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：越来越多的证据表明，阻塞性睡眠呼吸暂停（OSA）是最常见的疾病 睡眠呼吸障碍（SDB）是一种常见的睡眠呼吸障碍， 阿尔茨海默病（AD）的进展。OSA在老年人群中的患病率较高， 被认为是通过睡眠片段化和慢性间歇性缺氧（CIH）引起其有害影响。 最近的流行病学证据表明，CIH是老年人认知能力下降的最佳预测因子， OSA。氧饱和度下降指数（ODI）和呼吸暂停或呼吸不足时间百分比较高的老年受试者 患轻度认知障碍（MCI）和AD痴呆的风险增加。但 CIH影响认知的机制，以及AD的风险和进展在很大程度上仍然未知。 迫切需要在动物模型中进行研究，其中可以建立因果关系， 了解CIH在AD病理生理学中的确切作用。神经纤维缠结（NFT），一种主要的 AD的神经病理学标志，由异常过度磷酸化的tau蛋白形成，是众所周知的更好的 与认知功能下降的相关性高于淀粉样蛋白β斑块。我们有强有力的初步数据显示， CIH在AD的野生型小鼠和P301 S人tau小鼠模型中均诱导认知缺陷， 它通过连接的解剖神经回路促进tau蛋白的传播。的首要目标 该建议旨在阐明CIH与tau蛋白加重和进展之间的因果关系 增加AD发展和进展风险的病理学。我们的中心假设是，CIH扮演了一个 在异常过度磷酸化的tau积累和扩散以及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综合 在P301 S人tau转基因小鼠中CIH的背景下评估的方法，首先， 第二，区域神经网络失调 这可能导致过度兴奋，促进tau病理积累和传播，最后， 创新技术的潜在分子机制，即，翻译核糖体亲和纯化 （TRAP）-RNA-测序。TRAP为我们提供了一个独特的机会， 海马结构内的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（成对脉冲易化）和长期可塑性（长期 增强，LTP和长期抑郁，LTD），这可能为CIH提供神经生理学基础- 导致记忆缺失总的来说，这个项目将确定CIH对主要AD进展的影响 病理生理和表型特征。因此，它将解开细胞，分子和生理 OSA增加AD病理生理学风险和进展的潜在机制。这项建议 对开发AD的预防和治疗新靶点具有重要的转化意义。