We propose that sleep disturbances of Alzheimer's disease (AD) result from a reduction in the delivery of energy substrates from astrocytes to neurons. In particular, the focus of this project is the reduction in Slow Wave Activity (SWA) in non-rapid eye movement (NREM) sleep that is present in patients with AD (Lucey et al. 2019). Since the power of SWA is proportional to the drive or pressure to sleep, reduced SWA will result in fragmented and poor-quality sleep. Understanding what causes this reduced SWA will provide key insights into early disturbances in patients with AD. In our preliminary studies we have identified that a mouse model of AD displays this characteristic reduction in SWA and we hypothesize that hypo-glucose metabolism in AD leads to reduced supply of lactate from astrocytes to neurons which in turn causes a reduction in pyramidal neuron excitability and consequently to reduced power of SWA in NREM sleep. Our previous studies have shown that astrocyte-derived lactate, supplied by glial glycolysis, is shuttled to neurons where it is converted to pyruvate as an energy substrate. If lactate supply is depleted, via deletion of astrocytic connexin 43, and consequently neuronal pyruvate is decreased, a neuronal KATP channel is activated, hyperpolarizing and silencing neurons (Clasadonte et al. 2017): in the lateral hypothalamus this results in quiescence of orexinergic neurons that require activity to drive sustained wakefulness, and in the cortex reduced pyramidal neuron activity leads to a decrease in the power of SWA in NREM sleep (Figure 3). Since it is known that there is hypo-metabolism of glucose in AD we therefore propose that this leads to a reduced supply of astrocyte-derived lactate and impairment of neighboring neurons that rely on this energy substrate. In this R21 project we will bring together the tools for the study of the astrocyte-neuron lactate shuttle (ANLS) with expertise in studying Alzheimer's disease and sleep to test the hypothesis that a reduction in ANLS leads to reduced power of SWA in NREM sleep, a phenotype of patients with AD. We will test the following hypotheses:
Aim I : Alzheimer's mouse models show reduced power of SWA in NREM sleep.
Aim II : We will test the hypothesis that changes in extracellular lactate are diminished in AD mice during sleep/wake transitions.
Aim III : Deletion of monocarboxylate transporters reduces lactate transport and AD sleep/wake related phenotypes? We are submitting this project as an R21 since it represents a new area of study and though we demonstrate the feasibility of all approaches, we need to integrate several different experimental strategies to begin to test the hypothesis. Success in this project would then provide the preliminary data for subsequent RO1 applications studying the control of sleep in Alzheimer's disease.
We will determine whether sleep disturbances of Alzheimer's disease (AD) result from a reduction in the delivery of energy substrates from astrocytes to neurons. In this R21 project we will bring together the tools for the study of the astrocyte-neuron lactate shuttle (ANLS) with expertise in studying Alzheimer's disease and sleep to test the hypothesis that a reduction in ANLS leads to reduced power of SWA in NREM sleep, a phenotype of patients with AD.
