2023 Alzheimer's Association Research Grant (AARG)
Longitudinal prefrontal imaging of Aß accumulation and attention coding
How does the build-up of toxic proteins in the brain contribute to thinking and memory problems in Alzheimer’s?
Timothy Spellman, Ph.D.
University of Connecticut Health Center
Farmington, CT - United States
Background
Alzheimer’s is characterized by beta-amyloid, a toxic protein that forms clump-like “plaques” in the brain. Beta-amyloid plaques are believed to contribute to the difficulties with thinking and memory that are a central part of Alzheimer’s. However, brain scanning studies have found that some individuals with impaired thinking and memory and altered patterns of brain activity do not necessarily have beta-amyloid plaques in their brains. This suggests that disruptions to nerve cell activity may precede, rather than follow, the development of beta-amyloid plaques.
Research Plan
Dr. Timothy Spellman will work to understand the complex connection between beta-amyloid build-up, nerve cell disruption, and problems with thinking and memory. They will study how these different features progress over time using genetically-engineered Alzheimer’s-like mice that develop expedited and severe characteristics of the disease. Dr. Spellman will use brain scan techniques that allow monitoring of the brain and behavior of the same mouse at multiple time points.
The project will focus on the prefrontal cortex (PFC), which is one of the earliest brain regions to show elevations of beta-amyloid. Individual nerve cells in the PFC will be monitored using multiple imaging methods while the mice are engaged in a task that requires them to shift their attention from one stimulus to another. The study will measure PFC nerve cell activity patterns and nearby beta-amyloid build-up, while mice are performing the attention task. These data will be able to determine whether altered brain cell activity precedes or follows beta-amyloid build-up and whether certain kinds of PFC nerve cells are more susceptible to build-up than others. Further, this will help determine if the beta-amyloid build-up is related to impairments in attention task performance.
Next, the team will work to understand if normalizing nerve cell activity patterns may potentially halt the build-up. Dr. Spellman believes overactivity in certain kinds of nerve cells accelerates beta-amyloid build-up. To test this, the team will use a chemical that can raise or lower the activity of individual nerve cells on-demand. They will perform weekly imaging of beta-amyloid to see if this activity change has an effect on beta-amyloid build-up.
Impact
This research addresses the relationship between nerve cell activity and beta-amyloid build-up. The results could help explain the spread of beta-amyloid in the brain, and identify new therapeutic targets for Alzheimer’s.