Interactions between metabolism and sleep in Alzheimer's disease pathogenesis - PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease is the most common form of dementia, affecting over 45 million people worldwide and
costing over $800 billion in medical care. It is characterized by the accumulation of extracellular amyloid-beta
(Aβ) plaques and intracellular neurofibrillary tau tangles, which occur 5 to 15 years before symptom onset.
Metabolic perturbation and sleep disturbance are key features of Alzheimer’s disease, where they represent both
cause and consequence of disease pathophysiology. A bidirectional relationship exists between the two where
impaired sleep and metabolism individually contribute to Alzheimer’s disease development while the presence
of pathology leads to decreased cerebral metabolism, peripheral glucose intolerance, and disrupted sleep.
Further, individuals with type-2-diabetes (T2D) have a 2-4-fold increased risk of developing Alzheimer’s disease,
suggesting an underlying common mechanism. Chronic hyperglycemia, a defining characteristic of T2D, leads
to increased neuronal activity and Aβ levels within the hippocampus, an effect exacerbated by the presence of
Aβ pathology, indicating a relationship between peripheral metabolism, neuronal activity, and Aβ production that
is compromised by plaque pathology. These metrics all have diurnal rhythms maintained by the sleep/wake
cycle; therefore, acute changes in peripheral blood glucose levels, or glycemic variability, may be sufficient to
drive sleep disruptions and further peripheral metabolic dysfunction by modifying the relationship between
cerebral glucose metabolism and neuronal activity. The purpose of the training grant is to determine how acute
glycemic variability, common in both the development and treatment of T2D, synergizes with Alzheimer’s disease
pathology to affect cerebral metabolism, neuronal activity, and sleep/wake cycles. We will directly evaluate the
impact of peripheral glycemic challenges using biosensors implanted into the hippocampus of mice measuring
changes in interstitial fluid (ISF) glucose and lactate levels, measures of cerebral metabolism and neuronal
activity, respectively. We will determine the impact of glycemic variability on sleep/wake cycles through
simultaneous EEG/EMG recordings, evaluating both the total duration in each state as well as sleep
fragmentation. Finally, we will characterize baseline peripheral metabolism of the genetic model mice and
determine the effect of sleep deprivation and sleep rescue on peripheral glucose tolerance. Together, this
proposal will establish glycemic variability as mechanism driving decreased sleep, increased cerebral
metabolism and neuronal activity, and further peripheral glucose intolerance, all of which are well established
risk-factors in the development of Alzheimer’s disease. Defining these relationships will offer a more efficacious
approach to targeting the interactions between T2D and Alzheimer’s disease.
