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2023 Tau Pipeline Enabling Program (T-PEP)

Enhancing Retromer Function: A Novel Therapeutic Strategy for Tauopathies

Can strengthening a protein complex that helps clear unwanted proteins from the brain help treat tau-related brain disease?

Gregory Petsko, Ph.D.
Harvard Medical School and Brigham and Women's Hospital, Inc.
Boston, MA - 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. 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 lead to abnormal tau accumulation, the development of tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. Brain diseases believed to result from abnormal changes of the tau protein are collectively referred to as “tauopathies.”

According to recent studies, tauopathies may result, in part, from damage to the endolysosomal system. The endolysosomal system is a complex system responsible for sorting and breaking down unwanted materials in cells, including clearing abnormal tau from the brain. When problems in this system arise, they often do so because a group of proteins called the retromer can become impaired. The retromer is responsible for helping sort and move proteins throughout the cell to their correct destination. The endolysosomal system determines which substances are broken down and removed from the brain. When the retromer becomes impaired, however, the brain may lose its ability to dispose of unwanted proteins efficiently, which can lead to the accumulation of abnormal tau and other disease-related molecules. 

Dr. Gregory A. Petsko and colleagues have been exploring methods of improving the activity of the retromer and preventing tau build-up in the brain. In one method, they engineered mice to have a weakened retromer but also overexpress a gene which codes for a key protein in the retromer complex. They found that this strengthened retromer function in the animals and cleared disease-related proteins in their brains. Dr. Petsko’s team also identified a drug compound that could strengthen the retromer and prevent tau accumulation in brain cells from genetically engineered Alzheimer’s-like animals and, hopefully, from individuals who had Alzheimer’s. 

Research Plan

The investigators will now refine and further assess their genetic and drug techniques for strengthening the retromer and preventing tauopathies. First, they will test the gene therapy method on mice genetically engineered to develop abnormal tau. This effort will involve selecting the most effective adeno-associated viral (AAV) vectors, which are platforms that can safely deliver the gene into the animals’ brains. Next, they will identify and test drug compounds that can restore retromer function and clear tau tangles in cells grown in a laboratory dish and in living mice engineered to develop tauopathies.       


Results from this project could refine our understanding of how the retromer becomes damaged in brain disease, and how such damage impacts the accumulation of disease-related proteins. They could also identify, and possibly validate, potential therapeutic strategies for preventing or treating retromer damage and restoring brain health – strategies that could be tested in future human clinical trials.

The Tau Pipeline Enabling Program (T-PEP) is jointly funded by the Alzheimer's Association and Rainwater Charitable Foundation.

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