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

• 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
• 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' s Disease; Alzheimer' s disease pathology; Alzheimer' 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

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.

项目概要/摘要 载脂蛋白 E (APOE4) 的 ε4 变体是散发性遗传病最强且最常见的遗传危险因素。 阿尔茨海默病 (AD)，占 AD 病例的 95% 以上。 APOE4 已被证明 有助于促进 AD 病理学的许多分子过程，包括加速 β-淀粉样蛋白和 tau 蛋白聚集、免疫反应性增加、脂质代谢改变以及受损 脑血流，但 AD 风险的总体机制仍不清楚。作为主要风险 作为动脉粥样硬化和 AD 的因子，APOE4 对脉管系统具有深远的影响。之前的研究有 发现神经血管耦合失调、血管舒张剂一氧化氮水平升高以及血液流动受损 大脑动脉周围的脑脊液，表明类淋巴清除率降低，这一过程 在睡眠期间发生得最为剧烈。因此，生理睡眠模式也被认为是 AD 中被破坏，这表明许多已识别的 APOE4 失调过程中有一个共同主题。我们 提出改变神经血管耦合和血管舒张将改变睡眠阶段模式并扰乱 睡眠会影响大脑中细胞废物的清除。这些废物很多 产品，如蛋白质聚集体、炎症细胞因子和代谢物可能具有神经毒性，并且可以 创建一个积极的反馈循环，因为它们反过来影响神经活动和血管的完整性和功能，进一步 扰乱睡眠。为了验证这个想法，我们将结合三项研究的神经生物学和技术专业知识 研究不同水平的大脑功能的小组对大脑生理学进行综合、多尺度的研究 并在携带人源化 APOE4 和 APOE3 的敲入小鼠中发挥作用。首先，我们将使用定制开发的 用于对 APOE4 和 APOE3 小鼠进行长期脑电图监测的硬件以及专门的机器学习 实时表征睡眠阶段，以确定睡眠过程中睡眠模式和质量的变化 老化（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 光子成像来测量表现 APOE4 和 APOE3 的皮质动脉直径 在衰老过程中不同时间点的小鼠，无论是清醒状态还是自然睡眠状态。三、我们将表演 在白天（光）和夜间（黑暗）期间对 APOE4 和 APOE3 小鼠脑组织进行多重分析和组学分析 在衰老过程中量化炎症细胞因子和代谢物的水平。最后，我们将进一步 检验我们的假设并尝试通过引入运动作为有效的方法来改善 AD 促进病理学 血管扩张剂和脑血管健康刺激。完成拟议的工作后，我们将 确定睡眠阶段和质量改变、血管舒张受损和失调的轨迹 APOE4 中免疫和代谢产物的产生和清除，并测试了两者之间的关系 通过从年轻时开始锻炼来改善血管功能障碍，可以预防这些病症。