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.

项目概要/摘要 阿尔茨海默病 (AD) 是最常见的痴呆症，随着人口老龄化，它呈现出一种 神经炎症被认为是一个重大的公共卫生挑战，且日益紧迫。 然而，神经炎症反应和关键 AD 的分子调节剂。 保持这种能力的危险因素尚不清楚，缺氧会引发一种称为快速适应性反应的疾病。 缺氧会刺激无氧代谢和血管生成，从而保护宿主。 缺氧、免疫和新陈代谢之间的联系已在正常组织中牢固确立，并且 由于其高代谢，大脑是人体最需要能量的器官。 率，而氧气是人体，尤其是大脑中最重要的元素，尽管如此，它还是一种分子。 目前尚缺乏对缺氧如何改变 AD 发病机制，特别是神经炎症的了解。 神经炎症反应的激活与 AD 发病机制密切相关。 相关基因显着上调，多个AD风险基因改变小胶质细胞的功能， 我们已经鉴定出 I 型干扰素 (IFN) 细胞因子，它是抗病毒的关键成分。 先天免疫，由斑块相关的小胶质细胞产生，促进神经的各个方面 此外，我们在人类 tau 病理学中检测到 IFN 反应升高。 发现表达 tau 的神经元中存在干扰素和缺氧反应的共同诱导。 干扰素和缺氧在神经胶质炎症中的协同作用。 缺血、中风和心力衰竭总是会导致大脑缺氧，并增加 AD 大脑的风险。 显示脑血流量减少，脑灌注不足会增加β-淀粉样蛋白的沉积， 尽管缺氧具有强烈的意义，但缺氧的功能参与。 根据我们的研究，AD 中缺氧反应的主要调节因子（HIF）在很大程度上是未知的。 初步研究结果表明，HIF 通过影响 我们提出了三个具体目标 - 目标 1：映射 HIF 驱动。 进行性 tau 蛋白病大脑中的活性；目标 2：阐明小胶质细胞 HIF1α 在 tau 蛋白病；目标 3：检查 HIFα 的小胶质细胞过度稳定对 tau 蛋白病的影响。 获得内在缺氧反应的基础知识以及小胶质细胞 HIF1α 与 AD 相关 tau 蛋白病中的 HIF2α。