Can an abnormal form of tau in early Alzheimer’s disease be a target for a novel treatment?
Todd Cohen, Ph.D.
University of North Carolina at Chapel Hill
Chapel Hill, NC - United States
The brain cell’s nutrient and energy transport system is organized in parallel strands like railroad tracks. These tracks allow nutrients to travel across the cell, delivering key materials to the cells, providing them with energy and keeping them healthy. The tau protein normally helps keep the tracks straight. However, 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. One modification that can lead to the misfolding of tau is the addition of a phosphate molecule to specific parts of the tau protein in a process called phosphorylation. In Alzheimer’s and other brain diseases, when the tau protein becomes excessively phosphorylated it clumps together to form tangles.
More recently, it has been reported that tau can also be modified by a process known as acetylation. Abnormal tau acetylation may occur early in Alzheimer’s and it may also contribute to other Alzheimer’s-related brain changes. In initial studies, Dr. Todd J. Cohen and colleagues identified monoclonal antibodies ( molecules the immune system uses to recognize specific molecules and mark them for clearance) that can bind and mark acetylated tau for detection in brain cells grown in laboratory dishes, in the brains of individuals who died of Alzheimer’s, and in the brains of engineered Alzheimer’s-like mice.
To continue on this initial work, Dr. Cohen and team will work to determine whether their candidate monoclonal antibodies can be used as a therapy to block acetylated tau production. Using brain cells grown in a laboratory dish, they will study how well the antibodies can enter into the cells and bind to acetylated tau. Then, they will inject candidate monoclonal antibodies that will bind to acetylated tau into the brains of genetically engineered Alzheimer’s-like mice that develop abnormal tau. The researchers will then study the antibodies’ ability to prevent the disease-related brain changes, including the buildup of acetylated tau and subsequent development of tau tangles.
Results from this project may shed new light on the role of acetylated tau in early Alzheimer’s disease. They may also identify novel potential paths to develop these antibodies for treatment of dementia.
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