Abstract
Evidence from patients and animal models suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD) and that AD is associated with reduced brain tissue stiffness. To investigate whether intermittent hypoxia (IH) alters brain cortex tissue stiffness in AD mutant mice exposed to IH mimicking OSA. Six-eight month old (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) AD mutant mice and wild-type (WT) littermates were subjected to IH (21% O2 40 s to 5% O2 20 s; 6 h/day) or normoxia for 8 weeks. After euthanasia, the stiffness (E) of 200-μm brain cortex slices was measured by atomic force microscopy. Two-way ANOVA indicated significant cortical softening and weight increase in AD mice compared to WT littermates, but no significant effects of IH on cortical stiffness and weight were detected. In addition, reduced myelin was apparent in AD (vs. WT), but no significant differences emerged in the cortex extracellular matrix components laminin and glycosaminoglycans when comparing baseline AD and WT mice. AD mutant mice exhibit reduced brain tissue stiffness following both normoxia and IH mimicking sleep apnea, and such differences are commensurate with increased edema and demyelination in AD.
Highlights
Chronic intermittent hypoxia (IH), sleep fragmentation, and increased intrathoracic negative pressure swings are hallmark deleterious perturbations experienced by patients with obstructive sleep apnea (OSA)
No significant differences were observed in total brain weights for each factor (IH vs. normoxia; degrees of freedom (DF) = 1, F = 2.654, p = 0.111 and WT vs. Alzheimer’s disease model mice (ADm); DF = 1, F = 0.0992, p = 0.754)
Cortex weight was significantly higher in ADm (98.3 ± 2.5 and 93.1 ± 2.5 mg in room air (RA) and IH, respectively) when compared with WT (91.6 ± 1.9 and 89.6 ± 1.6 mg in RA and IH, respectively) mice (DF = 1, F = 6.042, p = 0.019)
Summary
Chronic intermittent hypoxia (IH), sleep fragmentation, and increased intrathoracic negative pressure swings are hallmark deleterious perturbations experienced by patients with obstructive sleep apnea (OSA). It has been proposed that the association between OSA and AD stems from the fact that both oxidative stress and inflammation are induced by OSA and enhance AD-related pathways [12,13,14,15,16,17,18] The existence of such an OSA-AD interdependence is supported by experimental data reporting that chronic IH boosts the expression of AD biomarkers and has negative neurocognitive impact in rodents [19], and by epidemiological studies showing a robust association between AD and OSA in humans [20, 21]. Evidence from patients and animal models suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer’s disease (AD) and that AD is associated with reduced brain tissue stiffness.
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