Over one billion adults worldwide are estimated to suffer from sleep apnea, a condition with wide-reaching effects on brain health. Sleep apnea causes cognitive decline and is a risk factor for neurodegenerative conditions such as Alzheimer’s disease. Rodents exposed to intermittent hypoxia (IH), a hallmark of sleep apnea, exhibit spatial memory deficits associated with impaired hippocampal neurophysiology and dysregulated adult neurogenesis. We demonstrate that IH creates a pro-oxidant condition that reduces the Tbr2+ neural progenitor pool early in the process, while also suppressing terminal differentiation of adult born neurons during late adult neurogenesis. We further show that IH-dependent cell-autonomous hypoxia inducible factor 1-alpha (HIF1a) signaling is activated in early neuroprogenitors and enhances the generation of adult born neurons upon termination of IH. Our findings indicate that oscillations in oxygen homeostasis, such as those found in sleep apnea, have complex stage-dependent influence over hippocampal adult neurogenesis.
Adult neurogenesis allows for the continual generation of neurons throughout adulthood. It is implicated in the maintenance of normal hippocampal function and is tightly regulated by oxygen homeostasis. Sleep apnea causes periodic cessations in breathing and leads to intermittent hypoxia (IH), which can impair hippocampal based learning and memory. This ongoing study examines how IH influences neural precursors and remodels the neurogenic niche in the hippocampus. We hypothesize that IH destabilizes the pool of intermediate neural progenitors (INPs) and recruits microglia into the area. Our findings indicate that the number of INPs is reduced by IH. Moreover, while IH does not change the number of microglia in the molecular and granular layers of the dentate gyrus, microglia appear to be uniquely recruited into the neurogenic niche (i.e., the subgranular zone) following IH. These findings suggest that IH‐dependent changes in hippocampal adult neurogenesis may stimulate microglial activity which in turn further impact normal hippocampal function. Such effects may play a significant role in influencing hippocampal physiology during untreated sleep apnea.
Support or Funding Information
This work was supported by NIH PO 1 HL 144454, NIH R01 NS10742101 awarded to AJG, and a grant from The BSD Office of Diversity & Inclusion at The University of Chicago awarded to AJG.
Stroke is the fifth leading cause of death in the United States and its most common type, ischemic stroke, is caused when a major blood vessel that carries oxygen and nutrients to the brain is blocked. This blockage initiates tissue death downstream resulting in inflammation and oxidative stress. Several studies have shown that microglia/macrophage neuroinflammatory responses significantly contribute to neuronal death in ischemic stroke. Bromodomain and extraterminal (BET) proteins‐ Brd2, Brd3, Brd4, and Brdt‐ bind to acetylated lysines on histones and act as a scaffold for transcription factors of several pro‐inflammatory genes important for the spread of cell death after stroke. To recreate the inflammatory process that occurs in response to ischemic stroke in vitro we subjected mouse SIM‐A9 microglia to lipopolysaccharide (LPS) stimulation and then treated with dBET1, a proteolysis‐targeting chimera (PROTAC) molecule that produces a targeted degradation of BET proteins. dBET1 is also a hybrid of the highly selective BET inhibitor, JQ1, that blocks the acetylated lysine‐binding pocket of BET proteins, complexed to a ligand for an E3 ubiquitin ligase. The PROTAC approach results in ubiquitination and subsequent degradation of the target protein by the proteasome. In this study, we did a dose‐response and a time course curve and found that 24 hours of treatment with 1 μM of dBET1 optimally decreases Brd2 and Brd4. Using Western blot and qRT‐PCR, we also found that treatment with dBET1 produced a dramatic reduction in the levels of inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), interleukin (IL)‐1β, tumor necrosis factor‐α (TNFα), IL‐6, chemokine ligand 2 (CCL‐2), and matrix metalloproteinase 9 (MMP‐9). This is the first study showing that dBET1‐mediated targeted degradation of BET proteins prevents pro‐inflammatory responses in LPS‐stimulated microglia. The data collected in vitro show promising results that suggest that in vivo studies using dBET1 may reduce the deleterious effects of stroke.Support or Funding InformationThis project was possible through the funding of the Neuroscience Summer Internship Program from the McKnight Brain Institute at the University of Florida. It also received funding through the University of Puerto Rico at Mayagüez's MARC U*STAR Program and the National Institutes of Health's grant 2T34GM008419‐26.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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