0085 Peripheral glucose metabolism bidirectionally modulates sleep in a model of Alzheimer's disease

Abstract Introduction Metabolic impairments and sleep disruptions are both recognized as modifiable risk factors in the development of Alzheimer’s disease (AD). A bidirectional relationship exists between sleep and AD where pathology can disrupt sleep, but sleep disturbances can also increase AD-related pathology. This results in a feed-forward cycle of disease progression and further sleep impairments. Sleep fragmentation and poor sleep quality can also cause glucose intolerance and insulin resistance. However, it remains unclear if peripheral metabolic dysfunction alone can impair sleep, particularly in the context of AD-related pathology. Therefore, the goal of this study was to establish mechanisms connecting peripheral metabolic and sleep disruptions and identify potential therapeutic targets for mitigating AD risk. Methods We implanted biosensors measuring interstitial fluid (ISF) levels of glucose and lactate, biomarkers of cerebral metabolism and neuronal activity, respectively, directly into the hippocampus of wildtype and APP/PS1 mice, a model of amyloid-beta (Aβ) overexpression. Biosensors were paired with cortical EEG and EMG recordings for simultaneous sleep/wake analysis. To understand the relationship between metabolic dysfunction and sleep, we altered the peripheral metabolic environment using two paradigms: an acute high-fat, high-sugar diet (HF/HSD) and a pharmacological metabolic rescue. Results We found short-term HF/HSD exposure was sufficient to disrupt ISF glucose and lactate diurnal rhythms, independent of changes to pathology burden. Moreover, we found significant sleep disruptions, particularly decreased delta power, indicating slow wave sleep impairments. These findings were exacerbated in mice with Aβ pathology who have disrupted metabolic and sleep functioning at baseline. Conversely, we found normalizing peripheral glucose tolerance in mice with Aβ pathology was sufficient to rescue impaired ISF glucose and lactate rhythms. We also saw a restoration of normal sleep-wake patterns, specifically within slow wave activity. Conclusion We found modulating peripheral glucose metabolism can bidirectionally alter sleep, particularly slow wave sleep, independent of changes in Aβ burden. This indicates sleep as a mediator in the relationship between metabolic impairments and AD pathophysiology. While impaired sleep increases AD risk, improved sleep slows pathology accumulation. Therefore, this study demonstrates targeting peripheral glucose regulation is a potential avenue for early AD intervention and risk mitigation. Support (if any) F31-AG066302, R01-AG068330, P30-AG072947