synaptic spread of tau pathology as well as tau aggregation and phosphorylation, second, regional neural network dysregulation that can result in hyperexcitability, facilitating tau pathology accumulation and propagation, and finally, its underlying molecular mechanisms with an innovative technology, i.e., translation ribosomal affinity purification (TRAP)-RNA-Sequencing. TRAP provides us with a unique opportunity to unravel the regional vulnerability to CIH within the hippocampal formation. Furthermore, we will also evaluate the effect of CIH on hippocampal synaptic plasticity, including short term plasticity (paired-pulse facilitation) and long-term plasticity (long-term potentiation, LTP, and long-term depression, LTD), which could provide a neurophysiological basis for CIH- induced memory deficit. Overall, this project will determine the effect of CIH on the progression of major AD pathophysiologic and phenotypic hallmarks. Thus, it will unravel the cellular, molecular, and physiological mechanisms underlying how OSA increases the risk and progression of AD pathophysiology. This proposal has high translational significance to develop preventive and new therapeutic targets for AD.

项目摘要：积累证据表明阻塞性睡眠呼吸暂停（OSA），最多 睡眠呼吸的常见形式（SDB）是开发的重要风险因素， 阿尔茨海默氏病（AD）的进展。 OSA在整个人口中的患病率较高，这是 被认为是通过睡眠碎片和慢性间歇性缺氧（CIH）引起其有害影响的。 最近的流行病学证据表明，CIH是较早的认知能力下降的最佳预测指标 OSA。具有较高氧饱和指数（ODI）和呼吸暂停时间百分比的老年受试者 患有轻度认知障碍（MCI）和AD痴呆症的风险增加。但是， CIH影响认知的机制，AD的风险和进展仍然很大未知。 对动物模型的投资有迫切需要，在该模型中可以建立因果关系 了解确切的CIH在AD病理生理学中的作用。神经原纤维缠结（NFTS），主要 由绝对磷酸化的tau组成的AD的神经病理标志是众所周知的更好 与AD中的淀粉样蛋白β斑块相比，与认知能力下降相关。我们有强大的初步数据，表明 CIH诱导认知在野生型小鼠和P301s的AD和相关的P301人tau小鼠模型中均定义 陶氏病并通过连接的解剖神经回路促进tau繁殖。主要目标 该建议是阐明CIH与TAU的加剧和进展之间的因果关系 病理学增加了AD发展和发展的风险。我们的中心假设是CIH玩 在绝对磷酸化的tau积累和扩散和脑网络功能障碍中的作用， 导致AD的分子和认知功能障碍。我们将利用多模式和集成 在P301S人类Tau转基因小鼠中评估CIH的方法，首先是反式突触传播 tau病理以及tau聚集和磷酸化，第二，区域神经网络失调 这可能导致过度兴奋，促进tau病理的积累和传播，最后是 具有创新技术的基本分子机制，即翻译核糖体亲和力纯化 （陷阱）-RNA-sequencing。陷阱为我们提供了一个独特的机会来揭示区域脆弱性 海马形成中的CIH。此外，我们还将评估CIH对海马的影响 突触可塑性，包括短期可塑性（配对脉冲设施）和长期可塑性（长期） 增强，有限公司和长期抑郁有限公司，可以为CIH提供神经生理基础 诱导记忆防御。总体而言，该项目将确定CIH对主要AD进展的影响 病理生理和表型标志。那将揭示细胞，分子和生理 OSA如何增加AD病理生理学的风险和进展的机制。这个建议 具有很高的翻译意义，可以为AD开发预防和新的治疗靶标。