Sleep Restoration, Microglia, and Alzheimer’s Disease

Detailed Non-Technical Summary

Our preliminary data and published work show sleep disruptions in APP mice at 8 months. In Aim 1, we will use chronic optogenetic treatment to increase slow-wave activity (SWA) and determine its effect on sleep restoration, AD pathophysiology, and memory function. In Aim 2, we will determine the effect of sleep restoration on disease-associated microglial response and microglial Aß clearance ability in APP mice. 

First, the concept of targeting sleep-dependent slow-wave activity (SWA) to slow Alzheimer’s disease is innovative. This work will provide an essential proof-of-concept for the role of GABAergic interneurons in Alzheimer’s disease (AD)-related sleep deficits. Additionally, we will uncover the responses of microglia using a multi-pronged design including morphological, functional, and genetic assessments. Second, a multitude of state-of-the-art methodological tools will be implemented, including optogenetics, multiphoton microscopy, flow cytometry, and sleep studies. If successful, this work will implicate interneurons and microglia in sleep-dependent circuit dysfunction underlying sleep and memory deficits Alzheimer’s patients exhibit. Thus, this work will potentially lead to a range of therapeutic strategies to be pursued in future studies, including therapeutic targeting of interneurons and their signaling mechanisms, microglia and neuroinflammation, as well as sleep-dependent brain rhythms.