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2020 Alzheimer's Association Research Grant (AARG)

Tau protein and misregulation of fast axonal transport directionality

How may modified tau disrupt nutrient transport inside nerve cells, in brain diseases?

Benjamin Combs, Ph.D.
Michigan State University
East Lansing, MI - United States



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, 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 of these diseases) and subsequent nerve cell damage. 

Modified tau can also disrupt the movement of proteins through the nerve cell transport system. Studies by Dr. Benjamin Combs and others have shown modified tau disrupts the ability of a protein called “dynein” to travel along the tracks and transport key nutrients along nerve cells – a process known as “fast axonal transport,” or FAT. FAT is necessary for normal cell function and is found to be disrupted in Alzheimer’s and other brain diseases. 
 

Research Plan

For their current study, Dr. Combs’ team will determine how the changes in the interaction between modified tau, dynein and an associated protein called “dynactin”, may contribute to FAT disruption.
 
The researchers will grow nerve cells - from genetically engineered mice lacking normal tau -  in laboratory dishes and expose them to six genetic variations of tau. The researchers will study how each of the genetic variations of tau impacts the ability of dynein and dynactin to transport key nutrients along nerve cells. Furthermore, the researchers will expose the nerve cells to abnormal tau to study how it impacts the functionality of dynein and dynactin.

Studies show that tau may also interact with another protein called C-Jun N-terminal kinase interacting protein-1 (JIP1) involved in the FAT process. This interaction may determine the direction in which proteins travel to transport nutrients within the nerve cells. To study the interaction between modified tau and JIP1, the researchers will expose the nerve cells in a laboratory dish as described previously, to either normal tau or abnormal tau. Researchers will investigate whether the interaction between abnormal tau and JIP1 may disrupt the directionality of the transport of specific nutrients in Alzheimer’s, and other abnormal tau-related brain diseases.
 

Impact

These studies could help the researchers understand the biological mechanisms by which modified tau may disrupt nutrient transport inside nerve cells. Since dynein and FAT are involved in several brain diseases, the findings could have broad implications in understanding the impact of modified tau in the brain.

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