2024 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)

Targeting EV-Mediated Tau Propagation via P2X Purinoreceptor 7

What biological mechanisms help abnormal tau move and accumulate in the brain?

Victor Bodart-Santos, Ph.D.
Mayo Clinic Florida
Jacksonville, FL - United States

Background

Tau is a protein that normally functions to transport nutrients and help nerve cells maintain their proper structure. In Alzheimer’s and other neurodegenerative diseases, tau protein can become abnormally modified or “misfolded,” a change that may contribute to tau tangles (a hallmark of these diseases) and subsequent nerve cell damage. However, the biological mechanism behind how abnormal tau moves through the brain is not fully understood. One possible mechanism of tau movement is through specialized brain structures called extracellular vesicles (EVs). EVs are tiny bubbles sent out of cells that contain molecules -- such as proteins, genetic material, and potentially tau proteins.

Dr. Victor Bodart-Santos and colleagues previously identified a novel mechanism through which EVs secreted by microglia, the brain’s immune cells, may help abnormal tau move throughout the brain. The researchers showed that decreasing the activity of a receptor called P2X purinoreceptor 7 (P2rx7) reduces EV secretion from microglia, reduces misfolded tau accumulation, and partially improves behavioral deficits in genetically engineered Alzheimer’s-like mice.

Research Plan

Dr. Bodart-Santos and team will further study the effect of microglia with decreased P2rx7 activity on tau accumulation in genetically engineered Alzheimer’s-like mice. First, they will study the brains of these mice with and without P2rx7 deficiency by measuring the amount of RNA (Ribonucleic Acid), genetic material that cells produce when they activate a gene. They will also study mice that have been genetically engineered to lack P2rx7 specifically in microglia cells. The researchers will conduct cognitive tests with these mice as well as examine their brains for tau accumulation, microglia activity, and EV accumulation. 

The research team will also study the impact of reducing microglial P2rx7 deficiency on tau accumulation using a specialized kind of stem cell derived from adult human cells called induced pluripotent stem cells (iPSCs). They will develop iPSCs into microglia and nerve cells and then investigate the effect of deleting P2rx7 on the movement of misfolded tau.

Impact

This study may provide insights into how abnormal tau spreads from cell to cell in the brain. The results may inform therapeutic strategies to reduce the movement of tau in Alzheimer’s and other brain diseases.