A bidirectional relationship exists between Alzheimer?s disease and sleep, where disrupted sleep increases amyloid-beta (A?) and tau pathology and conversely, A? and tau aggregation disrupt sleep. The sleep/wake cycle is a master regulator of metabolic and neuronal activity, where daily oscillations in activity are coupled to the production and clearance of A? and tau. Although modulating neuronal activity alters both sleep/wake cycles and A?/tau release, less is known about how fluctuations in glucose metabolism drive changes in sleep and Alzheimer?s disease related pathology. Therefore, the goal of this proposal is to determine whether changes in metabolic activity lead to changes in neuronal activity to disrupt sleep in Alzheimer?s disease and whether metabolic dysfunction can serve as a novel therapeutic target to rescue sleep and Alzheimer?s pathology. Using hippocampal biosensors coupled with EEG/EMG recordings, this proposal will investigate how glycemic variability and peripheral glucose intolerance affect sleep and Alzheimer?s disease in rodent models of Alzheimer?s related pathology. Moreover, we will establish whether normalizing peripheral glucose homeostasis through treatment with the diabetic medication, metformin, is sufficient to preserve and restore sleep architecture in the setting of Alzheimer?s disease.
Alzheimer?s disease is the 6th leading cause of death in the United States and is expect to triple by 2050. Individuals with Alzheimer?s disease suffer from sleep disturbances and sleep disorders are associated with an increased risk for Alzheimer?s disease. Since sleep/wake cycles are a dynamic interplay between metabolism and neuronal activity, the goal of this project is to understand how changes in metabolism impact the relationship between sleep and Alzheimer?s disease and whether metabolic dysfunction is a novel therapeutic target for treating Alzheimer?s disease and sleep.