2023 Alzheimer's Association Research Grant (AARG)

AD-EpiMark: Exploring the tRNA epitranscriptome as a novel AD modifier

Can a comprehensive RNA analysis identify genetic mechanisms underlying Alzheimer’s?

Ana Raquel Soares, Ph.D.
iBiMED-University of Aveiro
Aveiro, Portugal

Background

To better understand the role of genes in Alzheimer’s, many scientists are studying how gene expression (the conversion of genes into proteins) is affected in the disease. Gene expression takes place after the gene is turned “on” and a molecule called ribonucleic acid (RNA) is produced. Many enzymes (or cutting proteins) interact with and modify RNA during this process. These include tRNA-modifying enzymes, a group of enzymes that help ensure proteins are made properly. Collectively, the complex layer of RNA modifications is known as the “epitranscriptome.”

In initial studies, Dr. Ana Raquel Soares and colleagues have identified several tRNA-modifying enzymes, including ELP3, that are altered in individuals with late-onset Alzheimer’s (or LOAD, the most common form of Alzheimer’s) as well as in genetically engineered Alzheimer’s-like mice Low levels of ELP3 are associated with beta-amyloid plaques,  a hallmark brain change of Alzheimer’s. More research is needed to understand how these enzymes change during Alzheimer’s.

Research Plan

Dr. Ana Raquel Soares and colleagues will fully analyze tRNA-modifying enzymes, including ELP3, in different models of Alzheimer’s including genetically engineered Alzheimer’s-like mice and cells donated by individuals who had Alzheimer’s. First, the researchers will use genetic techniques to measure levels and locations of tRNA-modifying enzymes within the mouse brain tissue. They will also analyze RNA collected from the mice over time, to understand how genetic mechanisms change over the course of disease progression. Next, Dr. Soares’ team will change levels of ELP3 inside nerve cells to analyze how this affects beta-amyloid protein levels. They will determine whether increasing ELP3 levels might help protect the brain cells from changes often caused by Alzheimer’s.

Finally, Dr. Soares plans to measure levels of tRNA-modifying enzymes that are released by nerve cells through small, fluid-filled spheres known as exosomes. Exosomes released by cells can be taken-up by other cells, allowing materials to be transported between the cells. Dr. Soares’ goal is to determine whether measuring levels of these enzymes inside exosomes might serve as a useful biological marker, or biomarker, for Alzheimer’s.

Impact

Results from this study will provide much-needed insight into how RNA is modified during Alzheimer’s, and how this process changes over the course of disease progression. This study may also identify specific enzymes that might be targeted by new therapies to restore healthy protein production in Alzheimer’s.