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Study uncovers RNA changes in Alzheimer’s disease

Published on: Jun 10, 2025

New research from Dr. Wenbo Li’s lab at McGovern Medical School—including YiTing Chen and Yuqiang Shi (front row), and Benxia Hu, Nathan Drolet, and Dr. Wenbo Li (back row)—has shed light on critical RNA changes associated with Alzheimer’s disease (AD).

The study, published on June 6 in Nature Communications, provides new insight into what occurs within brain cells during Alzheimer’s, a debilitating neurodegenerative disorder. These findings could pave the way for improved understanding and treatment strategies.

Titled “Rewired m6A of promoter antisense RNAs in Alzheimer’s disease regulates neuronal genes in 3D nucleome,” the paper was co-authored by Benxia Hu and Yuqiang Shi, with Wenbo Li, PhD—associate professor of biochemistry and molecular biology—serving as the senior author directing the research.

This work significantly advances the field of epitranscriptomics, which studies chemical modifications on RNA molecules. Although this area has gained momentum over the past decade, the role of such RNA modifications in the human brain and in Alzheimer’s disease remains largely underexplored.

The research team analyzed RNA profiles from postmortem brain samples of 12 individuals—six diagnosed with Alzheimer’s and six without the disease. By using an antibody that targets N6-methyladenosine (m6A)—a key chemical mark on RNA—the team was able to map where this modification appears across all RNAs in the brain under both normal and Alzheimer’s conditions.

Their analysis revealed striking differences in a type of RNA called promoter-antisense RNAs (paRNAs) in Alzheimer’s-affected brains. Though paRNAs do not encode proteins, they play a crucial regulatory role in controlling gene expression—functioning like genetic dimmer switches.

One standout discovery was MAPT-paRNA, an RNA molecule highly active in neurons and found to be significantly more abundant in Alzheimer’s brains. Rather than directly influencing tau protein—the well-known pathological hallmark of Alzheimer’s—MAPT-paRNA acts more broadly, regulating the expression of around 200 genes across the genome. Remarkably, it exerts its influence by affecting chromosomal architecture, reaching beyond neighboring genes to distant ones on other chromosomes by altering the 3D structure of DNA in the cell nucleus.

Many of the genes under MAPT-paRNA’s regulation are essential for neuron survival and intercellular connectivity—key processes that are disrupted in Alzheimer’s. These findings establish a strong link between m6A modifications, paRNA activity, and the disease’s progression.

This study offers a promising new direction in Alzheimer’s research. By looking beyond conventional protein targets like tau and amyloid, it highlights the potential of RNA biology—especially RNA modifications—as a novel therapeutic avenue. The team’s work suggests that targeting specific RNAs and their epitranscriptomic marks could lead to innovative treatments for Alzheimer’s disease.

Source: https://med.uth.edu/blog/2025/06/10/study-uncovers-rna-changes-in-alzheimers-disease/

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