Apolipoprotein E-deficient mice exhibit increased vulnerability to intermittent hypoxia-induced spatial learning deficits

Sleep. 2005 Nov;28(11):1412-7. doi: 10.1093/sleep/28.11.1412.


Exposure to intermittent hypoxia, such as occurs in sleep-disordered breathing, is associated with oxidative stress, cognitive impairments, and increased neuronal apoptosis in brain regions involved in learning and memory. Apolipoprotein E (ApoE) has been implicated in neurodegenerative disorders, and in vitro studies suggest that one of the functions of ApoE may be to confer protection from oxidant stress-induced neuronal cell loss. Therefore, we hypothesized that ApoE-deficient (ApoE-/-) mice would display increased cognitive impairments following intermittent hypoxia. Twenty-four young adult male mice (ApoE-/-) and 24 wild-type littermates (ApoE +/+) were exposed to 14 days of normoxia (room air; n=12 per group) or intermittent hypoxia (5.7% O2 alternating with 21% O2 every 90 seconds, 12 daylight hours per day; n=12 per group). Behavioral testing consisting of a standard place-training reference memory task in the water maze revealed that ApoE+/+ and ApoE-/- mice exposed to intermittent hypoxia were found to require significantly longer times (latency) and distances (pathlength) to locate the hidden platform (P < .005), compared to mice exposed to room air. However, only intermittent hypoxia-exposed ApoE-/- mice were impaired on the final two days of training (P < .03), as well as on measures of spatial bias conducted 24 hours after completion of training (P < .02). Furthermore, increased prostaglandin E2 and malondiadehyde concentrations were present in hippocampal brain tissues following intermittent hypoxia but were significantly higher in ApoE-/- mice (P < .01). Thus, decreased ApoE function is associated with increased susceptibility to neurocognitive dysfunction in a rodent model of sleep-disordered breathing and may underlie the increased prevalence of Apolipoprotein E4 in patients with sleep-disordered breathing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / metabolism*
  • Cognition Disorders / etiology
  • Cognition Disorders / metabolism
  • Cognition Disorders / physiopathology
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Hypoxia* / complications
  • Hypoxia* / metabolism
  • Hypoxia* / physiopathology
  • Lipid Peroxidation / physiology
  • Male
  • Maze Learning / physiology*
  • Mice
  • Oxidative Stress / physiology
  • Perceptual Disorders* / etiology
  • Perceptual Disorders* / metabolism
  • Perceptual Disorders* / physiopathology
  • Severity of Illness Index
  • Space Perception*
  • Time Factors


  • Apolipoproteins E
  • Cyclooxygenase 2
  • Dinoprostone