Sleep Restoration, Microglia, and Alzheimer’s Disease
MentorStephen Gomperts, MD, PhD Massachusetts General Hospital
Using state-of-the-art laboratory technologies, we will develop effective strategies to restore sleep and assess its effect on memory function and pathological progression of Alzheimer’s disease (AD).
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.