2023 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)

Unraveling the Cell-Type Specific Role of TMEM106B in Tauopathy

What is the role of genetics in the movement and accumulation of tau protein in the brain?

George Edwards III, Ph.D.
Baylor College of Medicine
Houston, TX - United States

Background

Tau is a protein that helps to maintain the structure of brain cells. In Alzheimer’s and other brain diseases, 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. Brain diseases believed to result from abnormal modification of the tau protein are referred to as “tauopathies” and this includes Alzheimer’s, frontotemporal dementia, and Parkinson’s disease. 

Recent studies show that certain forms of tau can be released from nerve cells and may act as “seeds.” These “seeds” may be associated with the formation, transportation, and clumping of variations of abnormal tau into tangles throughout the brain. 

Studies have identified a gene called TMEM106B that appears to influence the risk for many brain diseases classified as tauopathies. This gene codes for a protein called transmembrane protein 106b found in lysosomes — compartments inside of brain cells that help degrade and dispose of waste in cells. Recent studies suggest that a variation of the TMEM106b gene may help protect brain function in both healthy older adults and in people with various dementias, including Alzheimer’s.

One possible mechanism of tau seeding may be through lysosomes. Although TMEM106B is reported to play a role in lysosomal transport, its impact on tau seeding is unknown.

Research Plan

In initial studies, Dr. George Edwards III and colleagues found that TMEM106B is involved in protecting against the accumulation of tau tangles and tau-induced cognitive dysfunction. For this project, the researchers will genetically engineer mice, deleting the TMEM106B gene from either their nerve cells or microglia (the primary immune cells of the brain). The team will first study whether deleting TMEM106B impacts cognitive impairment in the mice, after which they will examine the brains of the mice for signs of harmful tau accumulation. In addition, Dr. Edwards and colleagues will study how deleting TMEM106B impacts tau seeding and the movement of tau throughout the brains of the mice.

Impact

The results may shed light on the role of TMEM106B on the accumulation of tau tangles and movement of tau in the brain in brain diseases including Alzheimer’s.