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

Cellular and molecular mechanisms mediating pT217-tau phosphorylation in AD

How does tau become altered in Alzheimer’s?

Dibyadeep Datta, Ph.D.
Yale University
New Haven, CT - United States

Background

Tau is a protein that plays an important role in maintaining brain cell structure. In healthy brain cells, tau levels are balanced by a process called phosphorylation, or the addition of phosphate molecules to generate phosphorylated tau (pTau). In Alzheimer’s, tau becomes excessively phosphorylated (or hyperphosphorylated) and loses its ability to perform its normal functions. Additionally, hyperphosphorylated tau clumps together into structures called neurofibrillary tangles, one of the hallmark brain changes in Alzheimer’s that may impair brain cell communication and even contribute to brain cell death. 

A specific form of phosphorylated tau, called pT217-tau, is widely used as a biomarker for Alzheimer’s. However, the mechanisms by which this form of tau becomes elevated in Alzheimer’s are unknown.

Research Plan

Dr. Dibyadeep Datta and colleagues will investigate whether glutamatergic neurons, or specific nerve cells that produce the chemical glutamate that helps nerve cells communicate with one another, are responsible for producing pT217-tau in Alzheimer’s. They will use non-human Alzheimer’s-like primates that develop tau tangles as a model for their studies. First, the researchers will measure at what age pT217-tau becomes elevated in the brain and whether it is present in glutamatergic nerve cells. Next, the team will confirm their findings in brain tissue from individuals who had Alzheimer’s. Lastly, Dr. Datta and colleagues will examine the signaling pathways in glutamatergic nerve cells that promote pT217-tau accumulation.

Impact

Results from this study could shed new light on the mechanisms by which tau becomes hyperphosphorylated in Alzheimer’s. They could also lead to more advanced therapies targeting tau for preventing or slowing Alzheimer’s progression.