2017 Alzheimer's Association Research Grant (AARG)

Discovery of novel mechanisms by which sleep modulates Aß toxicity

Are there genes that mediate the relationships between sleep and beta-amyloid formation in the brain?

Ravi Allada, M.D.
Northwestern University - Evanston Campus
Evanston, IL - United States

Background

Beta-amyloid (also known as ABeta) is a protein fragment that is toxic to nerve cells and is thought to be important in the development and progression of Alzheimer’s disease. Several lines of evidence suggest that there is a strong relationship between beta-amyloid levels in the brain and sleep. Loss of sleep or sleep disruption increase levels of beta-amyloid in the brain. Furthermore, a high percentage of people with Alzheimer’s disease experience serious disruptions in their sleep cycles. Consistent with this effect in humans, animals experience disruptions in sleep and sleep rhythms when beta-amyloid levels are increased in their brains.

Research Plan

Ravi Allada, M.D., and colleagues have been studying the relationships between beta-amyloid and sleep using an advanced genetic model system. This model system, a fruit fly, has been used successfully in the past to identify specific genes responsible for numerous diseases, including brain diseases. Dr. Allada and colleagues have proposed to use this fruit fly model to identify the genes that mediate the relationships between beta-amyloid and sleep.

Dr. Allada’s team plans to study how sleep deprivation leads to increases in beta-amyloid levels and toxicity in the brain. A key goal of this research is to identify the genes affected by sleep deprivation and that lead to increased beta-amyloid levels, or that mediate the toxic effects of beta-amyloid caused by sleep deprivation. The researchers will also study molecular pathways that improve sleep to determine if activation of those pathways can reduce or eliminate beta-amyloid toxicity in the brain.

Impact

This research will improve our understanding of how impaired sleep increases the risk of Alzheimer’s disease, as well as identify some possible molecular mechanisms involved in this process. By identifying the genes involved in this relationship, the researchers may begin to develop ways to improve sleep or to reduce the toxicity of beta-amyloid that occurs when sleep is impaired.