Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia

Abstract

Intermittent hypoxia (IH) and sleep fragmentation (SF) are major manifestations of sleep apnea, a frequent condition in aging humans. Sleep perturbations are frequent in Alzheimer's disease (AD) and may underlie the progression of disease. We hypothesized that acute short-term IH, SF, and their combination (IH+SF) may reveal unique susceptibility in sleep integrity in a murine model of AD. The effects of acute IH, SF, and IH+SF on sleep architecture, delta power, sleep latency, and core body temperature were assessed in adult male human ApoE4-targeted replacement mice (hApoE4) and wild-type (WT) controls. Slow wave sleep (SWS) was significantly reduced, and rapid eye movement (REM) sleep was almost abolished during acute exposure to IH alone and IH+SF for 6 h in hApoE4, with milder effects in WT controls. Decreased delta power during SWS did not show postexposure rebound in hApoE4 unlike WT controls. IH and IH+SF induced hypothermia, which was more prominent in hApoE4 than WT controls. Mice subjected to SF also showed sleep deficits but without hypothermia. hApoE4 mice, unlike WT controls, exhibited increased sleep propensity, especially following IH and IH+SF, suggesting limited ability for sleep recovery in hApoE4 mice. These findings substantiate the potential impact of IH and SF in modulating sleep architecture and sleep homeostasis including maintenance of body temperature. Furthermore, the increased susceptibility and limited recovery ability of hApoE4 mice to sleep apnea suggests that early recognition and treatment of the latter in AD patients may restrict the progression and clinical manifestations of this frequent neurodegenerative disorder.

Fig. 1.

Experimental protocol diagram. Schematic diagram illustrating sleep, behavior, and multiple sleep latency test (MSLT) experiments with exposures to either intermittent hypoxia (IH), sleep fragmentation (SF), or IH+SF in both wild-type (WT) and human apolipoprotein E (ApoE)4-targeted replacement (hApoE4) mice. 12:12-h light:dark cycle represents light period from 7 AM to 7 PM and dark period from 7 PM to 7 AM.

Fig. 2.

Sleep wakefulness, electroencephalogram (EEG) delta power, and body temperature (IH). All graphs are plotted per 2 h for a 24-h period: percent time waking during baseline (black line) and IH (dotted line) in WT mice (A) and hApoE4 mice (B); percent time in nonrapid eye movement (NREM) sleep during baseline (black line) and IH (dotted line) in WT mice (C) and hApoE4 mice (D); percent time in REM sleep during baseline (black line) and IH (dotted line) in WT mice (E) and hApoE4 mice (F); number of wake episodes during baseline (black line) and IH (dotted line) in WT mice (G) and hApoE4 mice (H); NREM sleep delta power during baseline (black line) and IH (dotted line) in WT mice (I) and hApoE4 mice (J); body temperature during baseline (black line) and IH (dotted line) in WT mice (K) and hApoE4 mice (L). Black line indicates IH period (1 PM to 7 PM). Shaded area represents dark period, 7 PM to 7 AM. SWS, slow wave sleep. *P < 0.05. Error bar represent mean SE. See text for more details.

Fig. 3.

Sleep wakefulness, EEG delta power, and body temperature (SF). All graphs are plotted per 2 h for a 24-h period: percent time waking during baseline (black line) and SF (dotted line) in WT mice (A) and hApoE4 mice (B); percent time in NREM sleep during baseline (black line) and SF (dotted line) in WT mice (C) and hApoE4 mice (D); percent time in REM sleep during baseline (black line) and SF (dotted line) in WT mice (E) and hApoE4 mice (F); number of wake episodes during baseline (black line) and SF (dotted line) in WT mice (G) and hApoe4 mice (H); NREM sleep delta power during baseline (black line) and SF (dotted line) in WT mice (I) and hApoE4 mice (J); body temperature during baseline (black line) and SF (dotted line) in WT mice (K) and hApoE4 mice (L). Black line indicates SF period (1 PM to 7 PM). Shaded area represents dark period, 7 PM to 7 AM. *P < 0.05. Error bar represent mean SE. See text for more details.

Fig. 4.

Sleep wakefulness, EEG delta power, and body temperature (IH+SF). All graphs are plotted per 2 h for a 24-h period: percent time waking during baseline (black line) and IH+SF (dotted line) in WT mice (A) and hApoE4 mice (B); percent time in NREM sleep during baseline (black line) and IH+SF (dotted line) in WT mice (C) and hApoE4 mice (D); percent time in REM sleep during baseline (black line) and IH+SF (dotted line) in WT mice (E) and hApoE4 mice (F); number of wake episodes during baseline (black line) and IH+SF (dotted line) in WT mice (G) and hApoe4 mice (H); NREM sleep delta power during baseline (black line) and IH+SF (dotted line) in WT mice (I) and hApoE4 mice (J); body temperature during baseline (black line) and IH+SF (dotted line) in WT mice (K) and hApoE4 mice (L). Black line indicates IH+SF period (1 PM to 7 PM). Shaded area represents dark period, 7 PM to 7 AM. *P < 0.05. Error bar represent mean SE. See text for more details.

Fig. 5.

Changes in sleep following IH, SF, and IH+SF. All graphs are plotted as preintervention (6 h; 7 AM to1 PM), during intervention (6 h; 1 PM to 7 PM), and postintervention (12 h; 7 PM to 7 AM): percent time in wake in WT mice (open bar) and hApoE4 mice (filled bar) on IH (A), SF (B) and IH+SF (C); percent time in NREM sleep in WT mice (open bar) and hApoE4 mice (filled bar) on IH (D), SF (E), and IH+SF (F); percent time in REM sleep in WT mice (open bar) and hApoE4 mice (filled bar) on IH (G), SF (H), and IH+SF (I). *P < 0.05. Error bar represent mean SE.

Fig. 6.

Changes in delta power, body temperature, and wake episodes following IH, SF, and IH+SF. All graphs are plotted as preintervention (6 h; 7 AM to1 PM), during intervention (6 h; 1 PM to 7 PM), and postintervention (12 h; 7 PM to 7 AM): delta power during NREM sleep in WT mice (open bar) and hApoE4 mice (filled bar) on IH (A), SF (B), and IH+SF (C); changes in body temperature in WT mice (open bar) and hApoE4 mice (filled bar) on IH (D), SF (E), and IH+SF (F); number of wake episodes in WT mice (open bar) and hApoE4 mice (filled bar) on IH (G), SF (H) and IH+SF (I). *P < 0.05. Error bar represent mean SE.

Fig. 7.

Data shown are mean NREM sleep latency values (seconds) obtained using murine multiple sleep latency test. A: baseline NREM sleep latency in WT (black line) and hApoE4 mice (dotted line). B: NREM sleep latency in WT (black line) and hApoE4 mice (dotted line) during IH. C: NREM sleep latency in WT (black line) and hApoE4 mice (dotted line) during SF. D: NREM sleep latency in WT (black line) and hApoE4 mice (dotted line) during IH+SF. Note latency to NREM sleep is significantly reduced in hAPoE4 mice compared with WT. *P < 0.05. Error bar represent mean SE.