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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

项目摘要

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.

项目总结/文摘