Hypoxia inducible factors in shaping neuroinflammation and Alzheimer's pathogenesis

缺氧诱导因素影响神经炎症和阿尔茨海默病发病机制

• 批准号: 10709109
• 负责人: Wei Cao
• 金额: $ 39万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10709109
• 关键词: Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Applications Grants; Brain; Brain Diseases; Brain Hypoxia; Cells; Cerebral Ischemia; Cerebrovascular Circulation; Cognitive deficits; Dementia; Devices; Disease; Elements; Encephalitis; Gene Modified; Genes; Goals; HIF1A gene; Heart failure; Human; Human body; Hypoxia; Hypoxia Inducible Factor; Immune; Immunity; Impaired cognition; In Vitro; Inflammation; Interferons; Kinetics; Knowledge; Late Onset Alzheimer Disease; Link; Maps; Metabolism; Microglia; Modeling; Molecular; Mus; Myeloid Cells; Natural Immunity; Nerve Degeneration; Neurons; Normal tissue morphology; Obstructive Sleep Apnea; Organ; Oxygen; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Play; Population; Proteins; Public Health; Regional Anatomy; Reporter; Risk Factors; Role; Shapes; Source; Stroke; Synapses; Tauopathies; Therapeutic Intervention; Viral; Work; abeta deposition; age related; angiogenesis; cell behavior; cell type; cerebral atrophy; cerebral hypoperfusion; cytokine; deprivation; high risk; in vivo; insight; metabolic rate; neural; neuroinflammation; neuron loss; response; tau Proteins; tau-1

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common form of dementia, and as the population ages, it presents an enormous public health challenge with increasing urgency. Neuroinflammation is recognized as a major contributor to late-onset AD. However, the molecular modifiers for the neuroinflammatory response and key AD risk factors that hold such capacity remain unclear. Oxygen deprivation triggers a rapid adaptive response called hypoxia that stimulates anaerobic metabolism and angiogenesis to protect the host. In the past decade, a close connection between hypoxia, immunity, and metabolism has been firmly established in normal tissues and various disease conditions. The brain is the body’s most energy-demanding organ owing to its high metabolic rate, and oxygen is the most vital element in the human body, especially the brain. Despite this, a molecular understanding of how hypoxia modifies AD pathogenesis, specifically neuroinflammation, is currently lacking. Activation of neuroinflammatory responses is intimately linked to AD pathogenesis. In sporadic AD, immune- related genes are significantly upregulated, and multiple AD risk genes modify the function of microglia, which are brain-resident immune cells. We have identified that type I IFN (IFN) cytokine, a key component of antiviral innate immunity, is produced from plaque-associated microglia and promotes various aspects of neural pathology in diseased brains. Additionally, we detected an elevated IFN response in human tau pathology and found co-induction of IFN and hypoxic responses in tau-expressing neurons. Moreover, we recently discovered a synergistic interplay between IFN and hypoxia in glial inflammation. Obstructive sleep apnea, cerebral ischemia, stroke, and heart failure invariably promote brain hypoxia and increase the risk of AD. AD brains also display reduced cerebral blood flow, and cerebral hypoperfusion increases deposition of β-amyloid and phosphorylated tau proteins. Despite the strong implication of hypoxia, the functional involvement of hypoxia- inducible factors (HIFs), the master regulators of the hypoxia response, in AD is largely unknown. Based on our preliminary findings, we hypothesized that HIFs play a critical role(s) in AD-related tauopathy by affecting microglial function and promoting neuro-inflammation. We propose three specific aims - Aim 1: Map HIF-driven activity in brains with progressive tauopathy; Aim 2: Elucidate the essential roles of microglial HIF1αs in tauopathy; and Aim 3: Examine the impact of microglial overstabilization of HIFαs on tauopathy. Here we will gain fundamental knowledge of intrinsic hypoxic response as well as the essential roles of microglial HIF1α vs HIF2α in AD-related tauopathy.

项目摘要/摘要 阿尔茨海默氏病（AD）是痴呆症的最常见形式，随着人口的年龄，它呈现 紧迫性的巨大公共卫生挑战。神经炎症被认为是主要的 延迟发作广告的贡献者。但是，神经炎症反应和关键AD的分子修饰符 保持这种能力的风险因素尚不清楚。氧气剥夺会触发一种快速的自适应反应称为 刺激厌氧代谢和血管生成以保护宿主的缺氧。在过去的十年中，接近 缺氧，免疫学和代谢之间的联系首先在正常组织中建立 各种疾病状况。由于其高代谢，大脑是人体最能量的器官 速率和氧气是人体，尤其是大脑中最重要的元素。尽管如此，分子 目前缺乏了解缺氧如何修饰AD发病机理，特别是神经炎症的方法。 神经炎症反应的激活与AD发病机理密切相关。在零星广告中，免疫 - 相关基因被显着上调，多个AD风险基因改变了小胶质细胞的功能，这 是脑居住的免疫细胞。我们已经确定了I型IFN（IFN）细胞因子，这是抗病毒的关键成分 先天免疫是由斑块相关的小胶质细胞产生的，并促进了神经的各个方面 解剖的大脑中的病理学。此外，我们检测到人类tau病理学的IFN反应升高，并且 发现在表达tau的神经元中IFN和低氧反应的共同诱导。而且，我们最近发现了 神经胶质注射中IFN和缺氧之间的协同相互作用。阻塞性睡眠呼吸暂停，大脑 缺血，中风和心力衰竭总是促进大脑缺氧并增加AD的风险。广告大脑也是如此 显示脑血流减少，大脑灌注不足会增加β-淀粉样蛋白的沉积 尽管缺氧具有很强的影响，但缺氧的功能受累 AD中缺氧反应的主要调节剂诱导因子（HIF）在很大程度上未知。基于我们 初步发现，我们假设HIF通过影响与广告相关的Tauopathy起着关键作用 小胶质功能和促进神经炎症。我们提出了三个特定目标 - 目标1：地图hif驱动 进行性tauopathy的大脑活动； AIM 2：阐明小胶质HIF1α在 tauopathy;和目标3：检查HIFαs小胶质过度稳定对tauopathy的影响。我们会在这里 获得内在缺氧反应的基本知识以及小胶质的HIF1α与 HIF2α与广告相关的tauopathy中。