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: 10629413
• 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/10629413
• 关键词: Affinity Chromatography; Alzheimer' s Disease; Alzheimer' s disease model; Anatomy; Animal Model; Apnea; Bicuculline; Cerebrum; Chronic; Clinical; Cognition; Cognitive deficits; Data; Dementia; Deposition; Development; Disease; Elderly; Epidemiology; Frequencies; Functional disorder; Future; Genetic Transcription; Goals; Healthcare; High Prevalence; Hippocampal Formation; Hippocampus; 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 Profiling; Mus; Nature; Neuroanatomy; 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; neuropathology; neurophysiology; new therapeutic target; novel; public health relevance; tau Proteins; tau aggregation; tau mutation; 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.

项目总结：越来越多的证据表明，阻塞性睡眠呼吸暂停（OSA）是最常见的