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Can long-term changes in the brain’s immune cells lead to nerve cell damage and Alzheimer’s disease?
Pinar Ayata, Ph.D.
Research Foundation of CUNY
New York, NY - United States
Background
Microglia are the primary immune cells in the brain, and they serve as a first defense against brain cell damage. Microglia sense and help remove unwanted proteins, including dementia-related beta-amyloid and tau, from the brain. They do this in part through a process called phagocytosis, during which the microglial cells engulf (or “swallow”) the proteins. Research, however, has shown that microglia become impaired in Alzheimer’s and may lose their ability to clear unwanted molecules properly.
While scientists do not know exactly how microglia become damaged in Alzheimer’s, recent studies indicate that the process may involve several long-term genetic and molecular mechanisms. These mechanisms include proteostasis (or the ability of brain cells to replace unwanted proteins with new ones), mitochondrial metabolism (or the ability of energy-generating compartments within cells to convert sugar into energy), and DNA methylation (a process by which genetic material, or DNA, turns genes “on” and “off” during different phases of the body’s development). According to initial research by Dr. Pinar Ayata and colleagues, these mechanisms may become altered early in life. Over time, they may lead to “distressed” microglia that promote inflammation and other Alzheimer’s brain changes.
Research Plan
For their study grant, Dr. Ayata and team will clarify how long-term mechanisms may interact to alter the structure and function of microglia, and the relationship between microglia and brain diseases. First, using microglial cells collected from the brains of young mice, the researchers will evaluate the effect of compounds that alter proteostasis (or reduce the production of new proteins). They will then assess whether reducing the production impacts the ability of mitochondria to convert sugar into energy. Next, they will identify whether there are changes in the chemical modification of DNA in microglia from altered proteostasis.
The researchers will then develop genetically-engineered Alzheimer’s-like mice that undergo long-term changes in proteostasis and metabolism. When the mice reach an older age, the study team will examine how these alterations may impact the ability of the microglia to prevent Alzheimer’s-like brain changes.
Impact
Dr. Ayata’s study could shed new light on the mechanisms underlying microglia’s role in brain disease. It could also lead to novel dementia therapies that target microglia at an earlier stage of disease.
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