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Could cell waste clearance mechanisms help prevent the movement of abnormal tau in brain diseases, like Alzheimer’s?
Annika Deckert, Ph.D.
Max-Delbrück-Center for Molecular Medicine
Berlin, Germany
Background
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 helps keep these tracks straight. However, in Alzheimer’s and other brain diseases like frontotemporal dementia and Pick’s disease and over 20 other brain diseases the shape of tau protein becomes modified or “misfolded” and this could contribute to tau tangles (a hallmark brain change that occurs in these diseases) and subsequent nerve cell damage.
Studies suggest that movement of tau from one nerve cell to another may contribute to the formation, transportation and clumping of tau into tangles. This process may inform how tau tangles move across brain regions in these brain diseases. Dr. Annika Deckert and colleagues have developed a strategy to detect the presence of tau in brain tissue samples, and to identify specific genes that may be involved in the movement of tau. Based on prior work, Dr. Deckert’s suggests that a loss of certain genes that help nerve cells clear abnormal proteins through the cells’ natural trash and recycling systems (a process called “autophagy”) might be associated with the presence of abnormal tau.
Research Plan
Building on their preliminary results, the researchers will study nerve cells growing in laboratory dishes that have been genetically engineered to lack 5-10 genes associated with cell waste and recycling systems (identified in Dr. Deckert’s previous studies). They will measure how tau moves between the nerve cells as well as the size, location, and composition of any tau tangles formed. Through collaboration with other experts, the researchers will generate cell network models which may highlight genes and proteins associated with cell waste and recycling systems that may impact how tau moves from one nerve cell to another.
In the second part of the study, the researchers will study the most promising gene candidates in fruit flies in order to explore the biological mechanisms in more detail. Dr. Deckert and colleagues will lower levels of these genes associated with cell waste and recycling in the brains of fruit flies. They will study whether this approach might impact how tau moves between nerve cells and initiates the formation and movement of tau tangles in the brain.
Impact
This study could provide a better understanding of the biological mechanisms that may be associated with how tau contributes to the disease-related brain changes. The findings could inform the development of potential therapeutic compounds designed to interact with cell waste and recycling proteins that may prevent the formation and movement of tau in the brain in Alzheimer’s and other abnormal tau-related brain diseases.
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