2024 Alzheimer's Association Research Fellowship (AARF)
Dichotomy of Microglial C1q in the progression of Alzheimer’s Disease
How does an immune protein impact the progression of biological brain changes associated with Alzheimer’s?
Tiffany Petrisko, Ph.D.
University of California, Irvine
Irvine, CA - United States
Background
The immune system is complex and serves to maintain our overall health. Microglia are the primary immune cells of the brain, and they help to promote healthy nerve cells. Individuals with Alzheimer’s typically experience brain inflammation caused by dysregulation of the immune system, including increased activity of microglia, which can damage nearby nerve cells. Recent studies have shown that overly active microglia tend to gather in areas of the brain susceptible to other dementia-related brain changes, such as beta-amyloid plaques and tau tangles, two hallmark brain changes associated with Alzheimer’s.
The complement system is part of the immune system and is made of proteins that clear waste and promote inflammatory responses to help fight infection. Using genetically engineered Alzheimer’s-like mice, Dr. Tiffany Petrisko and colleagues found that activation of the complement system, and subsequent inflammation, may contribute to brain changes associated with cognitive impairment in Alzheimer’s. The team also found that a specific complement protein, called C1q, may decrease inflammation and protect nerve cells from damage associated with beta-amyloid accumulation. Dr. Petrisko and colleagues believe that C1q may play a protective role early in Alzheimer’s by enhancing the clearance of waste or impacting how beta-amyloid plaques interact with microglia.
Research Plan
In genetically engineered Alzheimer’s-like mice, the researchers will decrease C1q levels either early in life (before the accumulation of beta-amyloid plaques) or later in life (after beta-amyloid plaques have formed) and then conduct behavioral and memory tests. Next, the team will study which genes associated with inflammation are activated in Alzheimer’s-like mice and cognitively unimpaired mice after C1q removal early in life or later in life. Finally, Dr. Petrisko and colleagues will use powerful microscopes to study the impacts of removing C1q on beta-amyloid accumulation, microglia and other brain cells, and other biological brain changes associated with Alzheimer’s.
Impact
The findings may shed light on the role of specific immune proteins in the development and progression of Alzheimer’s. If successful, the results of this study may suggest potential novel therapies targeting inflammation and the immune system.