Investigating the impacts of pharmacological slow-wave sleep enhancement on cognition in an alzheimer's disease model

Abstract Introduction Alzheimer’s disease (AD) is a debilitating and irreversible neurodegenerative disease associated with major disruptions to sleep. Recent works point to a strong bidirectional relationship between loss of slow-wave sleep (SWS), the deepest sleep stage, and the pathological and cognitive features of AD. Here, we investigate the impacts of chronic pharmacological SWS enhancement with gaboxadol, a delta GABAA receptor agonist, on cognitive performance the APP/PS1 mouse model of AD. Currently, we are assessing the impacts of this intervention on Abeta plaque burden. Methods Using electroencephalography (EEG), we first assessed if gaboxadol is capable of stimulating SWS sleep in 6-month-old AD mice. Next, 6-month-old control (CTRL) or AD mice received gaboxadol 5x/week for 4 weeks at the start of the light cycle. Groups underwent subsequent testing in the open field (OF), Y-maze, and contextual fear conditioning (CFC) assays (n = 8-9 mice per group). Data were analyzed using two- or three-way ANOVAs, with repeated measures when appropriate. Results Our EEG studies demonstrate that gaboxadol (6 mg/kg) significantly enhances SWS/NREM from baseline (p < 0.0308). Gaboxadol did not impact gross locomotor behavior assessed by distance travelled in the in the OF. However, rearing was decreased in AD mice compared to CTRL mice (p < 0.0128). In the Y-maze, gaboxadol significantly increased time spent in the novel arm in CTRL (p < 0.0386) but not AD mice. We did not find significant effects of gaboxadol on memory recall in the CFC assay. Conclusion Chronic pharmacological stimulation of SWS using gaboxadol does not show robust cognition-enhancing effects in APP/PS1 mice, but may be cognitively enhancing in CTRL mice. It is possible that longer treatment duration is necessary to rescue cognitive deficits in AD mice. Support (if any) NIA: 5R21AG064774-02 T32 GM7367-46