The Relationship Between Sleep and Alzheimer’s Disease Progression

We will study how Alzheimer’s disease affects sleep quality, and whether improving sleep quality using cortical stimulation can mitigate disease progression in an Alzheimer’s disease mouse model. In Aim 1, we will investigate how sleep quality differs between normal and Alzheimer’s disease model mice. We will visualize the neural circuit activity during high- and low-quality sleep using advanced microscopy. In Aim 2, we will modify the sleep quality using a technique that has been used in the field of learning and memory. We will optogenetically stimulate a small portion of the cerebral cortex at the frequency of slow wave sleep, and examine how it influences amyloid beta (Aß) accumulation, which is tightly linked with Alzheimer’s disease progression.

Alzheimer’s disease (AD) is the most prevalent type of dementia, for which there is no effective treatment. Sleep disturbance is both an early symptom of AD in the prodromal phase, and one of the factors that exacerbates AD. Thus, detecting sleep disturbance and correcting it at an early phase of AD could be an effective treatment approach for delaying or even preventing the onset of cognitive decline. Toward this goal, it is necessary to obtain a mechanistic understanding of the relationship between sleep and AD progression. In this proposal, we will approach this question by studying the interactions between these two factors at the level of cortical circuits in an AD mouse model.

First, our approach of using longitudinal in vivo two-photon imaging of the neural circuits and Aß plaque formation provides a unique opportunity to identify the precise relationship between sleep disturbance and Aß deposition at the level of cortical circuits. Second, our optogenetic stimulation approach will clarify how to manipulate specific types of cells in the cortex to restore sleep quality. Together, these novel approaches will link the effects of brain modulation during sleep to specific components of the neural circuits.

Successful completion of the project will lead to improved strategies to restore sleep quality during the early phases of Alzheimer’s disease. Potentially, these approaches could also prevent or delay the progression of cognitive decline, providing a much-needed treatment option for Alzheimer’s disease patients.