Intermittent Hypoxia Differentially Modulates Endogenous Tau Phosphorylation in Rats

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Intermittent hypoxia, or periods of low oxygen, can have different effects depending on the dose of hypoxic episodes (duration, severity, number per day, etc). “Low dose” daily acute intermittent hypoxia (dAIH) elicits neuroprotection and neuroplasticity, whereas “high dose” chronic intermittent hypoxia (CIH) similar to that experienced during sleep apnea elicits neuropathology. Sleep apnea is comorbid with more than half of patients with Alzheimer’s Disease (AD)—a progressive, neurodegenerative disease consisting of brain amyloid plaque accumulation and tau pathology. Clinically, patients with sleep apnea present with higher levels of tau aggregation, consistent with levels observed in AD patients. However, it is not known if sleep apnea and the associated CIH accelerates the onset or progression of AD and related tauopathies. We hypothesized high dose intermittent hypoxia consistent with that experienced during mild or moderate sleep apnea would increase levels of soluble phosphorylated tau species in the hippocampus and frontal cortex. Thus, we measured Ser396/Ser404 (PHF‐1) and Ser202 (CP13)—sites associated with tau pathology—in adult male SD rats exposed to different intermittent hypoxia protocols for 7 or 28 consecutive days, including: 1) continuous normoxia; 2) dAIH (10, 5‐min 10.5% O2 episodes per day; 5‐min normoxic intervals); 3) mild chronic intermittent hypoxia (CIH5/5: 5‐min 10.5% O2 episodes, 5‐min intervals; 8 hrs/day); and 4) moderate chronic intermittent hypoxia (CIH2/2: 2‐min 10.5% O2 episodes, 2‐min intervals; 8 hrs/day). Rats were then anesthetized and hippocampal and prefrontal cortex tissues were freshly harvested for protein quantification by western blot or fixed in 4% paraformaldehyde for immunohistochemical analysis. PHF‐1 and CP13 protein was standardized to total tau and normalized to normoxic controls. After 7 days, there were significant increases in hippocampal PHF‐1 levels in CIH5/5 rats (p=0.039) and in PHF‐1 and CP13 levels of CIH2/2 rats (p=0.003 and p=0.004) vs. normoxic controls. Changes in phosphorylated tau were not detected in the prefrontal cortex. After 28 days, hippocampal PHF‐1 and CP13 were significantly elevated in rats exposed to CIH5/5 (p=0.018 and p=0.024) and CIH2/2 (p=0.012 and p=0.047). PHF‐1 and CP13 levels were also significantly elevated in the prefrontal cortex of rats exposed to CIH5/5 (p=0.007 and p<0.001) and CIH2/2 (p=0.006 and p=0.003). 28 days of dAIH also significantly increased hippocampal PHF‐1 (p=0.047) and prefrontal cortex PHF‐1 (p=0.033) and CP13 (p=0.001), however these effects were smaller in magnitude versus corresponding tissues with either CIH5/5 or CIH2/2. Thus, intermittent hypoxia induces dose‐dependent, region‐specific tau phosphorylation. However, the functional significance of increased phosphorylation is not yet known in these neurotypical rats. Clarifying the differential effects of intermittent hypoxia on AD onset and progression has both biological and translational significance, potentially guiding new therapeutic strategies to prevent or manage AD or other tauopathies.Support or Funding InformationFlorida Department of Health, Ed & Ethyl Moore Alzheimer’s Research Program; NIH HL148030 and McKnight Brain Institute.