Hypoxia inducible factors in shaping neuroinflammation and Alzheimer's pathogenesis

University Of Texas Hlth Sci Ctr Houston, Houston TX

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Abstract

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.