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. 2025 Aug;110(8):1154-1163.
doi: 10.1113/EP092018. Epub 2025 May 19.

Chronic intermittent hypoxia-mediated cognitive dysfunction in ovariectomized rats

Emily C Cheung  1   2 , Joan B Escobar  1 , Bridget R Alber  2 , Caitlin Ribeiro  1 , Ishan Abdullah  1 , Grant Kowalik  2 , Jeannette Rodriguez  2 , Grey Harral  2 , Makeda Melkie  2 , Aman Gill  2 , John T Ketzenberger  2 , John Bethea  3 , Vsevolod Y Polotsky  4 , Vivek Jain  5 , Kathryn Schunke  6 , Matthew W Kay  2 , David Mendelowitz  1
Affiliations

Chronic intermittent hypoxia-mediated cognitive dysfunction in ovariectomized rats

Emily C Cheung et al. Exp Physiol. 2025 Aug.

Abstract

Obstructive sleep apnoea (OSA) is a prevalent cardiorespiratory disorder associated with significant neurocognitive consequences. Despite the higher prevalence of OSA in men, there is a strong association between OSA and Alzheimer's disease (AD), which disproportionately affects women. This study aimed to investigate the impact of chronic intermittent hypoxia (CIH), a hallmark of OSA, on cognitive function and AD markers in ovariectomized, female rats. At 8 weeks of age, 16 Sprague-Dawley rats underwent ovariectomy and were exposed to CIH for 26 weeks. Cognitive function was assessed using the Morris water maze, revealing significant deficits in spatial learning (P < 0.0001) and memory (P = 0.008) in CIH-exposed rats, compared to controls. Analysis of hippocampal tissue showed increased total tau protein (P = 0.0078), indicative of AD pathology. Additionally, CIH-exposed rats exhibited respiratory dysfunction characterized by increased frequency of apnoeas (P = 0.0328). These findings provide preclinical evidence of the association between OSA, cognitive decline and AD pathology in females, emphasizing the importance of sex-specific research in understanding and addressing these pathophysiological interconnections.

Keywords: Alzheimer's disease; Morris water maze; obstructive sleep apnoea; ovariectomy; plethysmography; respiration.

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Conflict of interest statement

None declared.

Figures

FIGURE 1
FIGURE 1
Animal preparation and timeline. At 8 weeks of age, female SD rats were ovariectomized. At 12 weeks, they switched diets from normal chow to high‐fat diet (26% fructose, 1.5% NaCl adj calories diet) and began daily exposures to either RA or CIH (cycled between room air (21% O2, 79% N2) and hypoxia (6% O2, 94% N2), for 8 h/day for 26 weeks). At 38 weeks, the animals underwent water maze training. Eight weeks later, they underwent a series of tests, including the water maze test, open field test and whole‐body plethysmography, prior to sacrifice and tissue collection. CIH, chronic intermittent hypoxia; RA, room air.
FIGURE 2
FIGURE 2
Water maze training. Mean time taken (latency ± SD) by the experimental animals to find the platform across 10 training trials. CIH and non‐CIH animals showed statistically significant differences in latency in Trials 2–7 with two levels of significance (RM ANOVA); n = 8 for each group. CIH, chronic intermittent hypoxia.
FIGURE 3
FIGURE 3
Water maze test. (a) Heat map representation of the time and trajectory of experimental animals while searching for a hidden platform in the MWM test. The quarter of the pool containing the hidden platform target quadrant is marked at the lower right corner of each figure. (b) Mean time taken (latency, ±SD) by the experimental animals to find the hidden platform. Differences in latency between CIH and non‐CIH animals were statistically significant (unpaired t‐test, P = 0.0008). (c) Mean distance to the platform (±SD) was statistically significant(t‐test, P = 0.0044). (d) Mean speed to the platform, calculated by dividing distance by latency; n = 8 for each group. CIH, chronic intermittent hypoxia; MWM, Morris water maze.
FIGURE 4
FIGURE 4
Open field test. (a) Heat map representation of the time and trajectory of experimental animals during the open field test. The zones defined as ‘edge’ and ‘centre’ are delimited by the inner red square. (b, c) Mean proportion of time and distance spent at the edge and centre of the open field experimental arena (±SD); n = 8 for each group.
FIGURE 5
FIGURE 5
Tau quantification and haematocrit. (a) Protein quantification of the hippocampus revealed that CIH‐exposed animals had higher protein levels of total tau (mean ± SD; CIH: 325.7 ± 95.12 pg/mL, non‐CIH: 206.1 ± 53.48 pg/mL, unpaired t‐test, P = 0.0078). (b) Blood samples revealed that exposure to CIH increased haematocrit (mean ± SD; CIH: 43.4 ± 2.302%, non‐CIH: 37.88 ± 2.588%, unpaired t‐test, P = 0.0047); n = 8 for each group. CIH, chronic intermittent hypoxia.
FIGURE 6
FIGURE 6
Long‐term CIH contributes to respiratory dysfunction. (a) Graphic representation (obtained from raw plethysmography data) of a single apnoeic event in an animal previously exposed to CIH. (b) Whole body plethysmography revealed that, compared to non‐CIH animals, CIH animals had increased apnoea frequency (mean ± SD; CIH: 81.50 ± 51.35, non‐CIH: 37.00 ± 13.75, unpaired t‐test: P = 0.0328); n = 8 for each group. CIH, chronic intermittent hypoxia.
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