Impaired Vasoreactivity, Sleep Degradation, and Impaired Clearance in the APOE4 Brain

APOE4 大脑中的血管反应性受损、睡眠质量下降和清除受损

基本信息

批准号：
10370453
负责人：
Patrick James Drew
金额：
$ 77.64万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10370453
关键词：
Affect Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Animals Apolipoprotein E Appearance Area Arteries Atherosclerosis Behavioral Binding Biological Assay Blood Blood - brain barrier anatomy Blood Vessels Blood flow Brain Caliber Cause of Death Cerebrovascular Circulation Cerebrovascular system Cerebrum Chronic Custom Dependence Development Disease Electroencephalography Encephalitis Event Exercise Feedback Gene Frequency Genes Genotype Heart Diseases Human Image Immune Impairment Individual Inflammation Inflammatory Knock-in Knock-in Mouse Late Onset Alzheimer Disease Light Lipids Machine Learning Measures Mediating Metabolic Metabolic Pathway Molecular Molecular Profiling Monitor Movement Mus Neurobiology Nitric Oxide Pathologic Pathology Pathway interactions Pattern Pharmacology Phase Physiological Physiology Polysomnography Population Preventive therapy Process Production Research Risk Risk Factors Running Signal Transduction Sleep Sleep Stages Sleep disturbances Societies Staging Stimulus Technical Expertise Testing Time TimeLine Variant Vascular Diseases Vasodilation Vasodilator Agents Waste Products Work abeta accumulation actigraphy awake brain cell brain tissue cerebral artery cerebrospinal fluid flow cerebrovascular health cholesterol transporters cytokine driving force experience genetic risk factor glymphatic clearance immune clearance immunoreactivity improved lipid metabolism mathematical model metabolomics neuroinflammation neurotoxic neurovascular neurovascular coupling protein aggregation relating to nervous system response sedentary sleep pattern sleep quality tau Proteins two-photon vigilance wasting

项目摘要

PROJECT SUMMARY/ABSTRACT The ε4 variant of apolipoprotein E (APOE4) is the strongest and most common genetic risk factor for sporadic Alzheimer’s disease (AD), which makes up more than 95% of AD cases. APOE4 has been demonstrated to contribute to a number of molecular processes implicated as promoting AD pathology, including accelerated aggregation of amyloid-β and tau proteins, increased immunoreactivity, altered lipid metabolism, and impaired cerebral blood flow, but an over-arching mechanism of the conveyed AD risk remains unclear. As a leading risk factor for atherosclerosis as well as AD, APOE4 has profound effects on vasculature. Previous studies have found dysregulated neurovascular coupling, high levels of the vasodilator nitric oxide, and impaired flow of cerebrospinal fluid around arteries in the brain, suggesting decreased glymphatic clearance, a process that occurs most dramatically during sleep. Consequently, physiological sleep patterns are also known to be disrupted in AD, suggesting a common theme in many of the identified APOE4-dysregulated processes. We propose that altered neurovascular coupling and vasodilation will alter sleep stage patterns and disrupt sleep, which will impair the clearance of cellular waste products from the brain. Many of these waste products, such as protein aggregates, inflammatory cytokines, and metabolites can be neurotoxic, and can create a positive feedback cycle as they in turn affect neural activity and vascular integrity and function, further disrupting sleep. To test this idea, we will combine the neurobiological and technical expertise of three research groups studying distinct levels of brain function to perform an integrative, multi-scale study of brain physiology and function in knock-in mice carrying humanized APOE4 and APOE3. First, we will use custom-developed hardware for chronic, long-term EEG monitoring of APOE4 and APOE3 mice and specialized machine learning for real-time characterization of sleep stages to identify shifts in sleep patterns and quality over the course of aging (3 months to 15 months). Second, we will quantify impairment of cortical vasodilation and vasoreactivity by conducting 2-photon imaging to measure the diameter of cortical arteries in behaving APOE4 and APOE3 mice, both awake and in natural sleep, at different time points over the course of aging. Third, we will perform multiplexing and -omics assays of brain tissue from APOE4 and APOE3 mice during day (light) and night (dark) over the course of aging to quantify the levels of inflammatory cytokines and metabolites. Finally, we will further test our hypothesis and attempt to ameliorate AD-promoting pathology by introducing exercise as a potent vasodilator and stimulus of cerebrovascular health. Upon completion of the proposed work, we will have determined the trajectories of altered sleep stages and quality, impaired vasodilation, and dysregulated production and clearance of immune and metabolic products in APOE4, and tested the relationship between these pathologies by introducing exercise from young age to ameliorate vascular dysfunction.

项目摘要/摘要载脂蛋白E（APOE4）的ε4变体是零星的强度和最常见的遗传危险因素阿尔茨海默氏病（AD）占AD病例的95％以上。 APOE4已被证明有助于许多分子过程，以促进AD病理，包括加速淀粉样蛋白β和tau蛋白的聚集，免疫反应性升高，脂质代谢改变并受损脑血流，但是传达的AD风险的总体机制尚不清楚。作为领先的风险动脉粥样硬化和AD的因素，APOE4对脉管系统具有深远的影响。先前的研究已有发现神经血管耦合失调，高水平的血管扩张剂一氧化氮以及流动受损大脑中动脉周围的脑脊液，表明糖糖的清除率下降，这一过程是睡眠期间最急剧发生。因此，身体睡眠模式也已知在AD中被破坏，这在许多已识别的APOE4被调控过程中提出了一个共同的主题。我们改变神经血管耦合和血管舒张的建议将改变睡眠阶段模式并破坏睡眠，这会损害大脑清除细胞废物的清除。其中许多浪费产物，例如蛋白质聚集体，炎性细胞因子和代谢产物可以是神经毒性的，并且可以创建一个积极的反馈周期，进一步影响神经活动，血管完整性和功能，进一步破坏睡眠。为了测试这个想法，我们将结合三项研究的神经生物学和技术专长研究不同水平的大脑功能以进行脑生理的综合多尺度研究的小组以及携带人源化APOE4和APOE3的敲入小鼠的功能。首先，我们将使用自定义开发用于慢性，长期脑电图监测APOE4和APOE3小鼠的硬件以及专业的机器学习为了实时表征睡眠阶段，以确定睡眠方式和质量的变化衰老（3个月至15个月）。其次，我们将量化皮质血管舒张和血管反应性的损害通过进行2光子成像以测量行为APOE4和APOE3中皮质动脉的直径在衰老过程中的不同时间点醒着和自然睡眠。第三，我们将表演白天（光）和夜晚（黑暗）的APOE4和APOE3小鼠的脑组织的多路复用和-omics刺激在衰老的过程中，以量化炎性细胞因子和代谢产物的水平。最后，我们将进一步测试我们的假设，并试图通过引入锻炼作为有效的锻炼来改善广告促进病理脑血管健康的血管扩张剂和刺激。拟议的工作完成后，我们将确定睡眠阶段改变和质量，血管舒张不良和失调的轨迹 APOE4中免疫和代谢产物的生产和清除，并测试了这些病理通过从小到改善血管功能障碍的运动来进行这些病理。