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