Study objectives

The clinical importance of obstructive sleep apnea, which can be prevalent during rapid eye movement (REM) sleep, is unclear. The current study examines the effect of REM-related obstructive sleep apnea on motor memory consolidation as well as on mood states.

Methods

We compared performance on the motor sequence task (MST), psychomotor vigilance test (PVT), Functional Outcomes of Sleep Questionnaire, and the Profile of Mood State (POMS) survey between 3 groups: healthy controls (n = 18), REM-exclusive OSA (n = 17), and patients with OSA with respiratory events throughout REM and non-rapid eye movement (NREM) sleep (n = 18).

Results

As expected, performance on the MST improved overnight in the healthy control group. An improvement which was similar in magnitude was also observed in the REM-exclusive OSA group whereas patients with similar OSA during REM and NREM sleep showed reduced overnight memory consolidation. Consistent with these results, we found a correlation between overnight MST improvement and the apnea hypopnea index during NREM sleep (P = .041), but not during REM sleep (P = .424). However, patients with REM-exclusive apnea demonstrated the most negative emotions based on scoring highest on the POMS survey (P = .019).

Conclusions

Our results provide evidence that although apneas occurring only during REM sleep do not have an effect on the encoding and stabilization of motor sequence memories, they are deleterious for emotional health.

Rationale: A growing body of evidence suggests that sleep is critical for the adaptive processing and consolidation of emotional information into long-term memory. Previous research has indicated that emotional components of scenes particularly benefit from sleep in healthy groups, yet sleep-dependent emotional memory processes remain unexplored in clinical cohorts, including those with obstructive sleep apnea (OSA). This line of research is important as it will add to the understanding of how disrupted sleep in OSA contributes to both impaired cognition and emotion dysregulation. Objectives: To test the hypothesis that individuals with OSA will have impaired sleep-dependent memory consolidation, with the greatest impact being on memory for emotional content. Methods: In this study, a group of newly diagnosed patients with OSA (n = 26; 10 female; average age, 42.5 years) and a matched group of healthy control subjects (n = 24; 13 female; average age, 37 years) were enrolled in the study at Beth Israel Deaconess Medical Center. Participants encoded scenes with negative or neutral foreground objects placed on neutral backgrounds before a night of polysomnographically recorded sleep. In the morning, they completed a recognition test in which old and new scene objects and backgrounds, presented separately and one at a time, were judged as old, new, or similar compared with what had been previously viewed. Results: Patients with OSA had a deficit in recognition memory for the scenes. Overall recognition (the ability to recognize old items as either old or similar) was impaired across all scene elements, both negative and neutral objects and backgrounds, whereas specific recognition (correctly identifying old items as old) was impaired only for negative objects. Across all participants, successful overall recognition correlated positively with sleep efficiency and rapid eye movement (REM) sleep, whereas successful specific memory recognition correlated only with REM sleep. Conclusions: Our findings indicate that fragmented sleep and reduced REM sleep, both hallmarks of OSA, are associated with disruptions in general memory impairment and veridical memory for emotional content, which could alter emotional regulation and contribute to comorbid emotional distress in OSA.

Background

Amyloid precursor protein (APP) is enzymatically cleaved by gamma-secretase to form two peptide products, either Abeta40 or the more neurotoxic Abeta42. The Abeta42/40 ratio is increased in many cases of familial Alzheimer's disease (FAD). The transmembrane domain (TM) of APP contains the known dimerization motif GXXXA. We have investigated the dimerization of both wild type and FAD mutant APP transmembrane domains.

Results

Using synthetic peptides derived from the APP-TM domain, we show that this segment is capable of forming stable transmembrane dimers. A model of a dimeric APP-TM domain reveals a putative dimerization interface, and interestingly, majority of FAD mutations in APP are localized to this interface region. We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.

Conclusion

The dissociation constants are correlated to both the Abeta42/Abeta40 ratio and the mean age of disease onset in AD patients. We also show that these TM-peptides reduce Abeta production and Abeta42/Abeta40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma-secretase components, potentially revealing a new class of gamma-secretase inhibitors.