2023 Alzheimer's Association Research Grant to Promote Diversity (AARG-D)
PIAS4 A Novel Regulator of Pathological Tau Accumulation and Clearance
How does a chemical modification called phosphorylation impact tau tangle formation in Alzheimer’s?
Ana Liberman, Ph.D.
Scientific Foundation Felipe Fiorellino, Maimonides University
Buenos Aires, Argentina
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.
In initial studies, Dr. Ana Liberman and colleagues have identified a specific protein called PIAS4 that may play a role in tau phosphorylation.
Research Plan
Building on their initial findings, Dr. Liberman and team will study the mechanisms by which PIAS4 impacts tau tangle formation in Alzheimer’s. They will do this using brain nerve cells that have been harvested from genetically engineered Alzheimer’s like mice and grown in a laboratory dish. The team will first measure the level of tau tangles that form in the presence or absence of PIAS4. Next, the researchers will use genetically engineered Alzheimer’s-like mice to study the impact of PIAS4 on cognitive function and behavior in these mice.
Impact
The results of these studies will provide new insights into the biological mechanisms involved in the formation of tau tangles in Alzheimer’s. This work may also lay the foundation for future studies evaluating PIAS4-mediated tau phosphorylation as a new Alzheimer’s therapeutic target.