2022 Alzheimer's Association Research Fellowship (AARF)

Cellular Mechanisms of Tau Strains in Rapidly and Slowly Progressive AD

Is there a difference in how tau protein behaves in individuals with faster or slower progressing Alzheimer’s?

Lenka Hromadkova, Ph.D.
Case Western Reserve University
Cleveland, OH - United States

Background

Tau protein functions to help support nerve cell structure and transport nutrients within the cell. In Alzheimer’s and over twenty other brain diseases, such as frontotemporal dementia, Lewy body dementia, and others, tau protein becomes abnormally folded and clump into “tangles” in the brain, one of the characteristic features of these diseases. These tangles have been shown to cause nerve cell damage and be related to cell death. Studies show that abnormal tau protein can move from one nerve cell to another, possibly contributing to the progression of brain changes associated with these diseases, including Alzheimer’s, and the pace of tau movement appears to be different for each individual. 

Although most individuals who develop Alzheimer’s experience slower cognitive decline and related brain changes over many years, it is estimated that 10-30% of individuals with Alzheimer’s have a rapidly progressive form of the disease. These individuals experience accelerated cognitive decline and disease duration of up to three years. Research suggests that this more rapid form of disease may have distinct biological mechanisms of tau spread and movement. However, our understanding of these mechanisms, and how they contribute to different clinical outcomes, is limited.
 

Research Plan

Dr. Lenka Hromadkova and colleagues will study the patterns of replication and movement of tau in nerve cells. The researchers will also study different forms of tau isolated from the brains of individuals who had slowly progressive Alzheimer’s or rapidly progressive Alzheimer’s. These forms of tau will be tested on mouse nerve cells grown in laboratory dishes and to human nerve cells created from a special type of stem cell called induced pluripotent stem cells (iPSCs). The team will monitor differences in how the different sources of tau replicate and move between nerve cells, as well as how nerve cells function is impacted.

Impact

The results may help identify why individuals have differences in Alzheimer’s progression, potentially due to differences in the movement of tau between nerve cells. If successful, this study may contribute to the development of personalized approaches for slowing cognitive decline in Alzheimer’s as well as other brain diseases where tau plays a central role.