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Can damage to the brain’s waste-clearing system lead to buildup of Alzheimer’s related brain changes?
Molly Braun, Ph.D.
University of Washington
Seattle, WA - United States
Background
Alzheimer’s is associated with hallmark brain changes including the accumulation of the proteins beta-amyloid and tau into abnormal plaques and tangles, respectively. While scientists do not know exactly why the plaque accumulation occurs, one factor may be through impairments in the brain’s waste removal system, known as the glymphatic system.
According to recent studies, genetically engineered Alzheimer’s-like mice, which accumulate beta-amyloid plaques, experience reduced glymphatic system activity. These mice also have abnormal levels of immune cells called neutrophils around the beta-amyloid plaques. Neutrophils normally help heal damaged brain tissue and fight infections by releasing substances called neutrophil extracellular traps (NETs). However, abnormal neutrophil activity may prevent the glymphatic system from clearing unwanted substances from the brain, such as beta-amyloid.
Research Plan
Dr. Molly Braun and colleagues will study how NETs produced from neutrophils may lead to increases in beta-amyloid plaques and cognitive decline in Alzheimer’s-like mice. To do this, they will test whether a specialized protein called deoxyribonuclease I (DNase I) can decrease NET levels in the mice. They will then use brain scans to see how decreasing NET levels using DNaseI may improve the glymphatic system function.
In a related experiment, they will use genetically engineered Alzheimer’s-like mice that lack a gene required for neutrophils to create NETs. This will help show whether genetically removing NETs can improve the glymphatic system function. Lastly, Dr. Braun and colleagues will assess whether reducing NET function can reduce beta-amyloid levels in the mice and improve their cognitive functions.
Impact
This project could help clarify the role of the glymphatic system in Alzheimer’s disease and has the potential to identify NETs as a novel target for future Alzheimer’s therapies.
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