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Could a new laboratory model expose molecular pathways that contribute to tau tangles in Alzheimer’s?
Sarah Kaufman, M.D., Ph.D.
The Regents of the University of California, San Francisco
San Francisco, CA - United States
Background
Tau is a protein that helps maintain the structure of brain cells. In Alzheimer’s and other brain diseases called tauopathies, 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 challenge in studying tauopathies is a lack of appropriate laboratory models – particularly models that can accurately produce the kinds of tau proteins seen in human diseases. Dr. Sarah Kaufman and colleagues have developed a new model using a specialized type of stem cell collected from adult human tissue called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the human body and grown in laboratory dishes, including nerve cells. Dr. Kaufman’s team has reprogrammed these cells to make tau proteins originally derived from people with tauopathies. These cells are able to make longer tau proteins than those found in other models. The tau proteins are also labeled with a fluorescent dye so they are readily visible under specialized microscopes.
Research Plan
In the current study, Dr. Kaufman’s team will test whether blocking a certain molecular pathway inside their model cells might help reduce tau production. This pathway, which the researchers previously identified as related to tau production, could represent a new therapeutic target in tauopathies. The researchers will use genetic techniques to block each part of the pathway individually inside the cells, and then measure the health of the cells. This will help Dr. Kaufman determine exactly which portion(s) of the pathway might be most relevant to tau production.
In a second part of the study, Dr. Kaufman’s team will study two different kinds of cells developed using their new model. These cells will make tau originally derived from people who had one of two tauopathies: either progressive supranuclear palsy, or Alzheimer’s. The researchers will compare the levels of genes inside each of the cells. Their goal is to understand differences in the molecular pathways that underlie how tau is produced in different tauopathies. Finally, Dr. Kaufman will study the same pathways in brain tissue samples donated by people who had tauopathies, to help validate their findings.
Impact
This study offers an opportunity to test a new experimental model of Alzheimer’s. The model could be used by other researchers interested in studying how different tauopathies develop, and how these diseases might be prevented. Results from this study might also identify new molecular targets for drugs designed to delay or slow disease progression.
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