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How may dementia-related tau protein stop immune cells from clearing unwanted molecules from the brain?
Alejandro Avila, Ph.D.
New York University School of Medicine
New York, NY - United States
Background
Microglia are the primary immune cells in the brain that serve as one of the first defenses against nerve cell damage. Microglia sense and help remove unwanted proteins from the brain, in part through a process called phagocytosis, during which the microglial cells engulf (or “swallow”) the unwanted proteins.
Research has shown that microglia become impaired in Alzheimer’s and may lose their ability to clear unwanted molecules and proteins properly. In initial studies with genetically-engineered Alzheimer’s-like mice, Dr. Alejandro Avila and colleagues found that the structure of microglia may become altered and impaired when exposed to dementia-related tau protein. In Alzheimer’s and other brain diseases, the shape of tau protein becomes modified or “misfolded,” a change that may contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. These structural changes to tau may hinder the microglia’s ability to clear tau.
Research Plan
Dr. Avila and colleagues will investigate how changes to the structure of the microglia are linked to the tau protein and increased dementia risk. They will use genetically engineered Alzheimer’s-like mice that develop high levels of modified tau in the brain; the researchers will look for changes in the microglia structure that may prevent them from removing unwanted proteins. They will also determine if the microglia turn “on” (or express) a gene that is linked to cellular aging which has been previously linked with abnormal tau build-up. The researchers will then determine how blocking tau build-up through use of specialized tau antibodies (molecules the immune system uses to recognize specific disease-causing molecules and mark them for clearance) can impact the activity of microglia in the mice.
Impact
This project could shed new light on the role of microglia in Alzheimer’s and other brain disorders linked to abnormal tau. They could also lead to new opportunities to develop therapies aimed at the microglia activity for brain diseases.
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