2023 Alzheimer's Association Research Grant to Promote Diversity (AARG-D)

Molecular Dissection of the Pathoconversion of Tau in Alzheimer’s Disease

What leads to the accumulation of harmful tau tangles in the brain in Alzheimer’s and other diseases?

Kassandra Ori-McKenney, Ph.D.
University of California, Davis
Davis, CA - 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 include Alzheimer’s, frontotemporal dementia, Parkinson’s disease, and others. 

Microtubules are small, tube-like structures that act like a skeleton inside cells, maintaining cell structure and helping to transport nutrients throughout the cell. Recently, Dr. Kassandra Ori-McKenney and colleagues showed that healthy tau molecules can assemble with other tau molecules around microtubules to regulate microtubule activity, and then come apart again (unlike the harmful tangles of tau associated with tauopathies that cannot come apart once assembled). It is unknown how this ability of tau to self-assemble on microtubules may be related to the self-assembly and clumping of tau in tauopathies, or why tau cannot dissemble when it forms a tangle.

Research Plan

Dr. Ori-McKenney and colleagues will study the differences between healthy tau self-assembly and harmful, irreversible tau tangles. They will use biochemical and genetic methods in fruit flies to determine the biological mechanisms by which tau naturally assembles into harmful tau tangles. The results of these studies may reveal how this process may be targeted and disrupted in Alzheimer’s and other tauopathies. In addition, the researchers will study the impacts of healthy tau versus harmful tau tangles on the activities of microtubules. They will determine how harmful tau tangles disrupt microtubule-based processes using fruit fly nerve cells.

Impact

Results from this study may clarify our understanding of the roles microtubules play in brain disease, as well as the biological mechanisms by which abnormal tau accumulates in the brain in Alzheimer’s and other tauopathies. If successful, the findings could reveal a potentially new therapeutic target for abnormal tau-related brain diseases.